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Sample records for addition molecular docking

  1. Multipose binding in molecular docking.

    PubMed

    Atkovska, Kalina; Samsonov, Sergey A; Paszkowski-Rogacz, Maciej; Pisabarro, M Teresa

    2014-02-14

    Molecular docking has been extensively applied in virtual screening of small molecule libraries for lead identification and optimization. A necessary prerequisite for successful differentiation between active and non-active ligands is the accurate prediction of their binding affinities in the complex by use of docking scoring functions. However, many studies have shown rather poor correlations between docking scores and experimental binding affinities. Our work aimed to improve this correlation by implementing a multipose binding concept in the docking scoring scheme. Multipose binding, i.e., the property of certain protein-ligand complexes to exhibit different ligand binding modes, has been shown to occur in nature for a variety of molecules. We conducted a high-throughput docking study and implemented multipose binding in the scoring procedure by considering multiple docking solutions in binding affinity prediction. In general, improvement of the agreement between docking scores and experimental data was observed, and this was most pronounced in complexes with large and flexible ligands and high binding affinities. Further developments of the selection criteria for docking solutions for each individual complex are still necessary for a general utilization of the multipose binding concept for accurate binding affinity prediction by molecular docking.

  2. DockingShop: A Tool for Interactive Molecular Docking

    SciTech Connect

    Lu, Ting-Cheng; Max, Nelson L.; Ding, Jinhui; Bethel, E. Wes; Crivelli, Silvia N.

    2005-04-24

    Given two independently determined molecular structures, the molecular docking problem predicts the bound association, or best fit between them, while allowing for conformational changes of the individual molecules during construction of a molecular complex. Docking Shop is an integrated environment that permits interactive molecular docking by navigating a ligand or protein to an estimated binding site of a receptor with real-time graphical feedback of scoring factors as visual guides. Our program can be used to create initial configurations for a protein docking prediction process. Its output--the structure of aprotein-ligand or protein-protein complex--may serve as an input for aprotein docking algorithm, or an optimization process. This tool provides molecular graphics interfaces for structure modeling, interactive manipulation, navigation, optimization, and dynamic visualization to aid users steer the prediction process using their biological knowledge.

  3. Computational methods for molecular docking

    SciTech Connect

    Klebe, G.; Lengauer, T.

    1995-12-31

    This tutorial was one of eight tutorials selected to be presented at the Third International Conference on Intelligent Systems for Molecular Biology which was held in the United Kingdom from July 16 to 19, 1995. Recently, it has been demonstrated that the knowledge of the three-dimensional structure of the protein can be used to derive new protein ligands with improved binding properties. This tutorial focuses on the following questions: What is its binding affinity toward a particular receptor? What are putative conformations of a ligand at the binding site? What are the similarities of different ligands in terms of their recognition capabilities? Where and in which orientation will a ligand bind to the active site? How is a new putative protein ligand selected? An overview is presented of the algorithms which are presently used to handle and predict protein-ligand interactions and to dock small molecule ligands into proteins.

  4. NMR-Assisted Molecular Docking Methodologies.

    PubMed

    Sturlese, Mattia; Bellanda, Massimo; Moro, Stefano

    2015-08-01

    Nuclear magnetic resonance (NMR) spectroscopy and molecular docking are regularly being employed as helpful tools of drug discovery research. Molecular docking is an extremely rapid method to evaluate possible binders from a large chemical library in a fast and cheap manner. NMR techniques can directly detect a protein-ligand interaction, can determine the corresponding association constant, and can consistently identify the ligand binding cavity. Consequently, molecular docking and NMR techniques are naturally complementary techniques where the combination of the two has the potential to improve the overall efficiency of drug discovery process. In this review, we would like to summarize the state of the art of docking methods which have been recently bridged to NMR experiments to identify novel and effective therapeutic drug candidates.

  5. An anchor-dependent molecular docking process for docking small flexible molecules into rigid protein receptors.

    PubMed

    Lin, Thy-Hou; Lin, Guan-Liang

    2008-08-01

    A molecular docking method designated as ADDock, anchor-dependent molecular docking process for docking small flexible molecules into rigid protein receptors, is presented in this article. ADDock makes the bond connection lists for atoms based on anchors chosen for building molecular structures for docking small flexible molecules or ligands into rigid active sites of protein receptors. ADDock employs an extended version of piecewise linear potential for scoring the docked structures. Since no translational motion for small molecules is implemented during the docking process, ADDock searches the best docking result by systematically changing the anchors chosen, which are usually the single-edge connected nodes or terminal hydrogen atoms of ligands. ADDock takes intact ligand structures generated during the docking process for computing the docked scores; therefore, no energy minimization is required in the evaluation phase of docking. The docking accuracy by ADDock for 92 receptor-ligand complexes docked is 91.3%. All these complexes have been docked by other groups using other docking methods. The receptor-ligand steric interaction energies computed by ADDock for some sets of active and inactive compounds selected and docked into the same receptor active sites are apparently separated. These results show that based on the steric interaction energies computed between the docked structures and receptor active sites, ADDock is able to separate active from inactive compounds for both being docked into the same receptor.

  6. Molecular docking studies in factor XIa binding site

    NASA Astrophysics Data System (ADS)

    Balaji, Govardhan A.; Balaji, Vitukudi N.; Rao, Shashidhar N.

    2016-03-01

    Factor XIa inhibitors have been identified to have potential as anticoagulants with robust efficacy and low bleeding risks. In light of their significance and the availability of their 3-D X-ray data in the PDB, we present molecular docking studies carried out with a view to obtain docking protocols that will successfully reproduce the experimentally observed protein-ligand interactions in the case of various X-ray ligands. In this context, we have specifically investigated the efficacy of various cross-docking protocols in reproducing experimental data. Our studies demonstrate that an ensemble of the three apo proteins is capable of accurately docking a majority of the X-ray ligands accurately without invoking any additional conformational flexibility than that present in their experimental structures. Further, we demonstrate that such an ensemble is successfully able to enrich a collection of known active factor XIa inhibitors embedded in a decoy database of drug-like molecules.

  7. Molecular docking to ensembles of protein structures.

    PubMed

    Knegtel, R M; Kuntz, I D; Oshiro, C M

    1997-02-21

    Until recently, applications of molecular docking assumed that the macromolecular receptor exists in a single, rigid conformation. However, structural studies involving different ligands bound to the same target biomolecule frequently reveal modest but significant conformational changes in the target. In this paper, two related methods for molecular docking are described that utilize information on conformational variability from ensembles of experimental receptor structures. One method combines the information into an "energy-weighted average" of the interaction energy between a ligand and each receptor structure. The other method performs the averaging on a structural level, producing a "geometry-weighted average" of the inter-molecular force field score used in DOCK 3.5. Both methods have been applied in docking small molecules to ensembles of crystal and solution structures, and we show that experimentally determined binding orientations and computed energies of known ligands can be reproduced accurately. The use of composite grids, when conformationally different protein structures are available, yields an improvement in computational speed for database searches in proportion to the number of structures.

  8. Molecular Crowding Accelerates Ribozyme Docking and Catalysis

    PubMed Central

    2015-01-01

    All biological processes take place in highly crowded cellular environments. However, the effect that molecular crowding agents have on the folding and catalytic properties of RNA molecules remains largely unknown. Here, we have combined single-molecule fluorescence resonance energy transfer (smFRET) and bulk cleavage assays to determine the effect of a molecular crowding agents on the folding and catalysis of a model RNA enzyme, the hairpin ribozyme. Our single-molecule data reveal that PEG favors the formation of the docked (active) structure by increasing the docking rate constant with increasing PEG concentrations. Furthermore, Mg2+ ion-induced folding in the presence of PEG occurs at concentrations ∼7-fold lower than in the absence of PEG, near the physiological range (∼1 mM). Lastly, bulk cleavage assays in the presence of the crowding agent show that the ribozyme’s activity increases while the heterogeneity decreases. Our data is consistent with the idea that molecular crowding plays an important role in the stabilization of ribozyme active conformations in vivo. PMID:25399908

  9. Accelerating molecular docking calculations using graphics processing units.

    PubMed

    Korb, Oliver; Stützle, Thomas; Exner, Thomas E

    2011-04-25

    The generation of molecular conformations and the evaluation of interaction potentials are common tasks in molecular modeling applications, particularly in protein-ligand or protein-protein docking programs. In this work, we present a GPU-accelerated approach capable of speeding up these tasks considerably. For the evaluation of interaction potentials in the context of rigid protein-protein docking, the GPU-accelerated approach reached speedup factors of up to over 50 compared to an optimized CPU-based implementation. Treating the ligand and donor groups in the protein binding site as flexible, speedup factors of up to 16 can be observed in the evaluation of protein-ligand interaction potentials. Additionally, we introduce a parallel version of our protein-ligand docking algorithm PLANTS that can take advantage of this GPU-accelerated scoring function evaluation. We compared the GPU-accelerated parallel version to the same algorithm running on the CPU and also to the highly optimized sequential CPU-based version. In terms of dependence of the ligand size and the number of rotatable bonds, speedup factors of up to 10 and 7, respectively, can be observed. Finally, a fitness landscape analysis in the context of rigid protein-protein docking was performed. Using a systematic grid-based search methodology, the GPU-accelerated version outperformed the CPU-based version with speedup factors of up to 60.

  10. A hierarchical method for molecular docking using cloud computing.

    PubMed

    Kang, Ling; Guo, Quan; Wang, Xicheng

    2012-11-01

    Discovering small molecules that interact with protein targets will be a key part of future drug discovery efforts. Molecular docking of drug-like molecules is likely to be valuable in this field; however, the great number of such molecules makes the potential size of this task enormous. In this paper, a method to screen small molecular databases using cloud computing is proposed. This method is called the hierarchical method for molecular docking and can be completed in a relatively short period of time. In this method, the optimization of molecular docking is divided into two subproblems based on the different effects on the protein-ligand interaction energy. An adaptive genetic algorithm is developed to solve the optimization problem and a new docking program (FlexGAsDock) based on the hierarchical docking method has been developed. The implementation of docking on a cloud computing platform is then discussed. The docking results show that this method can be conveniently used for the efficient molecular design of drugs.

  11. PTools: an opensource molecular docking library

    PubMed Central

    Saladin, Adrien; Fiorucci, Sébastien; Poulain, Pierre; Prévost, Chantal; Zacharias, Martin

    2009-01-01

    Background Macromolecular docking is a challenging field of bioinformatics. Developing new algorithms is a slow process generally involving routine tasks that should be found in a robust library and not programmed from scratch for every new software application. Results We present an object-oriented Python/C++ library to help the development of new docking methods. This library contains low-level routines like PDB-format manipulation functions as well as high-level tools for docking and analyzing results. We also illustrate the ease of use of this library with the detailed implementation of a 3-body docking procedure. Conclusion The PTools library can handle molecules at coarse-grained or atomic resolution and allows users to rapidly develop new software. The library is already in use for protein-protein and protein-DNA docking with the ATTRACT program and for simulation analysis. This library is freely available under the GNU GPL license, together with detailed documentation. PMID:19409097

  12. Solving molecular docking problems with multi-objective metaheuristics.

    PubMed

    García-Godoy, María Jesús; López-Camacho, Esteban; García-Nieto, José; Aldana-Montes, Antonio J Nebroand José F

    2015-06-02

    Molecular docking is a hard optimization problem that has been tackled in the past with metaheuristics, demonstrating new and challenging results when looking for one objective: the minimum binding energy. However, only a few papers can be found in the literature that deal with this problem by means of a multi-objective approach, and no experimental comparisons have been made in order to clarify which of them has the best overall performance. In this paper, we use and compare, for the first time, a set of representative multi-objective optimization algorithms applied to solve complex molecular docking problems. The approach followed is focused on optimizing the intermolecular and intramolecular energies as two main objectives to minimize. Specifically, these algorithms are: two variants of the non-dominated sorting genetic algorithm II (NSGA-II), speed modulation multi-objective particle swarm optimization (SMPSO), third evolution step of generalized differential evolution (GDE3), multi-objective evolutionary algorithm based on decomposition (MOEA/D) and S-metric evolutionary multi-objective optimization (SMS-EMOA). We assess the performance of the algorithms by applying quality indicators intended to measure convergence and the diversity of the generated Pareto front approximations. We carry out a comparison with another reference mono-objective algorithm in the problem domain (Lamarckian genetic algorithm (LGA) provided by the AutoDock tool). Furthermore, the ligand binding site and molecular interactions of computed solutions are analyzed, showing promising results for the multi-objective approaches. In addition, a case study of application for aeroplysinin-1 is performed, showing the effectiveness of our multi-objective approach in drug discovery.

  13. Context-based preprocessing of molecular docking data

    PubMed Central

    2013-01-01

    Background Data preprocessing is a major step in data mining. In data preprocessing, several known techniques can be applied, or new ones developed, to improve data quality such that the mining results become more accurate and intelligible. Bioinformatics is one area with a high demand for generation of comprehensive models from large datasets. In this article, we propose a context-based data preprocessing approach to mine data from molecular docking simulation results. The test cases used a fully-flexible receptor (FFR) model of Mycobacterium tuberculosis InhA enzyme (FFR_InhA) and four different ligands. Results We generated an initial set of attributes as well as their respective instances. To improve this initial set, we applied two selection strategies. The first was based on our context-based approach while the second used the CFS (Correlation-based Feature Selection) machine learning algorithm. Additionally, we produced an extra dataset containing features selected by combining our context strategy and the CFS algorithm. To demonstrate the effectiveness of the proposed method, we evaluated its performance based on various predictive (RMSE, MAE, Correlation, and Nodes) and context (Precision, Recall and FScore) measures. Conclusions Statistical analysis of the results shows that the proposed context-based data preprocessing approach significantly improves predictive and context measures and outperforms the CFS algorithm. Context-based data preprocessing improves mining results by producing superior interpretable models, which makes it well-suited for practical applications in molecular docking simulations using FFR models. PMID:24564276

  14. Yada: a novel tool for molecular docking calculations

    NASA Astrophysics Data System (ADS)

    Piotto, S.; Di Biasi, L.; Fino, R.; Parisi, R.; Sessa, L.; Concilio, S.

    2016-09-01

    Molecular docking is a computational method employed to estimate the binding between a small ligand (the drug candidate) and a protein receptor that has become a standard part of workflow in drug discovery. Generally, when the binding site is known and a molecule is similar to known ligands, the most popular docking methods are rather accurate in the prediction of the geometry. Unfortunately, when the binding site is unknown, the blind docking analysis requires large computational resources and the results are often not accurate. Here we present Yada, a new tool for molecular docking that is capable to distribute efficiently calculations onto general purposes computer grid and that combines biological and structural information of the receptor. Yada is available for Windows and Linux and it is free to download at >www.yada.unisa.it.

  15. Yada: a novel tool for molecular docking calculations.

    PubMed

    Piotto, S; Di Biasi, L; Fino, R; Parisi, R; Sessa, L; Concilio, S

    2016-09-01

    Molecular docking is a computational method employed to estimate the binding between a small ligand (the drug candidate) and a protein receptor that has become a standard part of workflow in drug discovery. Generally, when the binding site is known and a molecule is similar to known ligands, the most popular docking methods are rather accurate in the prediction of the geometry. Unfortunately, when the binding site is unknown, the blind docking analysis requires large computational resources and the results are often not accurate. Here we present Yada, a new tool for molecular docking that is capable to distribute efficiently calculations onto general purposes computer grid and that combines biological and structural information of the receptor. Yada is available for Windows and Linux and it is free to download at www.yada.unisa.it .

  16. STALK : an interactive virtual molecular docking system.

    SciTech Connect

    Levine, D.; Facello, M.; Hallstrom, P.; Reeder, G.; Walenz, B.; Stevens, F.; Univ. of Illinois

    1997-04-01

    Several recent technologies-genetic algorithms, parallel and distributed computing, virtual reality, and high-speed networking-underlie a new approach to the computational study of how biomolecules interact or 'dock' together. With the Stalk system, a user in a virtual reality environment can interact with a genetic algorithm running on a parallel computer to help in the search for likely geometric configurations.

  17. Simulation of carbohydrates, from molecular docking to dynamics in water.

    PubMed

    Sapay, Nicolas; Nurisso, Alessandra; Imberty, Anne

    2013-01-01

    Modeling of carbohydrates is particularly challenging because of the variety of structures resulting for the high number of monosaccharides and possible linkages and also because of their intrinsic flexibility. The development of carbohydrate parameters for molecular modeling is still an active field. Nowadays, main carbohydrates force fields are GLYCAM06, CHARMM36, and GROMOS 45A4. GLYCAM06 includes the largest choice of compounds and is compatible with the AMBER force fields and associated. Furthermore, AMBER includes tools for the implementation of new parameters. When looking at protein-carbohydrate interaction, the choice of the starting structure is of importance. Such complex can be sometimes obtained from the Protein Data Bank-although the stereochemistry of sugars may require some corrections. When no experimental data is available, molecular docking simulation is generally used to the obtain protein-carbohydrate complex coordinates. As molecular docking parameters are not specifically dedicated to carbohydrates, inaccuracies should be expected, especially for the docking of polysaccharides. This issue can be addressed at least partially by combining molecular docking with molecular dynamics simulation in water.

  18. Molecular docking, spectroscopic studies and quantum calculations on nootropic drug.

    PubMed

    Uma Maheswari, J; Muthu, S; Sundius, Tom

    2014-04-05

    A systematic vibrational spectroscopic assignment and analysis of piracetam [(2-oxo-1-pyrrolidineacetamide)] have been carried out using FT-IR and FT-Raman spectral data. The vibrational analysis was aided by an electronic structure calculation based on the hybrid density functional method B3LYP using a 6-311G++(d,p) basis set. Molecular equilibrium geometries, electronic energies, IR and Raman intensities, and harmonic vibrational frequencies have been computed. The assignments are based on the experimental IR and Raman spectra, and a complete assignment of the observed spectra has been proposed. The UV-visible spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies and the maximum absorption wavelengths λmax were determined by the time-dependent DFT (TD-DFT) method. The geometrical parameters, vibrational frequencies and absorption wavelengths were compared with the experimental data. The complete vibrational assignments are performed on the basis of the potential energy distributions (PED) of the vibrational modes in terms of natural internal coordinates. The simulated FT-IR, FT-Raman, and UV spectra of the title compound have been constructed. Molecular docking studies have been carried out in the active site of piracetam by using Argus Lab. In addition, the potential energy surface, HOMO and LUMO energies, first-order hyperpolarizability and the molecular electrostatic potential have been computed.

  19. Virtual screening of RAGE inhibitors using molecular docking

    PubMed Central

    Devi Alaparthi, Malini; Gopinath, Gudipudi; Bandaru, Srinivas; Sankeshi, Venu; Mangalarapu, Madhavi; Sudha Nagamalla, Swetha; Sudhakar, Kota; Roja Rani, Anupalli; Rao Sagurthi, Someswar

    2016-01-01

    Advanced Glycation End products (AGEs) interaction with Receptor for AGEs (RAGE) activates downstream signaling and evokes inflammatory responses in vascular cells. Therefore, it is of interest to design a novel series of molecules with a library of 352 compounds based on natural Isoflavone and Argpyrimidine moities. The compounds screened against the optimized structure of RAGE (PDB code: 3CJJ) using MolDock aided with molecular docking algorithm. This exercise identified compound number 62 with appreciable ADME properties having no toxicity and pharmacophore features. Therefore, compound 62 identified as a RAGE inhibitor is proposed for further validation in the context of Diabetic Retinopathy (DR) and vascular complications. PMID:28149046

  20. Combining docking and molecular dynamic simulations in drug design.

    PubMed

    Alonso, Hernán; Bliznyuk, Andrey A; Gready, Jill E

    2006-09-01

    A rational approach is needed to maximize the chances of finding new drugs, and to exploit the opportunities of potential new drug targets emerging from genomic and proteomic initiatives, and from the large libraries of small compounds now readily available through combinatorial chemistry. Despite a shaky early history, computer-aided drug design techniques can now be effective in reducing costs and speeding up drug discovery. This happy outcome results from development of more accurate and reliable algorithms, use of more thoughtfully planned strategies to apply them, and greatly increased computer power to allow studies with the necessary reliability to be performed. Our review focuses on applications and protocols, with the main emphasis on critical analysis of recent studies where docking calculations and molecular dynamics (MD) simulations were combined to dock small molecules into protein receptors. We highlight successes to demonstrate what is possible now, but also point out drawbacks and future directions. The review is structured to lead the reader from the simpler to more compute-intensive methods. Thus, while inexpensive and fast docking algorithms can be used to scan large compound libraries and reduce their size, more accurate but expensive MD simulations can be applied when a few selected ligand candidates remain. MD simulations can be used: during the preparation of the protein receptor before docking, to optimize its structure and account for protein flexibility; for the refinement of docked complexes, to include solvent effects and account for induced fit; to calculate binding free energies, to provide an accurate ranking of the potential ligands; and in the latest developments, during the docking process itself to find the binding site and correctly dock the ligand a priori.

  1. Homology Modeling and Molecular Docking for the Science Curriculum

    PubMed Central

    McDougal, Owen M.; Comia, Nic; Sambasivarao, S.V.; Remm, Andrew; Mallory, Chris; Oxford, Julia Thom; Maupin, C. Mark; Andersen, Tim

    2015-01-01

    DockoMatic 2.0 is a powerful open source software program (downloadable from sourceforge.net) that simplifies the exploration of computational biochemistry. This manuscript describes a practical tutorial for use in the undergraduate curriculum that introduces students to macromolecular structure creation, ligand binding calculations, and visualization of docking results. A student procedure is provided that illustrates use of DockoMatic to create a homology model for the amino propeptide region (223 amino acids with two disulfide bonds) of collagen α1 (XI), followed by molecular docking of the commercial drug Arixtra® to the homology model of the amino propeptide domain of collagen α1 (XI), and finally, analysis of the results of the docking experiment. The activities and supplemental materials described are intended to educate students in the use of computational tools to create and investigate homology models for other systems of interest and to train students to be proficient with molecular docking and analyzing results. The tutorial also serves as a foundation for investigators seeking to explore the viability of using computational biochemistry to study their receptor-ligand binding motifs. PMID:24376157

  2. Probing Molecular Docking in a Charged Model Binding Site

    PubMed Central

    Brenk, Ruth; Vetter, Stefan W.; Boyce, Sarah E.; Goodin, David B.; Shoichet, Brian K.

    2011-01-01

    A model binding site was used to investigate charge–charge interactions in molecular docking. This simple site, a small (180 Å3) engineered cavity in cyctochrome c peroxidase (CCP), is negatively charged and completely buried from solvent, allowing us to explore the balance between electrostatic energy and ligand desolvation energy in a system where many of the common approximations in docking do not apply. A database with about 5300 molecules was docked into this cavity. Retrospective testing with known ligands and decoys showed that overall the balance between electrostatic interaction and desolvation energy was captured. More interesting were prospective docking scre”ens that looked for novel ligands, especially those that might reveal problems with the docking and energy methods. Based on screens of the 5300 compound database, both high-scoring and low-scoring molecules were acquired and tested for binding. Out of 16 new, high-scoring compounds tested, 15 were observed to bind. All of these were small heterocyclic cations. Binding constants were measured for a few of these, they ranged between 20 μM and 60 μM. Crystal structures were determined for ten of these ligands in complex with the protein. The observed ligand geometry corresponded closely to that predicted by docking. Several low-scoring alkyl amino cations were also tested and found to bind. The low docking score of these molecules owed to the relatively high charge density of the charged amino group and the corresponding high desolvation penalty. When the complex structures of those ligands were determined, a bound water molecule was observed interacting with the amino group and a backbone carbonyl group of the cavity. This water molecule mitigates the desolvation penalty and improves the interaction energy relative to that of the “naked” site used in the docking screen. Finally, six low-scoring neutral molecules were also tested, with a view to looking for false negative predictions

  3. Synthesis, characterization, biological evaluation and molecular docking of steroidal spirothiazolidinones

    NASA Astrophysics Data System (ADS)

    Shamsuzzaman; Abdul Baqi, Khan A. A.; Ali, Abad; Asif, Mohd; Mashrai, Ashraf; Khanam, Hena; Sherwani, Asif; Yaseen, Zahid; Owais, Mohammad

    2015-04-01

    The present work describes a convenient synthesis of steroidal spirothiazolidinone derivatives (3, 10-12) in a two-step process. All the newly synthesized compounds have been characterized by means of elemental analyses, IR, 1H NMR, 13C NMR and MS. Lipinski's 'Rule of Five' analysis and biological score predicted higher intrinsic quality of the synthesized compounds and revealed that these compounds have good passive oral absorption. The DNA binding studies of the synthesized compounds with CT-DNA were carried out by UV-vis and fluorescence spectroscopy. The molecular docking study suggested electrostatic interaction between synthesized compounds and nucleotide base pairs. The antitumor activity was tested in vitro against human leukemia cancer cell (Jurkat) and blood peripheral mononuclear normal cell (PBMCs) lines by MTT method. In addition, apoptosis and nonenzymatic degradation of DNA have been investigated. The acetylcholinesterase (AChE) inhibitor activities of the derivatives were also evaluated using Ellman's method. The present study has shown that steroidal spirothiazolidinone derivatives (3, 10-12) can be used as template to design more potent and selective cytotoxic and AChE inhibition agents through modification and derivatization.

  4. Discovery and optimization of triazine derivatives as ROCK1 inhibitors: molecular docking, molecular dynamics simulations and free energy calculations.

    PubMed

    Shen, Mingyun; Zhou, Shunye; Li, Youyong; Pan, Peichen; Zhang, Liling; Hou, Tingjun

    2013-03-01

    Rho-associated protein kinases (ROCK1 and ROCK2) are promising targets for a number of diseases, including cardiovascular disorders, nervous system diseases, cancers, etc. Recently, we have successfully identified a ROCK1 inhibitor (1) with the triazine core. In order to gain a deeper insight into the microscopic binding of this inhibitor with ROCK1 and design derivatives with improved potency, the interactions between ROCK1 and a series of triazine/pyrimidine-based inhibitors were studied by using an integrated computational protocol that combines molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decomposition analysis. First, three docking protocols, rigid receptor docking, induced fit docking, QM-polarized ligand docking, were used to determine the binding modes of the studied inhibitors in the active site of ROCK1. The results illustrate that rigid receptor docking achieves the best performance to rank the binding affinities of the studied inhibitors. Then, based on the predicted structures from molecular docking, MD simulations and MM/GBSA free energy calculations were employed to determine the dynamic binding process and compare the binding modes of the inhibitors with different activities. The binding free energies predicted by MM/GBSA are in good agreement with the experimental bioactivities, and the analysis of the individual energy terms suggests that the van der Waals interaction is the major driving force for ligand binding. In addition, the residue-inhibitor interaction spectra were obtained by the MM/GBSA free energy decomposition analysis, and the important residues for achieving strong binding were highlighted, which affords important guidance for the rational design of novel ROCK inhibitors. Finally, a variety of derivatives of inhibitor 1 were designed and four of them showed promising potency according to the predictions. We expect that our study can provide significant insight into the

  5. Ligand Pose and Orientational Sampling in Molecular Docking

    PubMed Central

    Coleman, Ryan G.; Carchia, Michael; Sterling, Teague; Irwin, John J.; Shoichet, Brian K.

    2013-01-01

    Molecular docking remains an important tool for structure-based screening to find new ligands and chemical probes. As docking ambitions grow to include new scoring function terms, and to address ever more targets, the reliability and extendability of the orientation sampling, and the throughput of the method, become pressing. Here we explore sampling techniques that eliminate stochastic behavior in DOCK3.6, allowing us to optimize the method for regularly variable sampling of orientations. This also enabled a focused effort to optimize the code for efficiency, with a three-fold increase in the speed of the program. This, in turn, facilitated extensive testing of the method on the 102 targets, 22,805 ligands and 1,411,214 decoys of the Directory of Useful Decoys - Enhanced (DUD-E) benchmarking set, at multiple levels of sampling. Encouragingly, we observe that as sampling increases from 50 to 500 to 2000 to 5000 to 20000 molecular orientations in the binding site (and so from about 1×1010 to 4×1010 to 1×1011 to 2×1011 to 5×1011 mean atoms scored per target, since multiple conformations are sampled per orientation), the enrichment of ligands over decoys monotonically increases for most DUD-E targets. Meanwhile, including internal electrostatics in the evaluation ligand conformational energies, and restricting aromatic hydroxyls to low energy rotamers, further improved enrichment values. Several of the strategies used here to improve the efficiency of the code are broadly applicable in the field. PMID:24098414

  6. Incorporating replacement free energy of binding-site waters in molecular docking.

    PubMed

    Sun, Hanzi; Zhao, Lifeng; Peng, Shiming; Huang, Niu

    2014-09-01

    Binding-site water molecules play a crucial role in protein-ligand recognition, either being displaced upon ligand binding or forming water bridges to stabilize the complex. However, rigorously treating explicit binding-site waters is challenging in molecular docking, which requires to fully sample ensembles of waters and to consider the free energy cost of replacing waters. Here, we describe a method to incorporate structural and energetic properties of binding-site waters into molecular docking. We first developed a solvent property analysis (SPA) program to compute the replacement free energies of binding-site water molecules by post-processing molecular dynamics trajectories obtained from ligand-free protein structure simulation in explicit water. Next, we implemented a distance-dependent scoring term into DOCK scoring function to take account of the water replacement free energy cost upon ligand binding. We assessed this approach in protein targets containing important binding-site waters, and we demonstrated that our approach is reliable in reproducing the crystal binding geometries of protein-ligand-water complexes, as well as moderately improving the ligand docking enrichment performance. In addition, SPA program (free available to academic users upon request) may be applied in identifying hot-spot binding-site residues and structure-based lead optimization.

  7. FReDoWS: a method to automate molecular docking simulations with explicit receptor flexibility and snapshots selection

    PubMed Central

    2011-01-01

    Background In silico molecular docking is an essential step in modern drug discovery when driven by a well defined macromolecular target. Hence, the process is called structure-based or rational drug design (RDD). In the docking step of RDD the macromolecule or receptor is usually considered a rigid body. However, we know from biology that macromolecules such as enzymes and membrane receptors are inherently flexible. Accounting for this flexibility in molecular docking experiments is not trivial. One possibility, which we call a fully-flexible receptor model, is to use a molecular dynamics simulation trajectory of the receptor to simulate its explicit flexibility. To benefit from this concept, which has been known since 2000, it is essential to develop and improve new tools that enable molecular docking simulations of fully-flexible receptor models. Results We have developed a Flexible-Receptor Docking Workflow System (FReDoWS) to automate molecular docking simulations using a fully-flexible receptor model. In addition, it includes a snapshot selection feature to facilitate acceleration the virtual screening of ligands for well defined disease targets. FReDoWS usefulness is demonstrated by investigating the docking of four different ligands to flexible models of Mycobacterium tuberculosis’ wild type InhA enzyme and mutants I21V and I16T. We find that all four ligands bind effectively to this receptor as expected from the literature on similar, but wet experiments. Conclusions A work that would usually need the manual execution of many computer programs, and the manipulation of thousands of files, was efficiently and automatically performed by FReDoWS. Its friendly interface allows the user to change the docking and execution parameters. Besides, the snapshot selection feature allowed the acceleration of docking simulations. We expect FReDoWS to help us explore more of the role flexibility plays in receptor-ligand interactions. FReDoWS can be made available upon

  8. In silico predictive studies of mAHR congener binding using homology modelling and molecular docking.

    PubMed

    Panda, Roshni; Cleave, A Suneetha Susan; Suresh, P K

    2014-09-01

    The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic, nuclear receptor that is responsible for the early events involved in the transcription of a complex set of genes comprising the CYP450 gene family. In the present computational study, homology modelling and molecular docking were carried out with the objective of predicting the relationship between the binding efficiency and the lipophilicity of different polychlorinated biphenyl (PCB) congeners and the AHR in silico. Homology model of the murine AHR was constructed by several automated servers and assessed by PROCHECK, ERRAT, VERIFY3D and WHAT IF. The resulting model of the AHR by MODWEB was used to carry out molecular docking of 36 PCB congeners using PatchDock server. The lipophilicity of the congeners was predicted using the XLOGP3 tool. The results suggest that the lipophilicity influences binding energy scores and is positively correlated with the same. Score and Log P were correlated with r = +0.506 at p = 0.01 level. In addition, the number of chlorine (Cl) atoms and Log P were highly correlated with r = +0.900 at p = 0.01 level. The number of Cl atoms and scores also showed a moderate positive correlation of r = +0.481 at p = 0.01 level. To the best of our knowledge, this is the first study employing PatchDock in the docking of AHR to the environmentally deleterious congeners and attempting to correlate structural features of the AHR with its biochemical properties with regards to PCBs. The result of this study are consistent with those of other computational studies reported in the previous literature that suggests that a combination of docking, scoring and ranking organic pollutants could be a possible predictive tool for investigating ligand-mediated toxicity, for their subsequent validation using wet lab-based studies.

  9. GPU Optimizations for a Production Molecular Docking Code.

    PubMed

    Landaverde, Raphael; Herbordt, Martin C

    2014-09-01

    Modeling molecular docking is critical to both understanding life processes and designing new drugs. In previous work we created the first published GPU-accelerated docking code (PIPER) which achieved a roughly 5× speed-up over a contemporaneous 4 core CPU. Advances in GPU architecture and in the CPU code, however, have since reduced this relalative performance by a factor of 10. In this paper we describe the upgrade of GPU PIPER. This required an entire rewrite, including algorithm changes and moving most remaining non-accelerated CPU code onto the GPU. The result is a 7× improvement in GPU performance and a 3.3× speedup over the CPU-only code. We find that this difference in time is almost entirely due to the difference in run times of the 3D FFT library functions on CPU (MKL) and GPU (cuFFT), respectively. The GPU code has been integrated into the ClusPro docking server which has over 4000 active users.

  10. pso@autodock: a fast flexible molecular docking program based on Swarm intelligence.

    PubMed

    Namasivayam, Vigneshwaran; Günther, Robert

    2007-12-01

    On the quest of novel therapeutics, molecular docking methods have proven to be valuable tools for screening large libraries of compounds determining the interactions of potential drugs with the target proteins. A widely used docking approach is the simulation of the docking process guided by a binding energy function. On the basis of the molecular docking program autodock, we present pso@autodock as a tool for fast flexible molecular docking. Our novel Particle Swarm Optimization (PSO) algorithms varCPSO and varCPSO-ls are suited for rapid docking of highly flexible ligands. Thus, a ligand with 23 rotatable bonds was successfully docked within as few as 100 000 computing steps (rmsd = 0.87 A), which corresponds to only 10% of the computing time demanded by autodock. In comparison to other docking techniques as gold 3.0, dock 6.0, flexx 2.2.0, autodock 3.05, and sodock, pso@autodock provides the smallest rmsd values for 12 in 37 protein-ligand complexes. The average rmsd value of 1.4 A is significantly lower then those obtained with the other docking programs, which are all above 2.0 A. Thus, pso@autodock is suggested as a highly efficient docking program in terms of speed and quality for flexible peptide-protein docking and virtual screening studies.

  11. Bio-inspired algorithms applied to molecular docking simulations.

    PubMed

    Heberlé, G; de Azevedo, W F

    2011-01-01

    Nature as a source of inspiration has been shown to have a great beneficial impact on the development of new computational methodologies. In this scenario, analyses of the interactions between a protein target and a ligand can be simulated by biologically inspired algorithms (BIAs). These algorithms mimic biological systems to create new paradigms for computation, such as neural networks, evolutionary computing, and swarm intelligence. This review provides a description of the main concepts behind BIAs applied to molecular docking simulations. Special attention is devoted to evolutionary algorithms, guided-directed evolutionary algorithms, and Lamarckian genetic algorithms. Recent applications of these methodologies to protein targets identified in the Mycobacterium tuberculosis genome are described.

  12. Metronidazole hydrazone conjugates: Design, synthesis, antiamoebic and molecular docking studies.

    PubMed

    Ansari, Mohammad Fawad; Siddiqui, Shadab Miyan; Agarwal, Subhash M; Vikramdeo, Kunwar Somesh; Mondal, Neelima; Azam, Amir

    2015-09-01

    Metronidazole hydrazone conjugates (2-13) were synthesized and screened in vitro for antiamoebic activity against HM1: IMSS strain of Entamoeba histolytica. Six compounds were found to be better inhibitors of E. histolytica than the reference drug metronidazole. These compounds showed greater than 50-60% viability against HeLa cervical cancer cell line after 72 h treatment. Also, molecular docking study was undertaken on E. histolytica thioredoxin reductase (EhTHRase) protein which showed significant binding affinity in the active site. Out of the six actives, some of the compounds showed lipophilic characteristics.

  13. Studies on Pidotimod Enantiomers With Chiralpak-IA: Crystal Structure, Thermodynamic Parameters and Molecular Docking.

    PubMed

    Dou, Xiaorui; Su, Xin; Wang, Yue; Chen, Yadong; Shen, Weiyang

    2015-11-01

    Pidotimod, a synthetic dipeptide, has two chiral centers with biological and immunological activity. Its enantiomers were characterized by x-ray crystallographic analysis. A chiral stationary phase (CSP) Chiralpak-IA based on amylose derivatized with tris-(3, 5-dimethylphenyl carbamate) was used to separate pidotimod enantiomers. The mobile phase was prepared in a ratio of 35:65:0.2 of methyl-tert-butyl-ether and acetonitrile trifluoroaceticacid. In addition, thermodynamics and molecular docking methods were used to explain the enantioseparation mechanism by Chiralpak-IA. Thermodynamic studies were carried out from 10 to 45 °C. In general, both retention and enantioselectivity decreased as the temperature increased. Thermodynamic parameters indicate that the interaction force between the pidotimod enantiomer (4S, 2'R) and IA CSP is stronger and their complex model is more stable. According to GOLD molecular docking simulation, Van der Waals force is the leading cause of pidotimod enantiomers separation by IA CSP.

  14. Isatin based thiosemicarbazone derivatives as potential bioactive agents: Anti-oxidant and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Haribabu, J.; Subhashree, G. R.; Saranya, S.; Gomathi, K.; Karvembu, R.; Gayathri, D.

    2016-04-01

    A new series of isatin based thiosemicarbazones has been synthesized from benzylisatin and unsubstituted/substituted thiosemicarbazides (1-5). The synthesized compounds were characterized by elemental analyses, and UV-Visible, FT-IR, 1H &13C NMR and mass spectroscopic techniques. Three dimensional molecular structure of three compounds (1, 3 and 4) was determined by single crystal X-ray crystallography. Anti-oxidant activity of the thiosemicarbazone derivatives showed their excellent scavenging effect against free radicals. In addition, all the compounds showed good anti-haemolytic activity. In silico molecular docking studies were performed to screen the anti-inflammatory and anti-tuberculosis properties of thiosemicarbazone derivatives.

  15. 3D-QSAR, molecular docking and molecular dynamics studies of a series of RORγt inhibitors.

    PubMed

    Wang, Fangfang; Yang, Wei; Shi, Yonghui; Le, Guowei

    2015-09-01

    The discovery of clinically relevant inhibitors of retinoic acid receptor-related orphan receptor-gamma-t (RORγt) for autoimmune diseases therapy has proven to be a challenging task. In the present work, to find out the structural features required for the inhibitory activity, we show for the first time a three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations for a series of novel thiazole/thiophene ketone amides with inhibitory activity at the RORγt receptor. The optimum CoMFA and CoMSIA models, derived from ligand-based superimposition I, exhibit leave-one-out cross-validated correlation coefficient (R(2)cv) of .859 and .805, respectively. Furthermore, the external predictive abilities of the models were evaluated by a test set, producing the predicted correlation coefficient (R(2)pred) of .7317 and .7097, respectively. In addition, molecular docking analysis was applied to explore the binding modes between the inhibitors and the receptor. MD simulation and MM/PBSA method were also employed to study the stability and rationality of the derived conformations, and the binding free energies in detail. The QSAR models and the results of molecular docking, MD simulation, binding free energies corroborate well with each other and further provide insights regarding the development of novel RORγt inhibitors with better activity.

  16. Clustering Molecular Dynamics Trajectories for Optimizing Docking Experiments

    PubMed Central

    De Paris, Renata; Quevedo, Christian V.; Ruiz, Duncan D.; Norberto de Souza, Osmar; Barros, Rodrigo C.

    2015-01-01

    Molecular dynamics simulations of protein receptors have become an attractive tool for rational drug discovery. However, the high computational cost of employing molecular dynamics trajectories in virtual screening of large repositories threats the feasibility of this task. Computational intelligence techniques have been applied in this context, with the ultimate goal of reducing the overall computational cost so the task can become feasible. Particularly, clustering algorithms have been widely used as a means to reduce the dimensionality of molecular dynamics trajectories. In this paper, we develop a novel methodology for clustering entire trajectories using structural features from the substrate-binding cavity of the receptor in order to optimize docking experiments on a cloud-based environment. The resulting partition was selected based on three clustering validity criteria, and it was further validated by analyzing the interactions between 20 ligands and a fully flexible receptor (FFR) model containing a 20 ns molecular dynamics simulation trajectory. Our proposed methodology shows that taking into account features of the substrate-binding cavity as input for the k-means algorithm is a promising technique for accurately selecting ensembles of representative structures tailored to a specific ligand. PMID:25873944

  17. Clustering molecular dynamics trajectories for optimizing docking experiments.

    PubMed

    De Paris, Renata; Quevedo, Christian V; Ruiz, Duncan D; Norberto de Souza, Osmar; Barros, Rodrigo C

    2015-01-01

    Molecular dynamics simulations of protein receptors have become an attractive tool for rational drug discovery. However, the high computational cost of employing molecular dynamics trajectories in virtual screening of large repositories threats the feasibility of this task. Computational intelligence techniques have been applied in this context, with the ultimate goal of reducing the overall computational cost so the task can become feasible. Particularly, clustering algorithms have been widely used as a means to reduce the dimensionality of molecular dynamics trajectories. In this paper, we develop a novel methodology for clustering entire trajectories using structural features from the substrate-binding cavity of the receptor in order to optimize docking experiments on a cloud-based environment. The resulting partition was selected based on three clustering validity criteria, and it was further validated by analyzing the interactions between 20 ligands and a fully flexible receptor (FFR) model containing a 20 ns molecular dynamics simulation trajectory. Our proposed methodology shows that taking into account features of the substrate-binding cavity as input for the k-means algorithm is a promising technique for accurately selecting ensembles of representative structures tailored to a specific ligand.

  18. Spectroscopic, quantum chemical calculation and molecular docking of dipfluzine

    NASA Astrophysics Data System (ADS)

    Srivastava, Karnica; Srivastava, Anubha; Tandon, Poonam; Sinha, Kirti; Wang, Jing

    2016-12-01

    Molecular structure and vibrational analysis of dipfluzine (C27H29FN2O) were presented using FT-IR and FT-Raman spectroscopy and quantum chemical calculations. The theoretical ground state geometry and electronic structure of dipfluzine are optimized by the DFT/B3LYP/6-311++G (d,p) method and compared with those of the crystal data. The 1D potential energy scan was performed by varying the dihedral angle using B3LYP functional at 6-31G(d,p) level of theory and thus the most stable conformer of the compound were determined. Molecular electrostatic potential surface (MEPS), frontier orbital analysis and electronic reactivity descriptor were used to predict the chemical reactivity of molecule. Energies of intra- and inter-molecular hydrogen bonds in molecule and their electronic aspects were investigated by natural bond orbital (NBO). To find out the anti-apoptotic activity of the title compound molecular docking studies have been performed against protein Fas.

  19. Interaction of glutathione with bovine serum albumin: Spectroscopy and molecular docking.

    PubMed

    Jahanban-Esfahlan, Ali; Panahi-Azar, Vahid

    2016-07-01

    This study aims to investigate the interaction between glutathione and bovine serum albumin (BSA) using ultraviolet-visible (UV-vis) absorption, fluorescence spectroscopies under simulated physiological conditions (pH 7.4) and molecular docking methods. The results of fluorescence spectroscopy indicated that the fluorescence intensity of BSA was decreased considerably upon the addition of glutathione through a static quenching mechanism. The fluorescence quenching obtained was related to the formation of BSA-glutathione complex. The values of KSV, Ka and Kb for the glutathione and BSA interaction were in the order of 10(5). The thermodynamic parameters including enthalpy change (ΔH), entropy change (ΔS) and also Gibb's free energy (ΔG) were determined using Van't Hoff equation. These values showed that hydrogen bonding and van der Waals forces were the main interactions in the binding of glutathione to BSA and the stabilization of the complex. Also, the interaction of glutathione and BSA was spontaneous. The effects of glutathione on the BSA conformation were determined using UV-vis spectroscopy. Moreover, glutathione was docked in BSA using ArgusLab as a molecular docking program. It was recognized that glutathione binds within the sub-domain IIA pocket in domain II of BSA.

  20. Molecular docking of balanol to dynamics snapshots of protein kinase A.

    PubMed

    Wong, Chung F; Kua, Jeremy; Zhang, Yingkai; Straatsma, T P; McCammon, J Andrew

    2005-12-01

    Even if the structure of a receptor has been determined experimentally, it may not be a conformation to which a ligand would bind when induced fit effects are significant. Molecular docking using such a receptor structure may thus fail to recognize a ligand to which the receptor can bind with reasonable affinity. Here, we examine one way to alleviate this problem by using an ensemble of receptor conformations generated from a molecular dynamics simulation for molecular docking. Two molecular dynamics simulations were conducted to generate snapshots for protein kinase A: one with the ligand bound, the other without. The ligand, balanol, was then docked to conformations of the receptors presented by these trajectories. The Lamarckian genetic algorithm in Autodock [Goodsell et al. J Mol Recognit 1996;9(1):1-5; Morris et al. J Comput Chem 1998;19(14):1639-1662] was used in the docking. Three ligand models were used: rigid, flexible, and flexible with torsional potentials. When the snapshots were taken from the molecular dynamics simulation of the protein-ligand complex, the correct docking structure could be recovered easily by the docking algorithm in all cases. This was an easier case for challenging the docking algorithm because, by using the structure of the protein in a protein-ligand complex, one essentially assumed that the protein already had a pocket to which the ligand can fit well. However, when the snapshots were taken from the ligand-free protein simulation, which is more useful for a practical application when the structure of the protein-ligand complex is not known, several clusters of structures were found. Of the 10 docking runs for each snapshot, at least one structure was close to the correctly docked structure when the flexible-ligand models were used. We found that a useful way to identify the correctly docked structure was to locate the structure that appeared most frequently as the lowest energy structure in the docking experiments to different

  1. Docking and molecular dynamics studies at trypanothione reductase and glutathione reductase active sites.

    PubMed

    Iribarne, Federico; Paulino, Margot; Aguilera, Sara; Murphy, Miguel; Tapia, Orlando

    2002-05-01

    A theoretical docking study on the active sites of trypanothione reductase (TR) and glutathione reductase (GR) with the corresponding natural substrates, trypanothione disulfide (T[S]2) and glutathione disulfide (GSSG), is reported. Molecular dynamics simulations were carried out in order to check the robustness of the docking results. The energetic results are in agreement with previous experimental findings and show the crossed complexes have lower stabilization energies than the natural ones. To test DOCK3.5, four nitro furanic compounds, previously designed as potentially active anti-chagasic molecules, were docked at the GR and TR active sites with the DOCK3.5 procedure. A good correlation was found between differential inhibitory activity and relative interaction energy (affinity). The results provide a validation test for the use of DOCK3.5 in connection with the design of anti-chagasic drugs.

  2. Comparison of several molecular docking programs: pose prediction and virtual screening accuracy.

    PubMed

    Cross, Jason B; Thompson, David C; Rai, Brajesh K; Baber, J Christian; Fan, Kristi Yi; Hu, Yongbo; Humblet, Christine

    2009-06-01

    Molecular docking programs are widely used modeling tools for predicting ligand binding modes and structure based virtual screening. In this study, six molecular docking programs (DOCK, FlexX, GLIDE, ICM, PhDOCK, and Surflex) were evaluated using metrics intended to assess docking pose and virtual screening accuracy. Cognate ligand docking to 68 diverse, high-resolution X-ray complexes revealed that ICM, GLIDE, and Surflex generated ligand poses close to the X-ray conformation more often than the other docking programs. GLIDE and Surflex also outperformed the other docking programs when used for virtual screening, based on mean ROC AUC and ROC enrichment values obtained for the 40 protein targets in the Directory of Useful Decoys (DUD). Further analysis uncovered general trends in accuracy that are specific for particular protein families. Modifying basic parameters in the software was shown to have a significant effect on docking and virtual screening results, suggesting that expert knowledge is critical for optimizing the accuracy of these methods.

  3. Molecular interactions of flavonoids to pepsin: Insights from spectroscopic and molecular docking studies.

    PubMed

    Zeng, Hua-Jin; Yang, Ran; Liang, Huili; Qu, Ling-Bo

    2015-01-01

    In the work described on this paper, the inhibitory effect of 10 flavonoids on pepsin and the interactions between them were investigated by a combination of spectroscopic and molecular docking methods. The results indicated that all flavonoids could bind with pepsin to form flavonoid-pepsin complexes. The binding parameters obtained from the data at different temperatures revealed that flavonoids could spontaneously interact with pepsin mainly through electrostatic forces and hydrophobic interactions with one binding site. According to synchronous and three-dimensional fluorescence spectra and molecular docking results, all flavonoids bound directly into the enzyme cavity site and the binding influenced the microenvironment and conformation of the pepsin activity site which resulted in the reduced enzyme activity. The present study provides direct evidence at a molecular level to understand the mechanism of digestion caused by flavonoids.

  4. Docking, molecular dynamics and free energy studies on aspartoacylase mutations involved in Canavan disease.

    PubMed

    Kocak, Abdulkadir; Yildiz, Muslum

    2017-03-19

    The disruption of aspartoacylase enzyme's catalytic activity causes fatal neurodegenerative Canavan disease. By molecular dynamics and docking methods, here we studied two deleterious mutations that have been identified in the Canavan patients' genotype E285A, F295S, and revealed the possible cause for the enzyme inhibition due to the drastic changes in active site dynamics, loss of interactions among Arg 71, Arg 168 and the substrate and pKa value of critical Glu178 residue. In addition to changes in the enzyme dynamics, free energy calculations show that the binding energy of substrate decreases dramatically up on mutations.

  5. Binding of an anticancer drug, axitinib to human serum albumin: Fluorescence quenching and molecular docking study.

    PubMed

    Tayyab, Saad; Izzudin, Mohamad Mirza; Kabir, Md Zahirul; Feroz, Shevin R; Tee, Wei-Ven; Mohamad, Saharuddin B; Alias, Zazali

    2016-09-01

    Binding characteristics of a promising anticancer drug, axitinib (AXT) to human serum albumin (HSA), the major transport protein in human blood circulation, were studied using fluorescence, UV-vis absorption and circular dichroism (CD) spectroscopy as well as molecular docking analysis. A gradual decrease in the Stern-Volmer quenching constant with increasing temperature revealed the static mode of the protein fluorescence quenching upon AXT addition, thus confirmed AXT-HSA complex formation. This was also confirmed from alteration in the UV-vis spectrum of HSA upon AXT addition. Fluorescence quenching titration results demonstrated moderately strong binding affinity between AXT and HSA based on the binding constant value (1.08±0.06×10(5)M(-1)), obtained in 10mM sodium phosphate buffer, pH7.4 at 25°C. The sign and magnitude of the enthalpy change (∆H=-8.38kJmol(-1)) as well as the entropy change (∆S=+68.21Jmol(-1)K(-1)) clearly suggested involvement of both hydrophobic interactions and hydrogen bonding in AXT-HSA complex formation. These results were well supported by molecular docking results. Three-dimensional fluorescence spectral results indicated significant microenvironmental changes around Trp and Tyr residues of HSA upon complexation with AXT. AXT binding to the protein produced significant alterations in both secondary and tertiary structures of HSA, as revealed from the far-UV and the near-UV CD spectral results. Competitive drug displacement results obtained with phenylbutazone (site I marker), ketoprofen (site II marker) and hemin (site III marker) along with molecular docking results suggested Sudlow's site I, located in subdomain IIA of HSA, as the preferred binding site of AXT.

  6. Molecular docking studies for the identification of novel melatoninergic inhibitors for acetylserotonin-O-methyltransferase using different docking routines

    PubMed Central

    2013-01-01

    Background N-Acetylserotonin O-methyltransferase (ASMT) is an enzyme which by converting nor-melatonin to melatonin catalyzes the final reaction in melatonin biosynthesis in tryptophan metabolism pathway. High Expression of ASMT gene is evident in PPTs. The presence of abnormally high levels of ASMT in pineal gland could serve as an indication of the existence of pineal parenchymal tumors (PPTs) in the brain (J Neuropathol Exp Neurol 65: 675–684, 2006). Different levels of melatonin are used as a trait marker for prescribing the mood disorders e.g. Seasonal affective disorder, bipolar disorder, or major depressive disorder. In addition, melatonin levels can also be used to calculate the severity of a patient’s illness at a given point in time. Methods Seventy three melatoninergic inhibitors were docked with acetylserotonin-O-methyltransferase in order to identify the potent inhibitor against the enzyme. The chemical nature of the protein and ligands greatly influence the performance of docking routines. Keeping this fact in view, critical evaluation of the performance of four different commonly used docking routines: AutoDock/Vina, GOLD, FlexX and FRED were performed. An evaluation criterion was based on the binding affinities/docking scores and experimental bioactivities. Results and conclusion Results indicated that both hydrogen bonding and hydrophobic interactions contributed significantly for its ligand binding and the compound selected as potent inhibitor is having minimum binding affinity, maximum GoldScore and minimum FlexX energy. The correlation value of r2 = 0. 66 may be useful in the selection of correct docked complexes based on the energy without having prior knowledge of the active site. This may lead to further understanding of structures, their reliability and Biomolecular activity especially in connection with bipolar disorders. PMID:24156411

  7. Improvements, trends, and new ideas in molecular docking: 2012-2013 in review.

    PubMed

    Yuriev, Elizabeth; Holien, Jessica; Ramsland, Paul A

    2015-10-01

    Molecular docking is a computational method for predicting the placement of ligands in the binding sites of their receptor(s). In this review, we discuss the methodological developments that occurred in the docking field in 2012 and 2013, with a particular focus on the more difficult aspects of this computational discipline. The main challenges and therefore focal points for developments in docking, covered in this review, are receptor flexibility, solvation, scoring, and virtual screening. We specifically deal with such aspects of molecular docking and its applications as selection criteria for constructing receptor ensembles, target dependence of scoring functions, integration of higher-level theory into scoring, implicit and explicit handling of solvation in the binding process, and comparison and evaluation of docking and scoring methods.

  8. Molecular docking simulation analysis of the interaction of dietary flavonols with heat shock protein 90

    PubMed Central

    Singh, Salam Pradeep; Deb, Chitta Ranjan; Ahmed, Sharif Udin; Saratchandra, Yenisetti; Konwar, Bolin Kumar

    2016-01-01

    Abstract Hsp90 is a major protein involved in the stabilization of various proteins in cancer cells. The present investigation focused on the molecular docking simulation studies of flavanols as inhibitors of Hsp90 at the high affinity adenosine triphosphate (ATP) binding site and analyzed absorption, distribution, metabolism, excretion and toxicity (ADME-toxicity). The molecular docking analysis revealed that the flavanols showed competitive inhibition with ATP molecule at the active site and enhanced pharmacological parameters.

  9. Halogen-directed drug design for Alzheimer's disease: a combined density functional and molecular docking study.

    PubMed

    Rahman, Adhip; Ali, Mohammad Tuhin; Shawan, Mohammad Mahfuz Ali Khan; Sarwar, Mohammed Golam; Khan, Mohammad A K; Halim, Mohammad A

    2016-01-01

    A series of halogen-directed donepezil drugs has been designed to inhibit acetyl cholinesterase (AChE). Density Functional theory (DFT) has been employed to optimize the chair as well as boat conformers of the parent drug and modified ligands at B3LYP/MidiX and B3LYP/6-311G + (d,p) level of theories. Charge distribution, dipole moment, enthalpy, free energy and molecular orbitals of these ligands are also investigated to understand how the halogen-directed modifications impact the ligand structure and govern the non-bonding interactions with the receptors. Molecular docking calculation has been performed to understand the similarities and differences between the binding modes of unmodified and halogenated chair-formed ligands. Molecular docking indicated donepezil and modified ligands had non-covalent interactions with hydrophobic gorges and anionic subsites of AChE. The -CF3-directed ligand possessed the most negative binding affinity. Non-covalent interactions within the ligand-receptor systems were found to be mostly hydrophobic and π- stacking type. F, Cl and -CF3 containing ligands emerge as effective and selective AChE inhibitors, which can strongly interact with the two active sites of AChE. In addition, we have also investigated selected pharmacokinetic parameters of the parent and modified ligands.

  10. Feasibility of using molecular docking-based virtual screening for searching dual target kinase inhibitors.

    PubMed

    Zhou, Shunye; Li, Youyong; Hou, Tingjun

    2013-04-22

    Multitarget agents have been extensively explored for solving limited efficacies, poor safety, and resistant profiles of an individual target. Theoretical approaches for searching and designing multitarget agents are critically useful. Here, the performance of molecular docking to search dual-target inhibitors for four kinase pairs (CDK2-GSK3B, EGFR-Src, Lck-Src, and Lck-VEGFR2) was assessed. First, the representative structures for each kinase target were chosen by structural clustering of available crystal structures. Next, the performance of molecular docking to distinguish inhibitors from noninhibitors for each individual kinase target was evaluated. The results show that molecular docking-based virtual screening illustrates good capability to find known inhibitors for individual targets, but the prediction accuracy is structurally dependent. Finally, the performance of molecular docking to identify the dual-target kinase inhibitors for four kinase pairs was evaluated. The analyses show that molecular docking successfully filters out most noninhibitors and achieves promising performance for identifying dual-kinase inhibitors for CDK2-GSK3B and Lck-VEGFR2. But a high false-positive rate leads to low enrichment of true dual-target inhibitors in the final list. This study suggests that molecular docking serves as a useful tool in searching inhibitors against dual or even multiple kinase targets, but integration with other virtual screening tools is necessary for achieving better predictions.

  11. Toxic interaction between acid yellow 23 and trypsin: spectroscopic methods coupled with molecular docking.

    PubMed

    Wang, Jing; Liu, Rutao; Qin, Pengfei

    2012-09-01

    Acid yellow 23 (AY23) is a pervasive azo dye used in many fields which is potentially harmful to the environment and human health. This paper studied the toxic effects of AY23 on trypsin by spectroscopic and molecular docking methods. The addition of AY23 effectively quenched the intrinsic fluorescence of trypsin via static quenching with association constants of K(290 K) = 3.67 × 10(5) L mol(-1) and K(310 K) = 1.83 × 10(5) L mol(-1). The calculated thermodynamic parameters conformed that AY23 binds to trypsin predominantly via electrostatic forces with one binding site. Conformational investigations indicated the skeletal structure of trypsin unfolded and the microenvironment of tryptophan changed with the addition of AY23. Molecular docking study showed that AY23 interacted with the His 57 and Lys 224 residue of trypsin and led to the inhibition of enzyme activity. This study offers a more comprehensive picture of AY23-trypsin interaction and indicates their interaction may perform toxic effects within the organism.

  12. Identification of Potential PPAR γ Agonists as Hypoglycemic Agents: Molecular Docking Approach.

    PubMed

    Mishra, Ganesh Prasad; Sharma, Rajesh

    2016-09-01

    Peroxisome proliferator-activated receptor gamma (PPAR γ) has become an attractive molecular target for drugs that aim to treat hyperglycemia. The object of our study is to identify the required molecular descriptor and essential amino acid residues for effective PPAR γ agonistic activity. In this work, we employed Molegro Virtual Docker program in all molecular docking simulations. Accuracy of receptor-compound docking was validated on a set of 15 PPAR γ-compound complexes for which crystallographic structures were available. The reliability of the docking results was acceptable with good root-mean-square deviation value (<2 Å). A significant correlation between different data derived from docking calculations and experimental data was revealed. Our results allowed identification of compounds with potential to become drugs against hyperglycemia.

  13. Flexibility and explicit solvent in molecular-dynamics-based docking of protein-glycosaminoglycan systems.

    PubMed

    Samsonov, Sergey A; Gehrcke, Jan-Philip; Pisabarro, M Teresa

    2014-02-24

    We present Dynamic Molecular Docking (DMD), a novel targeted molecular dynamics-based protocol developed to address ligand and receptor flexibility as well as the inclusion of explicit solvent in local molecular docking. A class of ligands for which docking performance especially benefits from overcoming these challenges is the glycosaminoglycans (GAGs). GAGs are periodic, highly flexible, and negatively charged polysaccharides playing an important role in the extracellular matrix via interaction with proteins such as growth factors and chemokines. The goal of our work has been to develop a proof of concept for an MD-based docking approach and to analyze its applicability for protein-GAG systems. DMD exploits the electrostatics-driven attraction of a ligand to its receptor, treats both as entirely flexible, and considers solvent explicitly. We show that DMD has high predictive significance for systems dominated by electrostatic attraction and demonstrate its capability to reliably identify the receptor residues contributing most to binding.

  14. Molecular mechanism of serotonin transporter inhibition elucidated by a new flexible docking protocol.

    PubMed

    Gabrielsen, Mari; Kurczab, Rafał; Ravna, Aina W; Kufareva, Irina; Abagyan, Ruben; Chilmonczyk, Zdzisław; Bojarski, Andrzej J; Sylte, Ingebrigt

    2012-01-01

    The two main groups of antidepressant drugs, the tricyclic antidepressants (TCAs) and the selective serotonin reuptake inhibitors (SSRIs), as well as several other compounds, act by inhibiting the serotonin transporter (SERT). However, the binding mode and molecular mechanism of inhibition in SERT are not fully understood. In this study, five classes of SERT inhibitors were docked into an outward-facing SERT homology model using a new 4D ensemble docking protocol. Unlike other docking protocols, where protein flexibility is not considered or is highly dependent on the ligand structure, flexibility was here obtained by side chain sampling of the amino acids of the binding pocket using biased probability Monte Carlo (BPMC) prior to docking. This resulted in the generation of multiple binding pocket conformations that the ligands were docked into. The docking results showed that the inhibitors were stacked between the aromatic amino acids of the extracellular gate (Y176, F335) presumably preventing its closure. The inhibitors interacted with amino acids in both the putative substrate binding site and more extracellular regions of the protein. A general structure-docking-based pharmacophore model was generated to explain binding of all studied classes of SERT inhibitors. Docking of a test set of actives and decoys furthermore showed that the outward-facing ensemble SERT homology model consistently and selectively scored the majority of active compounds above decoys, which indicates its usefulness in virtual screening.

  15. Novel aldehyde and thiosemicarbazone derivatives: Synthesis, spectroscopic characterization, structural studies and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Karakurt, Tuncay; Tahtaci, Hakan; Subasi, Nuriye Tuna; Er, Mustafa; Ağar, Erbil

    2016-12-01

    In this study our purpose is that, synthesis and characterization of compounds containing the aldehyde and thiosemicarbazone groups and comparison of the theoretical results with the experimental results. The structures of all synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, elemental analyses techniques. The structure of compound (4) (C9H8N4O2S) was also elucidated by X-ray diffraction analysis. In addition, the theoretical IR spectrum, 1H NMR and 13C NMR chemical shift values, frontier molecular orbital values (FMO) of these molecules were analyzed by using Becke-3- Lee-Yang-Parr (B3LYP) method with LanL2DZ basis set. Finally, molecular docking studies were performed on synthesized compounds using the 4DKI beta-lactam protein structure to determine the potential binding mode of inhibitors.

  16. Design, synthesis, α-glucosidase inhibitory activity, molecular docking and QSAR studies of benzimidazole derivatives

    NASA Astrophysics Data System (ADS)

    Dinparast, Leila; Valizadeh, Hassan; Bahadori, Mir Babak; Soltani, Somaieh; Asghari, Behvar; Rashidi, Mohammad-Reza

    2016-06-01

    In this study the green, one-pot, solvent-free and selective synthesis of benzimidazole derivatives is reported. The reactions were catalyzed by ZnO/MgO containing ZnO nanoparticles as a highly effective, non-toxic and environmentally friendly catalyst. The structure of synthesized benzimidazoles was characterized using spectroscopic technics (FT-IR, 1HNMR, 13CNMR). Synthesized compounds were evaluated for their α-glucosidase inhibitory potential. Compounds 3c, 3e, 3l and 4n were potent inhibitors with IC50 values ranging from 60.7 to 168.4 μM. In silico studies were performed to explore the binding modes and interactions between enzyme and synthesized benzimidazoles. Developed linear QSAR model based on density and molecular weight could predict bioactivity of newly synthesized compounds well. Molecular docking studies revealed the availability of some hydrophobic interactions. In addition, the bioactivity of most potent compounds had good correlation with estimated free energy of binding (ΔGbinding) which was calculated according to docked best conformations.

  17. Caffeine and sulfadiazine interact differently with human serum albumin: A combined fluorescence and molecular docking study

    NASA Astrophysics Data System (ADS)

    Islam, Mullah Muhaiminul; Sonu, Vikash K.; Gashnga, Pynsakhiat Miki; Moyon, N. Shaemningwar; Mitra, Sivaprasad

    2016-01-01

    The interaction and binding behavior of the well-known drug sulfadiazine (SDZ) and psychoactive stimulant caffeine (CAF) with human serum albumin (HSA) was monitored by in vitro fluorescence titration and molecular docking calculations under physiological condition. The quenching of protein fluorescence on addition of CAF is due to the formation of protein-drug complex in the ground state; whereas in case of SDZ, the experimental results were explained on the basis of sphere of action model. Although both these compounds bind preferentially in Sudlow's site 1 of the protein, the association constant is approximately two fold higher in case of SDZ (∼4.0 × 104 M-1) in comparison with CAF (∼9.3 × 102 M-1) and correlates well with physico-chemical properties like pKa and lipophilicity of the drugs. Temperature dependent fluorescence study reveals that both SDZ and CAF bind spontaneously with HSA. However, the binding of SDZ with the protein is mainly governed by the hydrophobic forces in contrast with that of CAF; where, the interaction is best explained in terms of electrostatic mechanism. Molecular docking calculation predicts the binding of these drugs in different location of sub-domain IIA in the protein structure.

  18. Molecular docking and multivariate analysis of xanthones as antimicrobial and antiviral agents.

    PubMed

    Bernal, Freddy A; Coy-Barrera, Ericsson

    2015-07-21

    Xanthones are secondary metabolites which have drawn considerable interest over the last decades due to their antimicrobial properties, among others. A great number of this kind of compounds has been therefore reported, but there is a limited amount of studies on screening for biological activity. Thus, as part of our research on antimicrobial agents of natural origin, a set of 272 xanthones were submitted to molecular docking (MD) calculations with a group of seven fungal and two viral enzymes. The results indicated that prenylated xanthones are important hits for inhibition of the analyzed enzymes. The MD scores were also analyzed by multivariate statistics. Important structural details were found to be crucial for the inhibition of the tested enzymes by the xanthones. In addition, the classification of active xanthones can be achieved by statistical analysis on molecular docking scores by an affinity-antifungal activity relationship approach. The obtained results therefore are a suitable starting point for the development of antifungal and antiviral agents based on xanthones.

  19. Caffeine and sulfadiazine interact differently with human serum albumin: A combined fluorescence and molecular docking study.

    PubMed

    Islam, Mullah Muhaiminul; Sonu, Vikash K; Gashnga, Pynsakhiat Miki; Moyon, N Shaemningwar; Mitra, Sivaprasad

    2016-01-05

    The interaction and binding behavior of the well-known drug sulfadiazine (SDZ) and psychoactive stimulant caffeine (CAF) with human serum albumin (HSA) was monitored by in vitro fluorescence titration and molecular docking calculations under physiological condition. The quenching of protein fluorescence on addition of CAF is due to the formation of protein-drug complex in the ground state; whereas in case of SDZ, the experimental results were explained on the basis of sphere of action model. Although both these compounds bind preferentially in Sudlow's site 1 of the protein, the association constant is approximately two fold higher in case of SDZ (∼4.0×10(4)M(-1)) in comparison with CAF (∼9.3×10(2)M(-1)) and correlates well with physico-chemical properties like pKa and lipophilicity of the drugs. Temperature dependent fluorescence study reveals that both SDZ and CAF bind spontaneously with HSA. However, the binding of SDZ with the protein is mainly governed by the hydrophobic forces in contrast with that of CAF; where, the interaction is best explained in terms of electrostatic mechanism. Molecular docking calculation predicts the binding of these drugs in different location of sub-domain IIA in the protein structure.

  20. Molecular docking studies of withanolides against Cox-2 enzyme.

    PubMed

    Prabhakaran, Yogeswaran; Dinakaran, Sathis Kumar; Macharala, Sravan Prasad; Ghosh, Somsubhra; Karanam, Sridevi Ranjitha; Kanthasamy, Naveena; Avasarala, Harani

    2012-07-01

    Withaniasomnifera (Ashwaganda) belonging to the family solanaceae is the subject of our present study. Withanoloides which are the major chemical constituents have been proved of interest because of their structural variations in the hybrids of different races. Docking is the process which brings the two structures together. In the present study we focus the extensive use of tool and graphical software for the identification of the binding energy of selected Withanolides like Withaferin -A, Withanolide-D from Withaniasomnifera and to screen the phytoconstituents that will dock/bind to the active sites of COX-2 enzyme. The relief from the symptoms of inflammation and pain can be by the Pharmacological inhibition of COX which involves the prediction of potential ligand for the treatment of inflammation. The energy value of docking between the target and the phytoconstituents under investigation and comparison with Diclofenac sodium was taken into consideration for coming into conclusion regarding the best pose and the binding ability.

  1. Investigation of the Effect of Bilayer Composition on PKCα-C2 Domain Docking Using Molecular Dynamics Simulations.

    PubMed

    Alwarawrah, Mohammad; Wereszczynski, Jeff

    2017-01-12

    The protein kinase Cα (PKCα) enzyme is a member of a broad family of serine/threonine kinases, which are involved in varied cellular signaling pathways. The initial step of PKCα activation involves the C2 subunit docking with the cell membrane, which is followed by interactions of the C1 domains with diacylglycerol (DAG) in the membrane. Notably, the molecular mechanisms of these interactions remain poorly understood, especially what effects, if any, DAG may have on the initial C2 docking. To further understand this process, we have performed a series of conventional molecular dynamics simulations to systematically investigate the interaction between PKCα-C2 domains and lipid bilayers with different compositions to examine the effects of POPS, PIP2, and 1-palmitoyl-2-oleoyl-sn-glycerol (POG) on domain docking. Our results show that the PKCα-C2 domain does not interact with the bilayer surface in the absence of POPS and PIP2. In contrast, the inclusion of POPS and PIP2 to the bilayer resulted in strong domain docking in both perpendicular and parallel orientations, whereas the further inclusion of POG resulted in only parallel domain docking. In addition, lysine residues in the C2 domain formed hydrogen bonds with PIP2 molecule bilayers containing POG. These effects were further explored with umbrella sampling calculations to estimate the free energy of domain docking to the lipid bilayer in the presence of one or two PIP2 molecules. The results show that the binding of one or two PIP2 molecules is thermodynamically favorable, although stronger in bilayers lacking POG. However, in POG-containing bilayers, the binding mode of the C2 domain appears to be more flexible, which may have implications for activation of full-length PKCα. Together, our results shed new insights into the process of C2 bilayer binding and suggest new mechanisms for the roles of different phospholipids in the activation process of PKCα.

  2. Combined 3D-QSAR, molecular docking and molecular dynamics study on thyroid hormone activity of hydroxylated polybrominated diphenyl ethers to thyroid receptors β

    SciTech Connect

    Li, Xiaolin; Ye, Li; Wang, Xiaoxiang; Wang, Xinzhou; Liu, Hongling; Zhu, Yongliang; Yu, Hongxia

    2012-12-15

    Several recent reports suggested that hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disturb thyroid hormone homeostasis. To illuminate the structural features for thyroid hormone activity of HO-PBDEs and the binding mode between HO-PBDEs and thyroid hormone receptor (TR), the hormone activity of a series of HO-PBDEs to thyroid receptors β was studied based on the combination of 3D-QSAR, molecular docking, and molecular dynamics (MD) methods. The ligand- and receptor-based 3D-QSAR models were obtained using Comparative Molecular Similarity Index Analysis (CoMSIA) method. The optimum CoMSIA model with region focusing yielded satisfactory statistical results: leave-one-out cross-validation correlation coefficient (q{sup 2}) was 0.571 and non-cross-validation correlation coefficient (r{sup 2}) was 0.951. Furthermore, the results of internal validation such as bootstrapping, leave-many-out cross-validation, and progressive scrambling as well as external validation indicated the rationality and good predictive ability of the best model. In addition, molecular docking elucidated the conformations of compounds and key amino acid residues at the docking pocket, MD simulation further determined the binding process and validated the rationality of docking results. -- Highlights: ► The thyroid hormone activities of HO-PBDEs were studied by 3D-QSAR. ► The binding modes between HO-PBDEs and TRβ were explored. ► 3D-QSAR, molecular docking, and molecular dynamics (MD) methods were performed.

  3. Spectroscopic investigations, molecular interactions, and molecular docking studies on the potential inhibitor "thiophene-2-carboxylicacid"

    NASA Astrophysics Data System (ADS)

    Karthick, T.; Balachandran, V.; Perumal, S.

    2015-04-01

    Thiophene derivatives have been focused in the past decades due to their remarkable biological and pharmacological activities. In connection with that the conformational stability, spectroscopic characterization, molecular (inter- and intra-) interactions, and molecular docking studies on thiophene-2-carboxylicacid have been performed in this work by experimental FT-IR and theoretical quantum chemical computations. Experimentally recorded FT-IR spectrum in the region 4000-400 cm-1 has been compared with the scaled theoretical spectrum and the spectral peaks have been assigned on the basis of potential energy distribution results obtained from MOLVIB program package. The conformational stability of monomer and dimer conformers has been examined. The presence of inter- and intramolecular interactions in the monomer and dimer conformers have been explained by natural bond orbital analysis. The UV-Vis spectra of the sample in different solvents have been simulated and solvent effects were predicted by polarisable continuum model with TD-DFT/B3LYP/6-31+G(d,p) method. To test the biological activity of the sample, molecular docking (ligand-protein) simulations have been performed using SWISSDOCK web server. The full fitness (FF) score and binding affinity values revealed that thiophene-2-carboxylicacid can act as potential inhibitor against inflammation.

  4. Pharmacoinformatic and molecular docking studies reveal potential novel antidepressants against neurodegenerative disorders by targeting HSPB8

    PubMed Central

    Sehgal, Sheikh Arslan; Mannan, Shazia; Ali, Sannia

    2016-01-01

    Charcot–Marie–Tooth (CMT) disease is an inherited peripheral neuromuscular disorder characterized by length-dependent and progressive degeneration of peripheral nerves, leading to muscular weakness. Research has shown that mutated HSPB8 may be responsible for depression, neurodegenerative disorders, and improper functioning of peripheral nerves, resulting in neuromuscular disorders like CMT. In the current work, a hybrid approach of virtual screening and molecular docking studies was followed by homology modeling and pharmacophore identification. Detailed screening analyses were carried out by 2-D similarity search against prescribed antidepressant drugs with physicochemical properties. LigandScout was employed to ascertain novel molecules and pharmacophore properties. In this study, we report three novel compounds that showed maximum binding affinity with HSPB8. Docking analysis elucidated that Met37, Ser57, Ser58, Trp60, Thr63, Thr114, Lys115, Asp116, Gly117, Val152, Val154, Leu186, Asp189, Ser190, Gln191, and Glu192 are critical residues for ligand–receptor interactions. Our analyses suggested paroxetine as a potent compound for targeting HSPB8. Selected compounds have more effective energy scores than the selected drug analogs. Additionally, site-directed mutagenesis could be significant for further analysis of the binding pocket. The novel findings based on an in silico approach may be momentous for potent drug design against depression and CMT. PMID:27226709

  5. A spectroscopic and molecular docking approach on the binding of tinzaparin sodium with human serum albumin

    NASA Astrophysics Data System (ADS)

    Abdullah, Saleh M. S.; Fatma, Sana; Rabbani, Gulam; Ashraf, Jalaluddin M.

    2017-01-01

    Protein bound toxins are poorly removed by conventional extracorporeal therapies. Venous thromboembolism (VTE) is a major cause of morbidity and mortality in patients with cancer. The interaction between tinzaparin, an inhibitor of angiotensin converting enzyme and human serum albumin, a principal plasma protein in the liver has been investigated in vitro under a simulated physiological condition by UV-vis spectrophotometry and fluorescence spectrometry. The intrinsic fluorescence intensity of human serum albumin was strongly quenched by tinzaparin (TP). The binding constants and binding stoichiometry can be calculated from the data obtained from fluorescence quenching experiments. The negative value of ΔG° reveals that the binding process is a spontaneous process. Thermodynamic analysis shows that the HSA-TP complex formation occurs via hydrogen bonds, hydrophobic interactions and undergoes slight structural changes as evident by far-UV CD. It indicated that the hydrophobic interactions play a main role in the binding of TP to human serum albumin. In addition, the distance between TP (acceptor) and tryptophan residues of human serum albumin (donor) was estimated to be 2.21 nm according to the Förster's resonance energy transfer theory. For the deeper understanding of the interaction, thermodynamic, and molecular docking studies were performed as well. Our docking results suggest that TP forms stable complex with HSA (Kb ∼ 104) and its primary binding site is located in subdomain IIA (Sudlow Site I). The results obtained herein will be of biological significance in pharmacology and clinical medicine.

  6. Combining pharmacophore search, automated docking, and molecular dynamics simulations as a novel strategy for flexible docking. Proof of concept: docking of arginine-glycine-aspartic acid-like compounds into the alphavbeta3 binding site.

    PubMed

    Moitessier, Nicolas; Henry, Christophe; Maigret, Bernard; Chapleur, Yves

    2004-08-12

    A novel and highly efficient flexible docking approach is presented where the conformations (internal degrees of freedom) and orientations (external degrees of freedom) of the ligands are successively considered. This hybrid method takes advantage of the synergistic effects of structure-based and ligand-based drug design techniques. Preliminary antagonist-derived pharmacophore determination provides the postulated bioactive conformation. Subsequent docking of this pharmacophore to the receptor crystal structure results in a postulated pharmacophore/receptor binding mode. Pharmacophore-oriented docking of antagonists is subsequently achieved by matching ligand interacting groups with pharmacophore points. Molecular dynamics in water refines the proposed complexes. To validate the method, arginine-glycine-aspartic acid (RGD) containing peptides, pseudopeptides, and RGD-like antagonists were docked to the crystal structure of alphavbeta3 holoprotein and apoprotein. The proposed directed docking was found to be more accurate, faster, and less biased with respect to the protein structure (holo and apoprotein) than DOCK, Autodock, and FlexX docking methods. The successful docking of an antagonist recently cocrystallized with the receptor to both apo and holoprotein is particularly appealing. The results summarized in this report illustrated the efficiency of our light CoMFA/rigid body docking hybrid method.

  7. Identification of Potential Herbal Inhibitor of Acetylcholinesterase Associated Alzheimer's Disorders Using Molecular Docking and Molecular Dynamics Simulation

    PubMed Central

    Seniya, Chandrabhan; Khan, Ghulam Jilani; Uchadia, Kuldeep

    2014-01-01

    Cholinesterase inhibitors (ChE-Is) are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA). Additionally, acetylcholinesterase (AChE) is the target for many Alzheimer's dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000 ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6) to AChE. Further, molecular dynamics simulations for 1000 ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential. PMID:25054066

  8. Identification of potential herbal inhibitor of acetylcholinesterase associated Alzheimer's disorders using molecular docking and molecular dynamics simulation.

    PubMed

    Seniya, Chandrabhan; Khan, Ghulam Jilani; Uchadia, Kuldeep

    2014-01-01

    Cholinesterase inhibitors (ChE-Is) are the standard for the therapy of AD associated disorders and are the only class of approved drugs by the Food and Drug Administration (FDA). Additionally, acetylcholinesterase (AChE) is the target for many Alzheimer's dementia drugs which block the function of AChE but have some side effects. Therefore, in this paper, an attempt was made to elucidate cholinesterase inhibition potential of secondary metabolite from Cannabis plant which has negligible or no side effect. Molecular docking of 500 herbal compounds, against AChE, was performed using Autodock 4.2 as per the standard protocols. Molecular dynamics simulations have also been carried out to check stability of binding complex in water for 1000 ps. Our molecular docking and simulation have predicted high binding affinity of secondary metabolite (C28H34N2O6) to AChE. Further, molecular dynamics simulations for 1000 ps suggest that ligand interaction with the residues Asp72, Tyr70-121-334, and Phe288 of AChE, all of which fall under active site/subsite or binding pocket, might be critical for the inhibitory activity of AChE. This approach might be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer's disease. The study provides evidence for consideration of C28H34N2O6 as a valuable small ligand molecule in treatment and prevention of AD associated disorders and further in vitro and in vivo investigations may prove its therapeutic potential.

  9. Exploring binding properties of naringenin with bovine β-lactoglobulin: a fluorescence, molecular docking and molecular dynamics simulation study.

    PubMed

    Gholami, Samira; Bordbar, Abdol-Khalegh

    2014-01-01

    In the present study, the binding properties of naringenin (NG) to β-lactoglobulin (BLG) were explored using spectrofluorimetric and molecular modeling techniques. Analysis of spectrofluorimetric titration data represented the formation of 1:1 complex, significant binding affinity, negative values of entropy and enthalpy changes and the essential role of hydrogen bonding and van der Waals interactions in binding of NG to BLG. The value of determined Förster's distance represents the static mechanism for quenching of BLG by NG. The results of fluorescence competitive binding experiments characterize the location of NG binding site in the outer surface of BLG. Molecular docking study showed that NG binds in the outer surface site of BLG which is accompanied with three hydrogen bonds. The support of molecular docking results by biochemical fluorescence experiments confirms the validity of docking calculation. Analysis of molecular dynamics results indicated that NG can interact with BLG without affecting the secondary structure of protein.

  10. Synthesis, molecular docking and antiamnesic activity of selected 2- naphthyloxy derivatives.

    PubMed

    Piplani, Poonam; Singh, Paramveer; Sharma, Anuradha

    2013-05-01

    The present paper describes the design and synthesis of a series of some 2-naphthyloxy derivatives with their antiamnesic activity using mice as the animal model and piracetam as the reference drug. All the synthesized compounds were characterized by spectroscopic techniques and were screened for their efficacy as cognition enhancers by elevated plus maze test and acetylcholinestrase inhibitory assay. Molecular modeling and docking studies of the selected compounds into the crystal structure of acetylcholinestrase complexed with functional ligand succinylcholine using GRAMM software was performed in order to predict the affinity and orientation of the synthesized derivatives at the active site. The binding energy of ligands was calculated using ArgusLab software. The docking score and hydrogen bonds formed with surrounding amino acids show the good agreement with predicted binding affinities obtained by molecular docking studies, as verified by acetylcholinestrase activity.

  11. A real-time proximity querying algorithm for haptic-based molecular docking.

    PubMed

    Iakovou, Georgios; Hayward, Steven; Laycock, Stephen

    2014-01-01

    Intermolecular binding underlies every metabolic and regulatory processes of the cell, and the therapeutic and pharmacological properties of drugs. Molecular docking systems model and simulate these interactions in silico and allow us to study the binding process. Haptic-based docking provides an immersive virtual docking environment where the user can interact with and guide the molecules to their binding pose. Moreover, it allows human perception, intuition and knowledge to assist and accelerate the docking process, and reduces incorrect binding poses. Crucial for interactive docking is the real-time calculation of interaction forces. For smooth and accurate haptic exploration and manipulation, force-feedback cues have to be updated at a rate of 1 kHz. Hence, force calculations must be performed within 1 ms. To achieve this, modern haptic-based docking approaches often utilize pre-computed force grids and linear interpolation. However, such grids are time-consuming to pre-compute (especially for large molecules), memory hungry, can induce rough force transitions at cell boundaries and cannot be applied to flexible docking. Here we propose an efficient proximity querying method for computing intermolecular forces in real time. Our motivation is the eventual development of a haptic-based docking solution that can model molecular flexibility. Uniquely in a haptics application we use octrees to decompose the 3D search space in order to identify the set of interacting atoms within a cut-off distance. Force calculations are then performed on this set in real time. The implementation constructs the trees dynamically, and computes the interaction forces of large molecular structures (i.e. consisting of thousands of atoms) within haptic refresh rates. We have implemented this method in an immersive, haptic-based, rigid-body, molecular docking application called Haptimol_RD. The user can use the haptic device to orientate the molecules in space, sense the interaction

  12. Cosolvent-Based Molecular Dynamics for Ensemble Docking: Practical Method for Generating Druggable Protein Conformations.

    PubMed

    Uehara, Shota; Tanaka, Shigenori

    2017-04-07

    Protein flexibility is a major hurdle in current structure-based virtual screening (VS). In spite of the recent advances in high-performance computing, protein-ligand docking methods still demand tremendous computational cost to take into account the full degree of protein flexibility. In this context, ensemble docking has proven its utility and efficiency for VS studies, but it still needs a rational and efficient method to select and/or generate multiple protein conformations. Molecular dynamics (MD) simulations are useful to produce distinct protein conformations without abundant experimental structures. In this study, we present a novel strategy that makes use of cosolvent-based molecular dynamics (CMD) simulations for ensemble docking. By mixing small organic molecules into a solvent, CMD can stimulate dynamic protein motions and induce partial conformational changes of binding pocket residues appropriate for the binding of diverse ligands. The present method has been applied to six diverse target proteins and assessed by VS experiments using many actives and decoys of DEKOIS 2.0. The simulation results have revealed that the CMD is beneficial for ensemble docking. Utilizing cosolvent simulation allows the generation of druggable protein conformations, improving the VS performance compared with the use of a single experimental structure or ensemble docking by standard MD with pure water as the solvent.

  13. Vibrational spectroscopic, molecular docking and density functional theory studies on 2-acetylamino-5-bromo-6-methylpyridine.

    PubMed

    Premkumar, S; Rekha, T N; Mohamed Asath, R; Mathavan, T; Milton Franklin Benial, A

    2016-01-20

    Conformational and molecular docking analysis of 2-acetylamino-5-bromo-6-methylpyridine molecule was carried out and the vibrational spectral analysis was also carried out using experimental and theoretical methods. The calculated and experimentally observed vibrational frequencies of the molecule were assigned and compared. The pyridine ring CH stretching and CH3 stretching vibrational modes were shifted towards higher wavenumber (blue shift). The C=O stretching vibrational frequency was shifted towards lower wavenumber (red shift). Ultraviolet-visible spectrum of the molecule simulated theoretically was further validated experimentally. Molecular reactivity and stability were investigated using the frontier molecular orbital analysis and the related quantum chemical molecular properties. Natural bond orbital analysis and the structure activity relations were also studied to confirm the bioactivity of the molecule. Anticancer activity was examined based on molecular docking analysis and it has been identified that the AABMP molecule can act as a good inhibitor against lung cancer.

  14. Molecular Docking of Enzyme Inhibitors: A Computational Tool for Structure-Based Drug Design

    ERIC Educational Resources Information Center

    Rudnitskaya, Aleksandra; Torok, Bela; Torok, Marianna

    2010-01-01

    Molecular docking is a frequently used method in structure-based rational drug design. It is used for evaluating the complex formation of small ligands with large biomolecules, predicting the strength of the bonding forces and finding the best geometrical arrangements. The major goal of this advanced undergraduate biochemistry laboratory exercise…

  15. Molecular Docking Studies to Explore Potential Binding Pockets and Inhibitors for Chikungunya Virus Envelope Glycoproteins.

    PubMed

    Nguyen, Phuong T V; Yu, Haibo; Keller, Paul A

    2017-03-11

    The chikungunya virus (CHIKV) envelope glycoproteins are considered important potential targets for anti-CHIKV drug discovery due to their crucial roles in virus attachment and virus entry. In this study, using two available crystal structures of the immature and mature forms of envelope glycoproteins, virtual screenings based on blind dockings and focused dockings were carried out to identify potential binding pockets and hit compounds for the virus. The chemical library database of compounds, NCI Diversity Set II, was used in these docking studies. In addition to reproducing previously reported examples, new binding pockets were identified, e.g., Pocket 2 in the 3N40, and Pocket 2 and Pocket 3 in the 3N42. Convergences in conformational sampling in docking using AutoDock Vina were evaluated. An analysis of docking results was carried out to understand interactions of the envelope glycoproteins complexes. Some key residues for interactions, for example Gly91 and His230, are identified as possessing important roles in the fusion process.

  16. Adaptive GPU-accelerated force calculation for interactive rigid molecular docking using haptics.

    PubMed

    Iakovou, Georgios; Hayward, Steven; Laycock, Stephen D

    2015-09-01

    Molecular docking systems model and simulate in silico the interactions of intermolecular binding. Haptics-assisted docking enables the user to interact with the simulation via their sense of touch but a stringent time constraint on the computation of forces is imposed due to the sensitivity of the human haptic system. To simulate high fidelity smooth and stable feedback the haptic feedback loop should run at rates of 500Hz to 1kHz. We present an adaptive force calculation approach that can be executed in parallel on a wide range of Graphics Processing Units (GPUs) for interactive haptics-assisted docking with wider applicability to molecular simulations. Prior to the interactive session either a regular grid or an octree is selected according to the available GPU memory to determine the set of interatomic interactions within a cutoff distance. The total force is then calculated from this set. The approach can achieve force updates in less than 2ms for molecular structures comprising hundreds of thousands of atoms each, with performance improvements of up to 90 times the speed of current CPU-based force calculation approaches used in interactive docking. Furthermore, it overcomes several computational limitations of previous approaches such as pre-computed force grids, and could potentially be used to model receptor flexibility at haptic refresh rates.

  17. Molecular docking of Glycine max and Medicago truncatula ureases with urea; bioinformatics approaches.

    PubMed

    Filiz, Ertugrul; Vatansever, Recep; Ozyigit, Ibrahim Ilker

    2016-03-01

    Urease (EC 3.5.1.5) is a nickel-dependent metalloenzyme catalyzing the hydrolysis of urea into ammonia and carbon dioxide. It is present in many bacteria, fungi, yeasts and plants. Most species, with few exceptions, use nickel metalloenzyme urease to hydrolyze urea, which is one of the commonly used nitrogen fertilizer in plant growth thus its enzymatic hydrolysis possesses vital importance in agricultural practices. Considering the essentiality and importance of urea and urease activity in most plants, this study aimed to comparatively investigate the ureases of two important legume species such as Glycine max (soybean) and Medicago truncatula (barrel medic) from Fabaceae family. With additional plant species, primary and secondary structures of 37 plant ureases were comparatively analyzed using various bioinformatics tools. A structure based phylogeny was constructed using predicted 3D models of G. max and M. truncatula, whose crystallographic structures are not available, along with three additional solved urease structures from Canavalia ensiformis (PDB: 4GY7), Bacillus pasteurii (PDB: 4UBP) and Klebsiella aerogenes (PDB: 1FWJ). In addition, urease structures of these species were docked with urea to analyze the binding affinities, interacting amino acids and atom distances in urease-urea complexes. Furthermore, mutable amino acids which could potentially affect the protein active site, stability and flexibility as well as overall protein stability were analyzed in urease structures of G. max and M. truncatula. Plant ureases demonstrated similar physico-chemical properties with 833-878 amino acid residues and 89.39-90.91 kDa molecular weight with mainly acidic (5.15-6.10 pI) nature. Four protein domain structures such as urease gamma, urease beta, urease alpha and amidohydro 1 characterized the plant ureases. Secondary structure of plant ureases also demonstrated conserved protein architecture, with predominantly α-helix and random coil structures. In

  18. Molecular docking and dynamics simulation study of flavonoids as BET bromodomain inhibitors.

    PubMed

    Raj, Utkarsh; Kumar, Himansu; Varadwaj, Pritish Kumar

    2016-08-05

    Bromodomains (BRDs) are the epigenetic proteins responsible for transcriptional regulation through its interaction with methylated or acetylated histone residues. The lysine residues of Bromodomain-1 (BD1) of Brd4 undergo ε-N-Acetylation posttranslational modifications to control transcription of genes. Due to its role in diverse cellular functions, Brd4 of bromodomain family, was considered as a prominent target for many diseases such as cancer, obesity, kidney disease, lung fibrosis, inflammatory diseases, etc. In this study, an attempt has been made to screen compounds from flavonoids and extended flavonoids libraries targeting acetylated lysine (KAc) binding site of BD1 of Brd4 using docking and molecular dynamics simulations. Two different docking programs AutoDock and Glide were used to compare their suitability for the receptor. Interestingly, in both the docking programs, the screened flavonoids have occupied the same binding pocket confirming the selection of active site. Further the MMGBSA binding free energy calculations and ADME analysis were carried out on screened compounds to establish their anti-cancerous properties. We have identified a flavonoid which shows docking and Glide e-model score comparatively much higher than those of already reported known inhibitors against Brd4. The protein-ligand complex with top-ranked flavonoid was used for dynamics simulation study for 50 ns in order to validate its stability inside the active site of Brd4 receptor. The results provide valuable information for structure-based drug design of Brd4 inhibitors.

  19. Molecular Docking, Molecular Dynamics Simulations, Computational Screening to Design Quorum Sensing Inhibitors Targeting LuxP of Vibrio harveyi and Its Biological Evaluation.

    PubMed

    Rajamanikandan, Sundaraj; Jeyakanthan, Jeyaraman; Srinivasan, Pappu

    2017-01-01

    Quorum sensing (QS) plays an important role in the biofilm formation, production of virulence factors and stress responses in Vibrio harveyi. Therefore, interrupting QS is a possible approach to modulate bacterial behavior. In the present study, three docking protocols, such as Rigid Receptor Docking (RRD), Induced Fit Docking (IFD), and Quantum Polarized Ligand Docking (QPLD) were used to elucidate the binding mode of boronic acid derivatives into the binding pocket of LuxP protein in V. harveyi. Among the three docking protocols, IFD accurately predicted the correct binding mode of the studied inhibitors. Molecular dynamics (MD) simulations of the protein-ligand complexes indicates that the inter-molecular hydrogen bonds formed between the protein and ligand complex remains stable during the simulation time. Pharmacophore and shape-based virtual screening were performed to find selective and potent compounds from ChemBridge database. Five hit compounds were selected and subjected to IFD and MD simulations to validate the binding mode. In addition, enrichment calculation was performed to discriminate and separate active compounds from the inactive compounds. Based on the computational studies, the potent Bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic acid-2,6-dimethylpyridine 1-oxide (ChemBridge_5144368) was selected for in vitro assays. The compound exhibited dose dependent inhibition in bioluminescence and also inhibits biofilm formation in V. harveyi to the level of 64.25 %. The result from the study suggests that ChemBridge_5144368 could serve as an anti-quorum sensing molecule for V. harveyi.

  20. Interaction of prometryn to human serum albumin: insights from spectroscopic and molecular docking studies.

    PubMed

    Wang, Yaping; Zhang, Guowen; Wang, Langhong

    2014-01-01

    Prometryn possesses much potential hazard to environment because of its chemical stability and biological toxicity. Here, the binding properties of prometryn with human serum albumin (HSA) and the protein structural changes were determined under simulative physiological conditions (pH 7.4) by multispectroscopic methods including fluorescence, UV-vis absorption, Fourier transform infrared (FT-IR) and circular dichroism (CD) spectroscopy, coupled with molecular modeling technique. The result of fluorescence titration suggested that the fluorescence quenching of HSA by prometryn was considered as a static quenching procedure. The negative enthalpy change (ΔH(○)) and positive entropy change (ΔS(○)) values indicated that the binding process was governed mainly by hydrophobic interactions and hydrogen bonds. The site marker displacement experiments suggested the location of prometryn binding to HSA was Sudlow's site I in subdomain IIA. Furthermore, molecular docking studies revealed prometryn can bind in the large hydrophobic activity of subdomain IIA. Analysis of UV-vis absorption, synchronous fluorescence, CD and FT-IR spectra demonstrated that the addition of prometryn resulted in rearrangement and conformational alteration of HSA with reduction in α-helix and increases in β-sheet, β-turn and random coil structures. This work provided reasonable model helping us further understand the transportation, distribution and toxicity effect of prometryn when it spreads into human blood serum.

  1. Interaction study of ciprofloxacin with human telomeric DNA by spectroscopy and molecular docking

    NASA Astrophysics Data System (ADS)

    Li, Huihui; Bu, Xiaoyang; Lu, Jia; Xu, Chongzheng; Wang, Xianlong; Yang, Xiaodi

    2013-04-01

    The interaction of ciprofloxacin (CIP) with human telomeric DNA was studied in vitro using multi-spectroscopy and molecular modeling methods. The hypochromic effect with a red shift in ultraviolet (UV) absorption indicated the occurrence of the interaction between CIP and DNA. The fluorescence quenching of CIP was observed with the addition of DNA and was proved to be the static quenching. The binding constant was found to be 9.62 × 104 L mol-1. Electrospray ionization mass spectrometry (ESI-MS) result further confirmed the formation of 1:1 non-covalent complex between DNA and CIP. Combined with the UV melting results, circular dichroism (CD) results confirmed the existence of groove binding mode, as well as conformational changes of DNA. Molecular docking studies illustrated the visual display of the CIP binding to the GC region in the minor groove of DNA. Specific hydrogen bonds and van der Waals forces were demonstrated as main acting forces between CIP and guanine bases of DNA.

  2. Binding of copper to lysozyme: Spectroscopic, isothermal titration calorimetry and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Jing, Mingyang; Song, Wei; Liu, Rutao

    2016-07-01

    Although copper is essential to all living organisms, its potential toxicity to human health have aroused wide concerns. Previous studies have reported copper could alter physical properties of lysozyme. The direct binding of copper with lysozyme might induce the conformational and functional changes of lysozyme and then influence the body's resistance to bacterial attack. To better understand the potential toxicity and toxic mechanisms of copper, the interaction of copper with lysozyme was investigated by biophysical methods including multi-spectroscopic measurements, isothermal titration calorimetry (ITC), molecular docking study and enzyme activity assay. Multi-spectroscopic measurements proved that copper quenched the intrinsic fluorescence of lysozyme in a static process accompanied by complex formation and conformational changes. The ITC results indicated that the binding interaction was a spontaneous process with approximately three thermodynamical binding sites at 298 K and the hydrophobic force is the predominant driven force. The enzyme activity was obviously inhibited by the addition of copper with catalytic residues Glu 35 and Asp 52 locating at the binding sites. This study helps to elucidate the molecular mechanism of the interaction between copper and lysozyme and provides reference for toxicological studies of copper.

  3. Docking of Secretory Vesicles Is Syntaxin Dependent

    PubMed Central

    de Wit, Heidi; Cornelisse, L. Niels; Toonen, Ruud F.G.; Verhage, Matthijs

    2006-01-01

    Secretory vesicles dock at the plasma membrane before they undergo fusion. Molecular docking mechanisms are poorly defined but believed to be independent of SNARE proteins. Here, we challenged this hypothesis by acute deletion of the target SNARE, syntaxin, in vertebrate neurons and neuroendocrine cells. Deletion resulted in fusion arrest in both systems. No docking defects were observed in synapses, in line with previous observations. However, a drastic reduction in morphologically docked secretory vesicles was observed in chromaffin cells. Syntaxin-deficient chromaffin cells showed a small reduction in total and plasma membrane staining for the docking factor Munc18-1, which appears insufficient to explain the drastic reduction in docking. The sub-membrane cortical actin network was unaffected by syntaxin deletion. These observations expose a docking role for syntaxin in the neuroendocrine system. Additional layers of regulation may have evolved to make syntaxin redundant for docking in highly specialized systems like synaptic active zones. PMID:17205130

  4. Spectroscopy and molecular docking study on the interaction behavior between nobiletin and pepsin.

    PubMed

    Zeng, Hua-jin; Qi, Tingting; Yang, Ran; You, Jing; Qu, Ling-bo

    2014-07-01

    In this study, the binding mode of nobiletin (NOB) with pepsin was investigated by spectroscopic and molecular docking methods. NOB can interact with pepsin to form a NOB-pepsin complex. The binding constant, number of binding sites and thermodynamic parameters were measured, which indicated that NOB could spontaneously bind with pepsin through hydrophobic and electrostatic forces with one binding site. Molecular docking results revealed that NOB bound into the pepsin cavity. Synchronous and three-dimensional fluorescence spectra results provide data concerning conformational and some micro-environmental changes of pepsin. Furthermore, the binding of NOB can inhibit pepsin activity in vitro. The present study provides direct evidence at a molecular level to show that NOB could induce changes in the enzyme pepsin structure and function.

  5. Investigation on the binding interaction between silybin and pepsin by spectral and molecular docking.

    PubMed

    Zeng, Hua-jin; You, Jing; Liang, Hui-li; Qi, Tingting; Yang, Ran; Qu, Ling-bo

    2014-06-01

    In this study, the binding mode of silybin with pepsin was investigated by spectroscopic and molecular docking methods. Silybin can interact with pepsin to form a silybin-pepsin complex. The binding constant, number of binding sites and thermodynamic parameters were measured, which indicated that silybin could spontaneously bind with pepsin mainly through hydrophobic interaction with one binding site. Molecular docking results revealed that silybin bound into the pepsin cavity site. Synchronous fluorescence and three-dimensional fluorescence results provide data concerning conformational and some micro-environmental changes of pepsin. Furthermore, in order to reveal whether the binding process can inhibit the activity of pepsin in vivo, the effect of silybin on pepsin activity in rat was investigated. The present study provides direct evidence at a molecular level to show that exposure to silybin could induce changes in the enzyme pepsin structure and function.

  6. Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study

    PubMed Central

    Antony, Priya; Vijayan, Ranjit

    2015-01-01

    Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors. PMID:26384019

  7. Identification of Novel Aldose Reductase Inhibitors from Spices: A Molecular Docking and Simulation Study.

    PubMed

    Antony, Priya; Vijayan, Ranjit

    2015-01-01

    Hyperglycemia in diabetic patients results in a diverse range of complications such as diabetic retinopathy, neuropathy, nephropathy and cardiovascular diseases. The role of aldose reductase (AR), the key enzyme in the polyol pathway, in these complications is well established. Due to notable side-effects of several drugs, phytochemicals as an alternative has gained considerable importance for the treatment of several ailments. In order to evaluate the inhibitory effects of dietary spices on AR, a collection of phytochemicals were identified from Zingiber officinale (ginger), Curcuma longa (turmeric) Allium sativum (garlic) and Trigonella foenum graecum (fenugreek). Molecular docking was performed for lead identification and molecular dynamics simulations were performed to study the dynamic behaviour of these protein-ligand interactions. Gingerenones A, B and C, lariciresinol, quercetin and calebin A from these spices exhibited high docking score, binding affinity and sustained protein-ligand interactions. Rescoring of protein ligand interactions at the end of MD simulations produced binding scores that were better than the initially docked conformations. Docking results, ligand interactions and ADMET properties of these molecules were significantly better than commercially available AR inhibitors like epalrestat, sorbinil and ranirestat. Thus, these natural molecules could be potent AR inhibitors.

  8. Identifying Potential Protein Targets for Toluene Using a Molecular Similarity Search, in Silico Docking and in Vitro Validation

    DTIC Science & Technology

    2015-01-01

    the applicability of an exploratory in silico toxicity tool, based on a molecular similarity search and protein-ligand docking for identification of...toluene-induced aggregation. These results demonstrate the applicability of an exploratory in silico toxicity tool, based on a molecular simi- larity... Molecular Similarity Search, in Silico Docking and in Vitro Validation 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6

  9. Molecular dynamics simulation of a myosin subfragment-1 docking with an actin filament.

    PubMed

    Masuda, Tadashi

    2013-09-01

    Myosins are typical molecular motor proteins, which convert the chemical energy of ATP into mechanical work. The fundamental mechanism of this energy conversion is still unknown. To explain the experimental results observed in molecular motors, Masuda has proposed a theory called the "Driven by Detachment (DbD)" mechanism for the working principle of myosins. Based on this theory, the energy used during the power stroke of the myosins originates from the attractive force between a detached myosin head and an actin filament, and does not directly arise from the energy of ATP. According to this theory, every step in the myosin working process may be reproduced by molecular dynamics (MD) simulations, except for the ATP hydrolysis step. Therefore, MD simulations were conducted to reproduce the docking process of a myosin subfragment-1 (S1) against an actin filament. A myosin S1 directed toward the barbed end of an actin filament was placed at three different positions by shifting it away from the filament axis. After 30 ns of MD simulations, in three cases out of ten trials on average, the myosin made a close contact with two actin monomers by changing the positions and the orientation of both the myosin and the actin as predicted in previous studies. Once the docking was achieved, the distance between the myosin and the actin showed smaller fluctuations, indicating that the docking is stable over time. If the docking was not achieved, the myosin moved randomly around the initial position or moved away from the actin filament. MD simulations thus successfully reproduced the docking of a myosin S1 with an actin filament. By extending the similar MD simulations to the other steps of the myosin working process, the validity of the DbD theory may be computationally demonstrated.

  10. Vibrational spectroscopic analysis, molecular dynamics simulations and molecular docking study of 5-nitro-2-phenoxymethyl benzimidazole

    NASA Astrophysics Data System (ADS)

    Menon, Vidya V.; Foto, Egemen; Mary, Y. Sheena; Karatas, Esin; Panicker, C. Yohannan; Yalcin, Gözde; Armaković, Stevan; Armaković, Sanja J.; Van Alsenoy, C.; Yildiz, Ilkay

    2017-02-01

    FT-IR and FT-Raman spectra of 5-nitro-2-phenoxymethylbenzimidazole were recorded and analyzed theoretically and experimentally. The splitting of Nsbnd H stretching mode in the IR spectrum with a red shift from the calculated value indicates the weakening of the NH bond. The theoretical calculations give the phenyl ring breathing modes at 999 cm-1 for mono substituted benzene ring and at 1040 cm-1 for tri-substituted benzene ring. The theoretical NMR chemical shifts are in agreement with the experimental chemical shifts. The most reactive sites for electrophilic and nucleophilic attack are predicted from the MEP analysis. HOMO of π nature is delocalized over the entire molecule whereas the LUMO is located over the complete molecule except mono-substituted phenyl ring and oxygen atom. Reactive sites of the title molecule have been located with the help of ALIE surfaces and Fukui functions. In order to determine locations prone to autoxidation and locations interesting for starting of degradation, bond dissociation energies have been calculated for all single acyclic bonds. For the determination of atoms with pronounced interactions with water we have calculated radial distribution functions obtained after molecular dynamics simulations. The calculated first hyperpolarizability of the title compound is 58.03 times that of standard nonlinear optical material urea. The substrate binding site interactions of the title compound with Topo II enzyme is reported by using molecular docking study. Biological activity studies show that the title compound can be leaded for developing new anticancer agents.

  11. Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking

    NASA Astrophysics Data System (ADS)

    Tsvetkov, Vladimir B.; Serbin, Alexander V.

    2014-06-01

    In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 ( HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [ HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics ( MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.

  12. Flavanoids as Potential NEDD-4 Inhibitors: In Silico Discovery Using Molecular Docking and ADME Studies.

    PubMed

    Chaudhary, Kamal Kumar; Gupta, Sarvesh Kumar; Mishra, Nidhi

    2017-03-01

    NEDD-4 are closely related E3 ubiquitin-protein ligases that include a C2 domain, three or four WW domains and a catalytic HECT ubiquitin ligase domain. The WW domains of NEDD-4 proteins recognize substrates for ubiquitination by binding the sequence L/PPxY (the PY-motif) present in target proteins. NEDD-4 functions as a suppressor of the epithelial Na+ channel (ENaC), which interacts with NEDD-4 WW domains via PY-motifs located at its C-terminus. Fifty compounds, all of them flavanoids, were subjected to molecular docking studies. The chemical structures were built, and docking studies were done using Schrodinger. ADMET studies were also performed. Furthermore, evidence is presented suggesting that interaction between NEDD-4 and the selected compounds from the database may also serve to regulate NEDD-4 stability, as this interaction leads to decreased NEDD-4 self-ubiquitination. Collectively, the studies presented here further our understanding of the substrate specificity and regulation of NEDD-4. We have performed molecular docking and molecular dynamics simulation to study the interactions. The results of molecular dynamics simulation confirmed the binding mode of compounds.

  13. Molecular Modeling on Berberine Derivatives toward BuChE: An Integrated Study with Quantitative Structure-Activity Relationships Models, Molecular Docking, and Molecular Dynamics Simulations.

    PubMed

    Fang, Jiansong; Pang, Xiaocong; Wu, Ping; Yan, Rong; Gao, Li; Li, Chao; Lian, Wenwen; Wang, Qi; Liu, Ai-lin; Du, Guan-hua

    2016-05-01

    A dataset of 67 berberine derivatives for the inhibition of butyrylcholinesterase (BuChE) was studied based on the combination of quantitative structure-activity relationships models, molecular docking, and molecular dynamics methods. First, a series of berberine derivatives were reported, and their inhibitory activities toward butyrylcholinesterase (BuChE) were evaluated. By 2D- quantitative structure-activity relationships studies, the best model built by partial least-square had a conventional correlation coefficient of the training set (R(2)) of 0.883, a cross-validation correlation coefficient (Qcv2) of 0.777, and a conventional correlation coefficient of the test set (Rpred2) of 0.775. The model was also confirmed by Y-randomization examination. In addition, the molecular docking and molecular dynamics simulation were performed to better elucidate the inhibitory mechanism of three typical berberine derivatives (berberine, C2, and C55) toward BuChE. The predicted binding free energy results were consistent with the experimental data and showed that the van der Waals energy term (ΔEvdw) difference played the most important role in differentiating the activity among the three inhibitors (berberine, C2, and C55). The developed quantitative structure-activity relationships models provide details on the fine relationship linking structure and activity and offer clues for structural modifications, and the molecular simulation helps to understand the inhibitory mechanism of the three typical inhibitors. In conclusion, the results of this study provide useful clues for new drug design and discovery of BuChE inhibitors from berberine derivatives.

  14. Impact of Aromatase protein variants and drug interactions in breast cancer: a molecular docking approach.

    PubMed

    Setti, Aravind; Venugopal Rao, V; Priyamvada Devi, A; Pawar, Smita C; Naresh, B; Kalyan, C S V V

    2012-08-01

    Breast cancer is a frequently reported cancer in women all over the world. Several methods available to cure the breast cancer based on stage. This study focused on chemoprevention drugs of Aromatase, a potential target in breast cancer. Natural variants of Aromatase are very common; they have been collected and modeled, optimized the energy of mutated Aromatase protein. Reversible (Anastrozole) and irreversible (Exemestane) Aromatase inhibitors are selected and performed molecular docking studies of each drug against each variant to see the binding affinity impact on protein variant and drugs. In this comparative study, Anastrozole, a cumene derivative showed more binding affinity and Diethylstilbestrol showed weak binding affinity against among all drugs. The comparative molecular docking revealed that the binding affinity between drug and Aromatase protein variant is imprecise but fairly close; therefore the protein variants of Aromatase can be conceived to be equal for chemoprevention of breast cancer therapy.

  15. Synthesis, In Vivo Anti-Inflammatory Activity, and Molecular Docking Studies of New Isatin Derivatives

    PubMed Central

    Jarapula, Ravi; Gangarapu, Kiran; Manda, Sarangapani; Rekulapally, Sriram

    2016-01-01

    A novel synthesis of 2-hydroxy-N′-(2-oxoindolin-3-ylidene) benzohydrazide derivatives was synthesized by the condensation of 2-hydroxybenzohydrazide with substituted isatins. The synthesized compounds were characterized by FT-IR, 1H-NMR, and mass spectral data. Further, the compounds were screened for in vivo anti-inflammatory activity by carrageenan induced paw edema method. The tested compounds have shown mild-to-moderate anti-inflammatory activity. The compounds VIIc and VIId exhibited 65% and 63% of paw edema reduction, respectively. The molecular docking studies were also carried out into the active site of COX-1 and COX-2 enzymes (PDB ID: 3N8Y, 3LN1, resp.) using VLife MDS 4.3. The compounds VIIc, VIId, and VIIf exhibited good docking scores of −57.27, −62.02, and −58.18 onto the active site of COX-2 and least dock scores of −8.03, −9.17, and −8.94 on COX-1 enzymes and were comparable with standard COX-2 inhibitor celecoxib. A significant correlation was observed between the in silico and the in vivo studies. The anti-inflammatory and docking results highlight the fact that the synthesized compounds VIIc, VIId, and VIIf could be considered as possible hit as therapeutic agents. PMID:27022484

  16. Febrifugine analogues as Leishmania donovani trypanothione reductase inhibitors: binding energy analysis assisted by molecular docking, ADMET and molecular dynamics simulation.

    PubMed

    Pandey, Rajan Kumar; Kumbhar, Bajarang Vasant; Srivastava, Shubham; Malik, Ruchi; Sundar, Shyam; Kunwar, Ambarish; Prajapati, Vijay Kumar

    2017-01-01

    Visceral leishmaniasis affects people from 70 countries worldwide, mostly from Indian, African and south American continent. The increasing resistance to antimonial, miltefosine and frequent toxicity of amphotericin B drives an urgent need to develop an antileishmanial drug with excellent efficacy and safety profile. In this study we have docked series of febrifugine analogues (n = 8813) against trypanothione reductase in three sequential docking modes. Extra precision docking resulted into 108 ligands showing better docking score as compared to two reference ligand. Furthermore, 108 febrifugine analogues and reference inhibitor clomipramine were subjected to ADMET, QikProp and molecular mechanics, the generalized born model and solvent accessibility study to ensure the toxicity caused by compounds and binding-free energy, respectively. Two best ligands (FFG7 and FFG2) qualifying above screening parameters were further subjected to molecular dynamics simulation. Conducting these studies, here we confirmed that 6-chloro-3-[3-(3-hydroxy-2-piperidyl)-2-oxo-propyl]-7-(4-pyridyl) quinazolin-4-one can be potential drug candidate to fight against Leishmania donovani parasites.

  17. Characterization of interaction of calf thymus DNA with gefitinib: spectroscopic methods and molecular docking.

    PubMed

    Shi, Jie-Hua; Liu, Ting-Ting; Jiang, Min; Chen, Jun; Wang, Qi

    2015-06-01

    The binding interaction of gefitinib with calf thymus DNA (ct-DNA) under the simulated physiological pH condition was studied employing UV absorption, fluorescence, circular dichroism (CD), viscosity measurement and molecular docking methods. The experimental results revealed that gefitinib preferred to bind to the minor groove of ct-DNA with the binding constant (Kb) of 1.29 × 10(4)Lmol(-1) at 298K. Base on the signs and magnitudes of the enthalpy change (ΔH(0)=-60.4 kJ mol(-1)) and entropy change (ΔS(0)=-124.7 J mol(-1)K(-1)) in the binding process and the results of molecular docking, it can be concluded that the main interaction forces between gefitinib and ct-DNA in the binding process were van der Waals force and hydrogen bonding interaction. The results of CD experiments revealed that gefitinib did not disturb native B-conformation of ct-DNA. And, the significant change in the conformation of gefitinib in gefitinib-ct-DNA complex was observed from the molecular docking results and the change was close relation with the structure of B-DNA fragments, indicating that the flexibility of gefitinib molecule also plays an important role in the formation of the stable gefitinib-ct-DNA complex.

  18. Binding interaction of sorafenib with bovine serum albumin: Spectroscopic methodologies and molecular docking.

    PubMed

    Shi, Jie-Hua; Chen, Jun; Wang, Jing; Zhu, Ying-Yao; Wang, Qi

    2015-01-01

    The binding interaction of sorafenib with bovine serum albumin (BSA) was studied using fluorescence, circular dichrosim (CD) and molecular docking methods. The results revealed that there was a static quenching of BSA induced by sorafenib due to the formation of sorafenib-BSA complex. The binding constant and number of binding site of sorafenib with BSA under simulated physiological condition (pH=7.4) were 6.8×10(4) M(-1) and 1 at 310 K, respectively. Base on the sign and magnitude of the enthalpy and entropy changes (ΔH(0)=-72.2 kJ mol(-1) and ΔS(0)=-140.4J mol(-1) K(-1)) and the results of molecular docking, it could be suggested that the binding process of sorafenib and BSA was spontaneous and the main interaction forces of sorafenib with BSA were van der Waals force and hydrogen bonding interaction. From the results of site marker competitive experiments and molecular docking, it could be deduced that sorafenib was inserted into the subdomain IIA (site I) of BSA and leads to a slight change of the conformation of BSA. And, the significant change of conformation of sorafenib occurred in the binding process with BSA to increase the stability of the sorafenib-BSA system, implying that the flexibility of sorafenib played an important role in the binding process.

  19. QSAR and molecular docking studies on oxindole derivatives as VEGFR-2 tyrosine kinase inhibitors.

    PubMed

    Kang, Cong-Min; Liu, Dong-Qing; Zhao, Xu-Hao; Dai, Ying-Jie; Cheng, Jia-Gao; Lv, Ying-Tao

    2016-01-01

    The three-dimensional quantitative structure-activity relationships (3D-QSAR) were established for 30 oxindole derivatives as vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors by using comparative molecular field analysis (CoMFA) and comparative similarity indices analysis comparative molecular similarity indices analysis (CoMSIA) techniques. With the CoMFA model, the cross-validated value (q(2)) was 0.777, the non-cross-validated value (R(2)) was 0.987, and the external cross-validated value ([Formula: see text]) was 0.72. And with the CoMSIA model, the corresponding q(2), R(2) and [Formula: see text] values were 0.710, 0.988 and 0.78, respectively. Docking studies were employed to bind the inhibitors into the active site to determine the probable binding conformation. The binding mode obtained by molecular docking was in good agreement with the 3D-QSAR results. Based on the QSAR models and the docking binding mode, a set of new VEGFR-2 tyrosine kinase inhibitors were designed, which showed excellent predicting inhibiting potencies. The result revealed that both QSAR models have good predictive capability to guide the design and structural modification of homologic compounds. It is also helpful for further research and development of new VEGFR-2 tyrosine kinase inhibitors.

  20. Molecular docking NS4B of DENV 1-4 with known bioactive phyto-chemicals

    PubMed Central

    Paul, Anubrata; Vibhuti, Arpana; Raj, Samuel

    2016-01-01

    Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS4B is a target for designing specific antivirals due to its importance in viral replication. Medicinal plants have been a savior for dengue virus as they consist of a class of phytochemicals having anti-viral activity and can pose a new approach ofstrong drug against viruses. The present study analyzes the activity of compounds against NS4B of DENV (1-4) serotypes. In this study Catechin, Cianidanol, Epicatechin, Eupatoretin, Glabranin, Laurifolin, DL-Catechin, astherapeutic agents were filtered by using Lipinski rule’s five and the drug-likeness property of these agents were used for assessment of pharmacological properties. The molecular docking results presented the 2-D structures of bioactive complex, which interacted with especially conserved residues of target domains. Interestingly, we find the Catechin, Laurifolin, Cianidanol have highest binding energy against NS4B in DENV-1,2,4 which is evident by the formation of more hydrogen bonds with the amino acid residues at the binding site of the receptor. Our results revealed that the bioactive compound, especially Catechin has significant anti-dengue activities. In addition, this study may be helpful in further experimental investigations. PMID:28149049

  1. Toll-Like Receptor 7 Agonists: Chemical Feature Based Pharmacophore Identification and Molecular Docking Studies

    PubMed Central

    Sun, Lidan; Zhang, Liangren; Sun, Gang; Wang, Zhanli; Yu, Yongchun

    2013-01-01

    Chemical feature based pharmacophore models were generated for Toll-like receptors 7 (TLR7) agonists using HypoGen algorithm, which is implemented in the Discovery Studio software. Several methods tools used in validation of pharmacophore model were presented. The first hypothesis Hypo1 was considered to be the best pharmacophore model, which consists of four features: one hydrogen bond acceptor, one hydrogen bond donor, and two hydrophobic features. In addition, homology modeling and molecular docking studies were employed to probe the intermolecular interactions between TLR7 and its agonists. The results further confirmed the reliability of the pharmacophore model. The obtained pharmacophore model (Hypo1) was then employed as a query to screen the Traditional Chinese Medicine Database (TCMD) for other potential lead compounds. One hit was identified as a potent TLR7 agonist, which has antiviral activity against hepatitis virus in vitro. Therefore, our current work provides confidence for the utility of the selected chemical feature based pharmacophore model to design novel TLR7 agonists with desired biological activity. PMID:23526932

  2. Insights into the Interactions between Maleimide Derivates and GSK3β Combining Molecular Docking and QSAR

    PubMed Central

    Quesada-Romero, Luisa; Mena-Ulecia, Karel; Tiznado, William; Caballero, Julio

    2014-01-01

    Many protein kinase (PK) inhibitors have been reported in recent years, but only a few have been approved for clinical use. The understanding of the available molecular information using computational tools is an alternative to contribute to this process. With this in mind, we studied the binding modes of 77 maleimide derivates inside the PK glycogen synthase kinase 3 beta (GSK3β) using docking experiments. We found that the orientations that these compounds adopt inside GSK3β binding site prioritize the formation of hydrogen bond (HB) interactions between the maleimide group and the residues at the hinge region (residues Val135 and Asp133), and adopt propeller-like conformations (where the maleimide is the propeller axis and the heterocyclic substituents are two slanted blades). In addition, quantitative structure–activity relationship (QSAR) models using CoMSIA methodology were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. We found a model to explain the structure–activity relationship of non-cyclic maleimide (NCM) derivatives (54 compounds). The best CoMSIA model (training set included 44 compounds) included steric, hydrophobic, and HB donor fields and had a good Q2 value of 0.539. It also predicted adequately the most active compounds contained in the test set. Furthermore, the analysis of the plots of the steric CoMSIA field describes the elements involved in the differential potency of the inhibitors that can be considered for the selection of suitable inhibitors. PMID:25010341

  3. Insights into the interactions between maleimide derivates and GSK3β combining molecular docking and QSAR.

    PubMed

    Quesada-Romero, Luisa; Mena-Ulecia, Karel; Tiznado, William; Caballero, Julio

    2014-01-01

    Many protein kinase (PK) inhibitors have been reported in recent years, but only a few have been approved for clinical use. The understanding of the available molecular information using computational tools is an alternative to contribute to this process. With this in mind, we studied the binding modes of 77 maleimide derivates inside the PK glycogen synthase kinase 3 beta (GSK3β) using docking experiments. We found that the orientations that these compounds adopt inside GSK3β binding site prioritize the formation of hydrogen bond (HB) interactions between the maleimide group and the residues at the hinge region (residues Val135 and Asp133), and adopt propeller-like conformations (where the maleimide is the propeller axis and the heterocyclic substituents are two slanted blades). In addition, quantitative structure-activity relationship (QSAR) models using CoMSIA methodology were constructed to explain the trend of the GSK3β inhibitory activities for the studied compounds. We found a model to explain the structure-activity relationship of non-cyclic maleimide (NCM) derivatives (54 compounds). The best CoMSIA model (training set included 44 compounds) included steric, hydrophobic, and HB donor fields and had a good Q(2) value of 0.539. It also predicted adequately the most active compounds contained in the test set. Furthermore, the analysis of the plots of the steric CoMSIA field describes the elements involved in the differential potency of the inhibitors that can be considered for the selection of suitable inhibitors.

  4. Interactions of cephalexin with bovine serum albumin: displacement reaction and molecular docking

    PubMed Central

    Hamishehkar, Hamed; Hosseini, Soheila; Naseri, Abdolhossein; Safarnejad, Azam; Rasoulzadeh, Farzaneh

    2016-01-01

    Introduction: The drug-plasma protein interaction is a fundamental issue in guessing and checking the serious drug side effects related with other drugs. The purpose of this research was to study the interaction of cephalexin with bovine serum albumin (BSA) and displacement reaction using site probes. Methods: The interaction mechanism concerning cephalexin (CPL) with BSA was investigated using various spectroscopic methods and molecular modeling method. The binding sites number, n, apparent binding constant, K, and thermodynamic parameters, ΔG0, ΔH0, and ΔS0 were considered at different temperatures. To evaluate the experimental results, molecular docking modeling was calculated. Results: The distance, r=1.156 nm between BSA and CPL were found in accordance with the Forster theory of non-radiation energy transfer (FRET) indicating energy transfer occurs between BSA and CPL. According to the binding parameters and ΔG0= negative values and ΔS0= 28.275 j mol-1K-1, a static quenching process is effective in the CPL-BSA interaction spontaneously. ΔG0 for the CPL-BSA complex obtained from the docking simulation is -28.99 kj mol-1, which is close to experimental ΔG of binding, -21.349 kj mol-1 that indicates a good agreement between the results of docking methods and experimental data. Conclusion: The outcomes of spectroscopic methods revealed that the conformation of BSA changed during drug-BSA interaction. The results of FRET propose that CPL quenches the fluorescence of BSA by static quenching and FRET. The displacement study showed that phenylbutazon and ketoprofen displaced CPL, indicating that its binding site on albumin is site I and Gentamicin cannot be displaced from the binding site of CPL. All results of molecular docking method agreed with the results of experimental data. PMID:27853676

  5. An Investigation of Molecular Docking and Molecular Dynamic Simulation on Imidazopyridines as B-Raf Kinase Inhibitors.

    PubMed

    Xie, Huiding; Li, Yupeng; Yu, Fang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

    2015-11-16

    In the recent cancer treatment, B-Raf kinase is one of key targets. Nowadays, a group of imidazopyridines as B-Raf kinase inhibitors have been reported. In order to investigate the interaction between this group of inhibitors and B-Raf kinase, molecular docking, molecular dynamic (MD) simulation and binding free energy (ΔGbind) calculation were performed in this work. Molecular docking was carried out to identify the key residues in the binding site, and MD simulations were performed to determine the detail binding mode. The results obtained from MD simulation reveal that the binding site is stable during the MD simulations, and some hydrogen bonds (H-bonds) in MD simulations are different from H-bonds in the docking mode. Based on the obtained MD trajectories, ΔGbind was computed by using Molecular Mechanics Generalized Born Surface Area (MM-GBSA), and the obtained energies are consistent with the activities. An energetic analysis reveals that both electrostatic and van der Waals contributions are important to ΔGbind, and the unfavorable polar solvation contribution results in the instability of the inhibitor with the lowest activity. These results are expected to understand the binding between B-Raf and imidazopyridines and provide some useful information to design potential B-Raf inhibitors.

  6. An Investigation of Molecular Docking and Molecular Dynamic Simulation on Imidazopyridines as B-Raf Kinase Inhibitors

    PubMed Central

    Xie, Huiding; Li, Yupeng; Yu, Fang; Xie, Xiaoguang; Qiu, Kaixiong; Fu, Jijun

    2015-01-01

    In the recent cancer treatment, B-Raf kinase is one of key targets. Nowadays, a group of imidazopyridines as B-Raf kinase inhibitors have been reported. In order to investigate the interaction between this group of inhibitors and B-Raf kinase, molecular docking, molecular dynamic (MD) simulation and binding free energy (ΔGbind) calculation were performed in this work. Molecular docking was carried out to identify the key residues in the binding site, and MD simulations were performed to determine the detail binding mode. The results obtained from MD simulation reveal that the binding site is stable during the MD simulations, and some hydrogen bonds (H-bonds) in MD simulations are different from H-bonds in the docking mode. Based on the obtained MD trajectories, ΔGbind was computed by using Molecular Mechanics Generalized Born Surface Area (MM-GBSA), and the obtained energies are consistent with the activities. An energetic analysis reveals that both electrostatic and van der Waals contributions are important to ΔGbind, and the unfavorable polar solvation contribution results in the instability of the inhibitor with the lowest activity. These results are expected to understand the binding between B-Raf and imidazopyridines and provide some useful information to design potential B-Raf inhibitors. PMID:26580609

  7. An investigation of molecular dynamics simulation and molecular docking: interaction of citrus flavonoids and bovine β-lactoglobulin in focus.

    PubMed

    Sahihi, M; Ghayeb, Y

    2014-08-01

    Citrus flavonoids are natural compounds with important health benefits. The study of their interaction with a transport protein, such as bovine β-lactoglobulin (BLG), at the atomic level could be a valuable factor to control their transport to biological sites. In the present study, molecular docking and molecular dynamics simulation methods were used to investigate the interaction of hesperetin, naringenin, nobiletin and tangeretin as citrus flavonoids and BLG as transport protein. The molecular docking results revealed that these flavonoids bind in the internal cavity of BLG and the BLG affinity for binding the flavonoids follows naringenin>hesperetin>tangeretin>nobiletin. The docking results also indicated that the BLG-flavonoid complexes are stabilized through hydrophobic interactions, hydrogen bond interactions and π-π stacking interactions. The analysis of molecular dynamics (MD) simulation trajectories showed that the root mean square deviation (RMSD) of various systems reaches equilibrium and fluctuates around the mean value at various times. Time evolution of the radius of gyration, total solvent accessible surface of the protein and the second structure of protein showed as well that BLG and BLG-flavonoid complexes were stable around 2500ps, and there was not any conformational change as for BLG-flavonoid complexes. Further, the profiles of atomic fluctuations indicated the rigidity of the ligand binding site during the simulation.

  8. Combined 3D-QSAR modeling and molecular docking study on azacycles CCR5 antagonists

    NASA Astrophysics Data System (ADS)

    Ji, Yongjun; Shu, Mao; Lin, Yong; Wang, Yuanqiang; Wang, Rui; Hu, Yong; Lin, Zhihua

    2013-08-01

    The beta chemokine receptor 5 (CCR5) is an attractive target for pharmaceutical industry in the HIV-1, inflammation and cancer therapeutic areas. In this study, we have developed quantitative structure activity relationship (QSAR) models for a series of 41 azacycles CCR5 antagonists using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and Topomer CoMFA methods. The cross-validated coefficient q2 values of 3D-QASR (CoMFA, CoMSIA, and Topomer CoMFA) methods were 0.630, 0.758, and 0.852, respectively, the non-cross-validated R2 values were 0.979, 0.978, and 0.990, respectively. Docking studies were also employed to determine the most probable binding mode. 3D contour maps and docking results suggested that bulky groups and electron-withdrawing groups on the core part would decrease antiviral activity. Furthermore, docking results indicated that H-bonds and π bonds were favorable for antiviral activities. Finally, a set of novel derivatives with predicted activities were designed.

  9. Spectroscopic and molecular docking studies on the interaction of troxerutin with DNA.

    PubMed

    Subastri, A; Ramamurthy, C H; Suyavaran, A; Mareeswaran, R; Lokeswara Rao, P; Harikrishna, M; Suresh Kumar, M; Sujatha, V; Thirunavukkarasu, C

    2015-01-01

    Troxerutin (TXER) is a derivative of naturally occurring bioflavonoid rutin. It possesses different biological activities in rising clinical world. The biological activity possessed by most of the drugs mainly targets on macromolecules. Hence, in the current study we have examined the interaction mechanism of TXER with calf thymus DNA (CT-DNA) by using various spectroscopic methods, isothermal titration calorimetry (ITC) and molecular docking studies. Further, DNA cleavage study was carried out to find the DNA protection activity of TXER. UV-absorption and emission spectroscopy showed low binding constant values via groove binding. Circular dichroism study indicates that TXER does not modify native B-form of DNA, and it retains the native B-conformation. Furthermore, no effective positive potential peak shift was observed in TXER-DNA complex during electrochemical analysis by which it represents an interaction of TXER with DNA through groove binding. Molecular docking study showed thymine guanine based interaction with docking score -7.09 kcal/mol. This result was compared to experimental ITC value. The DNA cleavage study illustrates that TXER does not cause any DNA damage as well as TXER showed DNA protection against hydroxyl radical induced DNA damage. From this study, we conclude that TXER interacts with DNA by fashion of groove binding.

  10. Molecular docking and pharmacophore studies of heterocyclic compounds as Heat shock protein 90 (Hsp90) Inhibitors

    PubMed Central

    Baby, Suby T; Sharma, Shailendra; Enaganti, Sreenivas; Cherian, P. Roby

    2016-01-01

    Heat Shock Protein 90 was a key molecular chaperone involved in the proteome stability maintenance and its interference in many signaling networks associated with cancer progression, makes it of an important target for cancer therapeutics. The present study aimed to identify potential lead molecule among the selected heterocyclic compounds against Human Hsp90 (PDB: 1YET) through docking using GOLD 3.1 and pharmacophore studies using Discovery studio 2.1. On the basis of the GOLD Fitness scores, the compounds Q1G and T21 showed better binding affinity. Further the analyzed structure pharmacophore results are in consistence with the docking results indicating that both these compounds show antagonistic activity towards HSP90 respectively.

  11. Interaction of sulfanilamide and sulfamethoxazole with bovine serum albumin and adenine: Spectroscopic and molecular docking investigations

    NASA Astrophysics Data System (ADS)

    Rajendiran, N.; Thulasidhasan, J.

    2015-06-01

    Interaction between sulfanilamide (SAM) and sulfamethoxazole (SMO) with BSA and DNA base (adenine) was investigated by UV-visible, fluorescence, cyclic voltammetry and molecular docking studies. Stern-Volmer fluorescence quenching constant (Ka) suggests SMO is more quenched with BSA/adenine than that of SAM. The distance r between donor (BSA/adenine) and acceptor (SAM and SMO) was obtained according to fluorescence resonance energy transfer (FRET). The results showed that hydrophobic forces, electrostatic interactions, and hydrogen bonds played vital roles in the SAM and SMO with BSA/adenine binding interaction. During the interaction, sulfa drugs could insert into the hydrophobic pocket, where the non-radioactive energy transfer from BSA/adenine to sulfa drugs occurred with high possibility. Cyclic voltammetry results suggested that when the drug concentration is increased, the anodic electrode potential deceased. The docking method indicates aniline group is interacted with the BSA molecules.

  12. Interaction of sulfanilamide and sulfamethoxazole with bovine serum albumin and adenine: spectroscopic and molecular docking investigations.

    PubMed

    Rajendiran, N; Thulasidhasan, J

    2015-06-05

    Interaction between sulfanilamide (SAM) and sulfamethoxazole (SMO) with BSA and DNA base (adenine) was investigated by UV-visible, fluorescence, cyclic voltammetry and molecular docking studies. Stern-Volmer fluorescence quenching constant (Ka) suggests SMO is more quenched with BSA/adenine than that of SAM. The distance r between donor (BSA/adenine) and acceptor (SAM and SMO) was obtained according to fluorescence resonance energy transfer (FRET). The results showed that hydrophobic forces, electrostatic interactions, and hydrogen bonds played vital roles in the SAM and SMO with BSA/adenine binding interaction. During the interaction, sulfa drugs could insert into the hydrophobic pocket, where the non-radioactive energy transfer from BSA/adenine to sulfa drugs occurred with high possibility. Cyclic voltammetry results suggested that when the drug concentration is increased, the anodic electrode potential deceased. The docking method indicates aniline group is interacted with the BSA molecules.

  13. Synthesis, Urease Inhibition, Antioxidant, Antibacterial, and Molecular Docking Studies of 1,3,4-Oxadiazole Derivatives

    PubMed Central

    Hanif, Muhammad; Shoaib, Khurram; Saleem, Muhammad; Hasan Rama, Nasim; Zaib, Sumera; Iqbal, Jamshed

    2012-01-01

    A series of eighteen 1,3,4-oxadiazole derivatives have been synthesized by treating aromatic acid hydrazides with carbon disulfide in ethanolic potassium hydroxide yielding potassium salts of 1,3,4-oxadiazoles. Upon neutralization with 1 N hydrochloric acid yielded crude crystals of 1,3,4-oxadiazoles, which were purified by recrystallization in boiling methanol. The synthesized 1,3,4-oxadiazoles derivatives were evaluated in vitro for their urease inhibitory activities, most of the investigated compounds were potent inhibitors of Jack bean urease. The molecular docking studies were performed by docking them into the crystal structure of Jack bean urease to observe the mode of interaction of synthesized compounds. The synthesized compounds were also tested for antibacterial and antioxidant activities and some derivatives exhibited very promising results. PMID:22934191

  14. Molecular docking analysis of UniProtKB nitrate reductase enzyme with known natural flavonoids

    PubMed Central

    Shaik, Ayub; Thumma, Vishnu; Kotha, Aruna Kumari; Kramadhati, Sandhya; Pochampally, Jalapathy; Bandi, Seshagiri

    2016-01-01

    The functional inference of UniProtKB nitrate reductase enzyme (UniProtKB - P0AF33) through structural modeling is of interest in plant biology. Therefore, a homology model for UniProtKB variant of the enzyme was constructed using available data with the MODELER software tool. The model was further docked with five natural flavonoid structures such as hesperetin, naringenin, leucocyanidin, quercetin and hesperetin triacetate using the AUTODOCK (version 4.2) software tool. The structure aided molecular interactions of these flavonoids with nitrate reductase is documented in this study. The binding features (binding energy (ΔG) value, H bonds and docking score) hesperetin to the enzyme model is relatively high, satisfactory and notable. This data provides valuable insights to the relative binding of several naturally occurring flavonoids to nitrate reductase enzyme and its relevance in plant biology.

  15. Molecular docking and analgesic studies of Erythrina variegata׳s derived phytochemicals with COX enzymes.

    PubMed

    Uddin, Mir Muhammad Nasir; Emran, Talha Bin; Mahib, Muhammad Mamunur Rashid; Dash, Raju

    2014-01-01

    Secondary metabolites from plants are a good source for the NSAID drug development. We studied the analgesic activity of ethanolic extract of Erythrina variegata L. (Fabaceae) followed by molecular docking analysis. The analgesic activity of Erythrina variegata L. is evaluated by various methods viz., acetic acid-induced writhing test, hot plate and tail immersion test. Subsequently, molecular docking analysis has been performed to identify compounds having activity against COX-1 and COX-2 enzymes by using GOLD docking fitness. The result of preliminary phytochemical screening revealed that the extract contains alkaloids and flavonoids. In analgesic activity tests, the extract at the doses of 50, 100 and 200 mg/kg body weight (b.w.) produced a increase in pain threshold in a dose dependent manner. In acetic acid induced writhing test, the inhibitory effect was similar to the reference drug diclofenac sodium. The extract showed 18.89% writhing inhibitory effect at the dose 200 mg/kg b.w., whereas diclofenac sodium showed 79.42% inhibition of writhing at a dose of 10 mg/kg b.w. The results of tail immersion and hot plate test also showed potential analgesic activity of the extract which is also comparable to the standard drug morphine (5 mg/kg b.w.). Docking studies shows that phaseollin of Erythrina variegata L. has the best fitness score against the COX-1 which is 56.64 and 59.63 for COX- 2 enzyme. Phaseollin of Erythrina variegata L. detected with significant fitness score and hydrogen bonding against COX-1 and COX-2 is reported for further validation.

  16. Molecular modeling studies of phenoxypyrimidinyl imidazoles as p38 kinase inhibitors using QSAR and docking.

    PubMed

    Ravindra, G K; Achaiah, G; Sastry, G N

    2008-04-01

    p38 Kinase plays a vital role in inflammation mediated by tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) pathways and inhibitors of p38 kinase provide effective approach for the treatment of inflammatory diseases. Pyridinyl and pyrimidinyl imidazoles, selectively inhibit p38alpha MAP kinase, are useful in the treatment of inflammatory diseases like rheumatoid arthritis. Three dimensional quantitative structure-activity relationship studies (3D-QSAR) involving comparative molecular field analysis (CoMFA) and comparative similarity indices analysis (CoMSIA) and molecular docking were performed on 44 phenoxypyrimidinyl imidazole p38 kinase inhibitors to find out the structural relationship with the activity. The best predictive CoMFA model with atom fit alignment resulted in cross-validated r(2) value of 0.553, noncross-validated r(2) value of 0.908 and standard error of estimate 0.187. Similarly the best predictive CoMSIA model was derived with q(2) of 0.508, noncross-validated r(2) of 0.894 and standard error of estimate of 0.197, comprising steric, electrostatic, hydrophobic and hydrogen bond donor fields. These models were able to predict the activity of test set molecules efficiently within an acceptable error range. GOLD and FlexX were employed to dock the inhibitors into the active site of the p38 kinase and these docking studies revealed the vital interactions and binding conformation of the inhibitors. The information rendered by 3D-QSAR models and the docking interactions may afford valuable clues to optimize the lead and design new potential inhibitors.

  17. Antimicrobial, antioxidant, cytotoxic and molecular docking properties of N-benzyl-2,2,2-trifluoroacetamide

    NASA Astrophysics Data System (ADS)

    Balachandran, C.; Kumar, P. Saravana; Arun, Y.; Duraipandiyan, V.; Sundaram, R. Lakshmi; Vijayakumar, A.; Balakrishna, K.; Ignacimuthu, S.; Al-Dhabi, N. A.; Perumal, P. T.

    2015-02-01

    N-Benzyl-2,2,2-trifluoroacetamide was obtained by acylation of benzylamine with trifluoroacetic anhydride using Friedel-Crafts acylation method. The synthesised compound was confirmed by spectroscopic and crystallographic techniques. N-Benzyl-2,2,2 -trifluoroacetamide was assessed for its antimicrobial, antioxidant, cytotoxic and molecular docking properties. It showed good antifungal activity against tested fungi and moderate antibacterial activity. The minimum inhibitory concentration values of N-benzyl-2,2,2 -trifluoroacetamide against fungi were 15.62 μg/mL against A. flavus, 31.25 μg/mL against B. Cinerea and 62.5 μg/mL against T. mentagrophytes, Scopulariopsis sp., C. albicans and M. pachydermatis. N-Benzyl-2,2,2-trifluoroacetamide showed 78.97 ± 2.24 of antioxidant activity at 1,000 μg/mL. Cupric ion reducing antioxidant capacity of N-benzyl-2,2,2-trifluoroacetamide was dependent on the concentration. Ferric reducing antioxidant power assay of N-benzyl-2,2,2-trifluoroacetamide showed (1.352 ± 0.04 mM Fe(II)/g) twofold higher value compared to the standard. N-Benzyl-2,2,2-trifluoroacetamide showed 75.3 % cytotoxic activity at the dose of 200 μg/mL with IC50 (54.7 %) value of 100 μg/mL. N-Benzyl-2,2,2-trifluoroacetamide was subjected to molecular docking studies for the inhibition AmpC beta-lactamase, Glucosamine-6-Phosphate Synthase and lanosterol 14 alpha-demethylase (CYP51) enzymes which are targets for antibacterial and antifungal drugs. Docking studies of N-benzyl-2,2,2-trifluoroacetamide showed low docking energy. N-Benzyl-2,2,2-trifluoroacetamide can be evaluated further for drug development.

  18. Discovery of Potential Inhibitors of Aldosterone Synthase from Chinese Herbs Using Pharmacophore Modeling, Molecular Docking, and Molecular Dynamics Simulation Studies

    PubMed Central

    Lu, Fang; Qiao, Liansheng; Chen, Xi; Li, Gongyu

    2016-01-01

    Aldosterone synthase (CYP11B2) is a key enzyme for the biosynthesis of aldosterone, which plays a significant role for the regulation of blood pressure. Excess aldosterone can cause the dysregulation of the renin-angiotensin-aldosterone system (RAAS) and lead to hypertension. Therefore, research and development of CYP11B2 inhibitor are regarded as a novel approach for the treatment of hypertension. In this study, the pharmacophore models of CYP11B2 inhibitors were generated and the optimal model was used to identify potential CYP11B2 inhibitors from the Traditional Chinese Medicine Database (TCMD, Version 2009). The hits were further refined by molecular docking and the interactions between compounds and CYP11B2 were analyzed. Compounds with high Fitvalue, high docking score, and expected interactions with key residues were selected as potential CYP11B2 inhibitors. Two most promising compounds, ethyl caffeate and labiatenic acid, with high Fitvalue and docking score were reserved for molecular dynamics (MD) study. All of them have stability of ligand binding which suggested that they might perform the inhibitory effect on CYP11B2. This study provided candidates for novel drug-like CYP11B2 inhibitors by molecular simulation methods for the hypertension treatment. PMID:27781210

  19. Molecular modeling and ligand docking for Solute Carrier (SLC) transporters

    PubMed Central

    Schlessinger, Avner; Khuri, Natalia; Giacomini, Kathleen M.; Sali, Andrej

    2014-01-01

    Solute Carrier (SLC) transporters are membrane proteins that transport solutes, such as ions, metabolites, peptides, and drugs, across biological membranes, using diverse energy coupling mechanisms. In human, there are 386 SLC transporters, many of which contribute to the absorption, distribution, metabolism, and excretion of drugs and/or can be targeted directly by therapeutics. Recent atomic structures of SLC transporters determined by X-ray crystallography and NMR spectroscopy have significantly expanded the applicability of structure-based prediction of SLC transporter ligands, by enabling both comparative modeling of additional SLC transporters and virtual screening of small molecules libraries against experimental structures as well as comparative models. In this review, we begin by describing computational tools, including sequence analysis, comparative modeling, and virtual screening, that are used to predict the structures and functions of membrane proteins such as SLC transporters. We then illustrate the applications of these tools to predicting ligand specificities of select SLC transporters, followed by experimental validation using uptake kinetic measurements and other assays. We conclude by discussing future directions in the discovery of the SLC transporter ligands. PMID:23578028

  20. Additional diverse findings expand the clinical presentation of DOCK8 deficiency.

    PubMed

    Sanal, Ozden; Jing, Huie; Ozgur, Tuba; Ayvaz, Deniz; Strauss-Albee, Dara M; Ersoy-Evans, Sibel; Tezcan, Ilhan; Turkkani, Gulten; Matthews, Helen F; Haliloglu, Goknur; Yuce, Aysel; Yalcin, Bilgehan; Gokoz, Ozay; Oguz, Kader K; Su, Helen C

    2012-08-01

    We describe seven Turkish children with DOCK8 deficiency who have not been previously reported. Three patients presented with typical features of recurrent or severe cutaneous viral infections, atopic dermatitis, and recurrent respiratory or gastrointestinal tract infections. However, four patients presented with other features. Patient 1-1 featured sclerosing cholangitis and colitis; patient 2-1, granulomatous soft tissue lesion and central nervous system involvement, with primary central nervous system lymphoma found on follow-up; patient 3-1, a fatal metastatic leiomyosarcoma; and patient 4-2 showed no other symptoms initially besides atopic dermatitis. Similar to other previously reported Turkish patients, but in contrast to patients of non-Turkish ethnicity, the patients' lymphopenia was primarily restricted to CD4(+) T cells. Patients had homozygous mutations in DOCK8 that altered splicing, introduced premature terminations, destabilized protein, or involved large deletions within the gene. Genotyping of remaining family members showed that DOCK8 deficiency is a fully penetrant, autosomal recessive disease. In our patients, bone marrow transplantation resulted in rapid improvement followed by disappearance of viral skin lesions, including lesions resembling epidermodysplasia verruciformis, atopic dermatitis, and recurrent infections. Particularly for patients who feature unusual clinical manifestations, immunological testing, in conjunction with genetic testing, can prove invaluable in diagnosing DOCK8 deficiency and providing potentially curative treatment.

  1. Exploring the biophysical aspects and binding mechanism of thionine with bovine hemoglobin by optical spectroscopic and molecular docking methods.

    PubMed

    Shanmugaraj, Krishnamoorthy; Anandakumar, Shanmugam; Ilanchelian, Malaichamy

    2014-02-05

    In the present investigation, we have elucidated the interaction between thionine (TH) and bovine hemoglobin (BHb) under physiological conditions by using absorption, emission, time resolved fluorescence, synchronous fluorescence, circular dichroism (CD) and three dimensional emission (3D) spectral studies. Molecular docking experiment was also carried out to establish the possible binding site of TH on BHb. The emission spectral studies revealed that, TH have the ability to bind with BHb and form a ground state complex via static quenching process. The calculated binding constant and the number of binding sites was found to be 3.65×10(4)dm(3)mol(-1) and 1.04, respectively. Förster Resonance Energy Transfer (FRET) theory was employed to calculate the distance (r) between donor (BHb) and acceptor (TH) as 3.64nm. Furthermore, the conformational changes of BHb induced by TH complexation showed some degree of structural unfolding. In addition, molecular docking study confirmed that the most probable binding site of TH was located within the active cavity constituted by α1 and α2 subunits of BHb.

  2. Binding analysis for interaction of diacetylcurcumin with β-casein nanoparticles by using fluorescence spectroscopy and molecular docking calculations.

    PubMed

    Mehranfar, Fahimeh; Bordbar, Abdol-Khalegh; Fani, Najme; Keyhanfar, Mehrnaz

    2013-11-01

    The interaction of diacetylcurcumin (DAC), as a novel synthetic derivative of curcumin, with bovine β-casein (an abundant milk protein that is highly amphiphilic and self assembles into stable micellar nanoparticles in aqueous solution) was investigated using fluorescence quenching experiments, Forster energy transfer measurements and molecular docking calculations. The fluorescence quenching measurements revealed the presence of a single binding site on β-casein for DAC with the binding constant value equals to (4.40±0.03)×10(4)M(-1). Forster energy transfer measurements suggested that the distance between bound DAC and Trp143 residue is higher than the respective critical distance, hence, the static quenching is more likely responsible for fluorescence quenching other than the mechanism of non-radiative energy transfer. Our results from molecular docking calculations indicated that binding of DAC to β-casein predominantly occurred through hydrophobic contacts in the hydrophobic core of protein. Additionally, in vitro investigation of the cytotoxicity of free DAC and DAC-β-casein complex in human breast cancer cell line MCF7 revealed the higher cytotoxic effect of DAC-β-casein complex.

  3. Binding analysis for interaction of diacetylcurcumin with β-casein nanoparticles by using fluorescence spectroscopy and molecular docking calculations

    NASA Astrophysics Data System (ADS)

    Mehranfar, Fahimeh; Bordbar, Abdol-Khalegh; Fani, Najme; Keyhanfar, Mehrnaz

    2013-11-01

    The interaction of diacetylcurcumin (DAC), as a novel synthetic derivative of curcumin, with bovine β-casein (an abundant milk protein that is highly amphiphilic and self assembles into stable micellar nanoparticles in aqueous solution) was investigated using fluorescence quenching experiments, Forster energy transfer measurements and molecular docking calculations. The fluorescence quenching measurements revealed the presence of a single binding site on β-casein for DAC with the binding constant value equals to (4.40 ± 0.03) × 104 M-1. Forster energy transfer measurements suggested that the distance between bound DAC and Trp143 residue is higher than the respective critical distance, hence, the static quenching is more likely responsible for fluorescence quenching other than the mechanism of non-radiative energy transfer. Our results from molecular docking calculations indicated that binding of DAC to β-casein predominantly occurred through hydrophobic contacts in the hydrophobic core of protein. Additionally, in vitro investigation of the cytotoxicity of free DAC and DAC-β-casein complex in human breast cancer cell line MCF7 revealed the higher cytotoxic effect of DAC-β-casein complex.

  4. Evaluation of the interaction between naringenin and human serum albumin: Insights from fluorescence spectroscopy, electrochemical measurement and molecular docking.

    PubMed

    Tu, Bao; Wang, Yang; Mi, Ran; Ouyang, Yu; Hu, Yan-Jun

    2015-01-01

    Naringenin (Nar) is a flavanone compound found in grapefruits that is endowed with diverse pharmacological and biological activities. Here, the interaction between Nar and human serum albumin (HSA) was investigated via various methods, including fluorescence spectroscopy, electrochemical methods and molecular docking. The Stern-Volmer quenching constants inversely correlated with temperature, demonstrating that the fluorescence quenching about HSA-Nar system is initiated by the formation of a compound, which has confirmed by electrochemical measurements. Three-dimensional fluorescence demonstrated that Nar induces the slight unfolding of the polypeptides of HSA. The calculated thermodynamic parameters suggesting that the binding of Nar to HSA is spontaneous, and the mainly force is electrostatic interactions. In addition, site marker competitive experiments indicated that Nar binds to HSA both on site I (subdomain IIA) and site II (subdomain IIIA), with higher affinity to the latter one, consistence with molecular docking. Furthermore, the fluorescence resonance energy transfer (FRET) experiment showed the binding distance (r) is 2.65 nm. And the effects of metal ions on the HSA-Nar system are also discussed.

  5. Synthesis, molecular docking, and biological evaluation of some novel hydrazones and pyrazole derivatives as anti-inflammatory agents.

    PubMed

    Mohammed, Khaled O; Nissan, Yassin M

    2014-10-01

    2-Hydrazinyl-N-(4-sulfamoylphenyl)acetamide 3 was the key intermediate for the synthesis of novel hydrazones 4-10 and pyrazole derivatives 11-17. All compounds were tested for their in vivo anti-inflammatory activity and their ability to inhibit the production of PGE(2) in serum samples of rats. IC(50) values for the most active compounds for inhibition of COX-1 and COX-2 enzymes were determined in vitro, and they were also tested for their ulcerogenic effect. Molecular docking was performed on the active site of COX-2 to predict their mode of binding to the amino acids. Most of the synthesized compounds showed good anti-inflammatory activity especially compounds 3, 4, 8, 9, 15, and 17 which showed better activity than diclofenac as the reference drug. Compounds 3, 8, 9, 13, and 15-17 were less ulcerogenic than indomethacine as the reference drug. Most of the synthesized compounds interacted with Tyr 385 and Ser 530 in molecular docking study with additional hydrogen bond for compound 17. Compound 17 showed good selectivity index value of 11.1 for COX-1/COX-2 inhibition in vitro.

  6. Catalytic Interactions and Molecular Docking of Bile Salt Hydrolase (BSH) from L. plantarum RYPR1 and Its Prebiotic Utilization

    PubMed Central

    Yadav, Ruby; Singh, Puneet K.; Puniya, Anil K.; Shukla, Pratyoosh

    2017-01-01

    Prebiotics are the non-digestible carbohydrate, which passes through the small intestine into unmetabolized form, reaches the large intestine and undergoes fermentation by the colonic bacteria thus; prebiotics stimulate the growth of probiotic bacteria. Further, bile salt hydrolase (BSH) is an enzyme that catalyses the deconjugation of bile salt, so it has enormous potential toward utilizing such capability of Lactobacillus plantarum RYPR1 toward detoxifying through BSH enzyme activity. In the present study, six isolates of Lactobacillus were evaluated for the co-aggregation assay and the isolate Lactobacillus plantarum RYPR1 was further selected for studies of prebiotic utilization, catalytic interactions and molecular docking. The prebiotic utilization ability was assessed by using commercially available prebiotics lactulose, inulin, xylitol, raffinose, and oligofructose P95. The results obtained revealed that RYPR1 is able to utilize these probiotics, maximum with lactulose by showing an increase in viable cell count (7.33 ± 0.02 to 8.18 ± 0.08). In addition, the molecular docking of BSH from Lactobacillus plantarum RYPR1 was performed which revealed the binding energy –4.42 and 7.03 KJ/mol. This proves a considerably good interactions among BSH and its substrates like Taurocholic acid (–4.42 KJ/mol) and Glycocholic acid (–7.03 KJ/mol). These results from this study establishes that Lactobacillus plantarum RYPR1 possesses good probiotic effects so it could be used for such applications. Further, molecular dynamics simulations were used to analyze the dynamic stability of the of modeled protein to stabilize it for further protein ligand docking and it was observed that residues Asn12, Ile8, and Leu6 were interacting among BSH and its substrates, i.e., Taurocholic acid and Lys88 and Asp126 were interacting with Glycocholic acid. These residues were interacting when the docking was carried out with stabilized BSH protein structure, thus, these residues may

  7. Catalytic Interactions and Molecular Docking of Bile Salt Hydrolase (BSH) from L. plantarum RYPR1 and Its Prebiotic Utilization.

    PubMed

    Yadav, Ruby; Singh, Puneet K; Puniya, Anil K; Shukla, Pratyoosh

    2016-01-01

    Prebiotics are the non-digestible carbohydrate, which passes through the small intestine into unmetabolized form, reaches the large intestine and undergoes fermentation by the colonic bacteria thus; prebiotics stimulate the growth of probiotic bacteria. Further, bile salt hydrolase (BSH) is an enzyme that catalyses the deconjugation of bile salt, so it has enormous potential toward utilizing such capability of Lactobacillus plantarum RYPR1 toward detoxifying through BSH enzyme activity. In the present study, six isolates of Lactobacillus were evaluated for the co-aggregation assay and the isolate Lactobacillus plantarum RYPR1 was further selected for studies of prebiotic utilization, catalytic interactions and molecular docking. The prebiotic utilization ability was assessed by using commercially available prebiotics lactulose, inulin, xylitol, raffinose, and oligofructose P95. The results obtained revealed that RYPR1 is able to utilize these probiotics, maximum with lactulose by showing an increase in viable cell count (7.33 ± 0.02 to 8.18 ± 0.08). In addition, the molecular docking of BSH from Lactobacillus plantarum RYPR1 was performed which revealed the binding energy -4.42 and 7.03 KJ/mol. This proves a considerably good interactions among BSH and its substrates like Taurocholic acid (-4.42 KJ/mol) and Glycocholic acid (-7.03 KJ/mol). These results from this study establishes that Lactobacillus plantarum RYPR1 possesses good probiotic effects so it could be used for such applications. Further, molecular dynamics simulations were used to analyze the dynamic stability of the of modeled protein to stabilize it for further protein ligand docking and it was observed that residues Asn12, Ile8, and Leu6 were interacting among BSH and its substrates, i.e., Taurocholic acid and Lys88 and Asp126 were interacting with Glycocholic acid. These residues were interacting when the docking was carried out with stabilized BSH protein structure, thus, these residues may have a

  8. Surflex-Dock: Docking benchmarks and real-world application.

    PubMed

    Spitzer, Russell; Jain, Ajay N

    2012-06-01

    Benchmarks for molecular docking have historically focused on re-docking the cognate ligand of a well-determined protein-ligand complex to measure geometric pose prediction accuracy, and measurement of virtual screening performance has been focused on increasingly large and diverse sets of target protein structures, cognate ligands, and various types of decoy sets. Here, pose prediction is reported on the Astex Diverse set of 85 protein ligand complexes, and virtual screening performance is reported on the DUD set of 40 protein targets. In both cases, prepared structures of targets and ligands were provided by symposium organizers. The re-prepared data sets yielded results not significantly different than previous reports of Surflex-Dock on the two benchmarks. Minor changes to protein coordinates resulting from complex pre-optimization had large effects on observed performance, highlighting the limitations of cognate ligand re-docking for pose prediction assessment. Docking protocols developed for cross-docking, which address protein flexibility and produce discrete families of predicted poses, produced substantially better performance for pose prediction. Performance on virtual screening performance was shown to benefit by employing and combining multiple screening methods: docking, 2D molecular similarity, and 3D molecular similarity. In addition, use of multiple protein conformations significantly improved screening enrichment.

  9. Surflex-Dock: Docking benchmarks and real-world application

    NASA Astrophysics Data System (ADS)

    Spitzer, Russell; Jain, Ajay N.

    2012-06-01

    Benchmarks for molecular docking have historically focused on re-docking the cognate ligand of a well-determined protein-ligand complex to measure geometric pose prediction accuracy, and measurement of virtual screening performance has been focused on increasingly large and diverse sets of target protein structures, cognate ligands, and various types of decoy sets. Here, pose prediction is reported on the Astex Diverse set of 85 protein ligand complexes, and virtual screening performance is reported on the DUD set of 40 protein targets. In both cases, prepared structures of targets and ligands were provided by symposium organizers. The re-prepared data sets yielded results not significantly different than previous reports of Surflex-Dock on the two benchmarks. Minor changes to protein coordinates resulting from complex pre-optimization had large effects on observed performance, highlighting the limitations of cognate ligand re-docking for pose prediction assessment. Docking protocols developed for cross-docking, which address protein flexibility and produce discrete families of predicted poses, produced substantially better performance for pose prediction. Performance on virtual screening performance was shown to benefit by employing and combining multiple screening methods: docking, 2D molecular similarity, and 3D molecular similarity. In addition, use of multiple protein conformations significantly improved screening enrichment.

  10. Molecular docking studies of a group of hydroxamate inhibitors with gelatinase-A by molecular dynamics

    NASA Astrophysics Data System (ADS)

    Hou, Tingjun; Zhang, Wei; Xu, Xiaojie

    2002-01-01

    We have performed docking and molecular dynamics simulations of hydroxamates complexed with human gelatinase-A (MMP-2) to gain insight into the structural and energetic preferences of these inhibitors. The study was conducted on a selected set of eleven compounds with variation in structure and activity. Molecular dynamics simulations were performed at 300 K for 100 ps with equilibration for 50 ps. The structural analyses of the trajectories indicate that the coordinate bond interactions, the hydrogen bond interactions, the van der Waals interactions as well as the hydrophobic interactions between ligand and receptor are responsible simultaneously for the preference of inhibition and potency. The ligand hydroxamate group is coordinated to the catalytic zinc ion and form stable hydrogen bonds with the carbonyl oxygen of Gly 162. The P1' group makes extensive van der Waals and hydrophobic contacts with the nonpolar side chains of several residues in the S1' subsite, including Leu 197, Val 198, Leu 218 and Tyr 223. Moreover, four to eight hydrogen bonds between hydroxamates and MMP-2 are formed to stabilize the inhibitors in the active site. Compared with the P2' and P3' groups, the P1' groups of inhibitors are oriented regularly, which is produced by the restrain of the S1' subsite. From the relationship between the length of the nonpolar P1' group and the biological activity, we confirm that MMP-2 has a pocket-like S1' subsite, not a channel-like S1' subsite proposed by Kiyama (Kiyama, R. et al., J. Med. Chem. 42 (1999), 1723). The energetic analyses show that the experimental binding free energies can be well correlated with the interactions between the inhibitors and their environments, which could be used as a simple score function to evaluate the binding affinities for other similar hydroxamates. The validity of the force field parameters and the MD simulations can be fully testified by the satisfactory agreements between the experimental structure

  11. Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization

    NASA Astrophysics Data System (ADS)

    Kumar, Rajnish; Långström, Bengt; Darreh-Shori, Taher

    2016-08-01

    Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of α-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, α-NETA exhibited an IC50 of ~30 μM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer’s disease.

  12. Novel ligands of Choline Acetyltransferase designed by in silico molecular docking, hologram QSAR and lead optimization

    PubMed Central

    Kumar, Rajnish; Långström, Bengt; Darreh-Shori, Taher

    2016-01-01

    Recent reports have brought back the acetylcholine synthesizing enzyme, choline acetyltransferase in the mainstream research in dementia and the cholinergic anti-inflammatory pathway. Here we report, a specific strategy for the design of novel ChAT ligands based on molecular docking, Hologram Quantitative Structure Activity Relationship (HQSAR) and lead optimization. Molecular docking was performed on a series of ChAT inhibitors to decipher the molecular fingerprint of their interaction with the active site of ChAT. Then robust statistical fragment HQSAR models were developed. A library of novel ligands was generated based on the pharmacophoric and shape similarity scoring function, and evaluated in silico for their molecular interactions with ChAT. Ten of the top scoring invented compounds are reported here. We confirmed the activity of α-NETA, the only commercially available ChAT inhibitor, and one of the seed compounds in our model, using a new simple colorimetric ChAT assay (IC50 ~ 88 nM). In contrast, α-NETA exhibited an IC50 of ~30 μM for the ACh-degrading cholinesterases. In conclusion, the overall results may provide useful insight for discovering novel ChAT ligands and potential positron emission tomography tracers as in vivo functional biomarkers of the health of central cholinergic system in neurodegenerative disorders, such as Alzheimer’s disease. PMID:27507101

  13. Molecular docking studies and in vitro cholinesterase enzyme inhibitory activities of chemical constituents of Garcinia hombroniana.

    PubMed

    Jamila, Nargis; Yeong, Khaw Kooi; Murugaiyah, Vikneswaran; Atlas, Amir; Khan, Imran; Khan, Naeem; Khan, Sadiq Noor; Khairuddean, Melati; Osman, Hasnah

    2015-01-01

    Garcinia species are reported to possess antimicrobial, anti-inflammatory, anticancer, anti-HIV and anti-Alzheimer's activities. This study aimed to investigate the in vitro cholinesterase enzyme inhibitory activities of garcihombronane C (1), garcihombronane F (2), garcihombronane I (3), garcihombronane N (4), friedelin (5), clerosterol (6), spinasterol glucoside (7) and 3β-hydroxy lup-12,20(29)-diene (8) isolated from Garcinia hombroniana, and to perform molecular docking simulation to get insight into the binding interactions of the ligands and enzymes. The cholinesterase inhibitory activities were evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. In this study, compound 4 displayed the highest concentration-dependent inhibition of both AChE and BChE. Docking studies exhibited that compound 4 binds through hydrogen bonds to amino acid residues of AChE and BChE. The calculated docking and binding energies also supported the in vitro inhibitory profiles of IC50. In conclusion, garcihombronanes C, F, I and N (1-4) exhibited dual and moderate inhibitory activities against AChE and BChE.

  14. Molecular docking based screening of compounds against VP40 from Ebola virus

    PubMed Central

    M Alam El-Din, Hanaa; A. Loutfy, Samah; Fathy, Nasra; H Elberry, Mostafa; M Mayla, Ahmed; Kassem, Sara; Naqvi, Asif

    2016-01-01

    Ebola virus causes severe and often fatal hemorrhagic fevers in humans. The 2014 Ebola epidemic affected multiple countries. The virus matrix protein (VP40) plays a central role in virus assembly and budding. Since there is no FDA-approved vaccine or medicine against Ebola viral infection, discovering new compounds with different binding patterns against it is required. Therefore, we aim to identify small molecules that target the Arg 134 RNA binding and active site of VP40 protein. 1800 molecules were retrieved from PubChem compound database based on Structure Similarity and Conformers of pyrimidine-2, 4-dione. Molecular docking approach using Lamarckian Genetic Algorithm was carried out to find the potent inhibitors for VP40 based on calculated ligand-protein pairwise interaction energies. The grid maps representing the protein were calculated using auto grid and grid size was set to 60*60*60 points with grid spacing of 0.375 Ǻ. Ten independent docking runs were carried out for each ligand and results were clustered according to the 1.0 Ǻ RMSD criteria. The post-docking analysis showed that binding energies ranged from -8.87 to 0.6 Kcal/mol. We report 7 molecules, which showed promising ADMET results, LD-50, as well as H-bond interaction in the binding pocket. The small molecules discovered could act as potential inhibitors for VP40 and could interfere with virus assembly and budding process. PMID:28149054

  15. Molecular docking based screening of compounds against VP40 from Ebola virus.

    PubMed

    M Alam El-Din, Hanaa; A Loutfy, Samah; Fathy, Nasra; H Elberry, Mostafa; M Mayla, Ahmed; Kassem, Sara; Naqvi, Asif

    2016-01-01

    Ebola virus causes severe and often fatal hemorrhagic fevers in humans. The 2014 Ebola epidemic affected multiple countries. The virus matrix protein (VP40) plays a central role in virus assembly and budding. Since there is no FDA-approved vaccine or medicine against Ebola viral infection, discovering new compounds with different binding patterns against it is required. Therefore, we aim to identify small molecules that target the Arg 134 RNA binding and active site of VP40 protein. 1800 molecules were retrieved from PubChem compound database based on Structure Similarity and Conformers of pyrimidine-2, 4-dione. Molecular docking approach using Lamarckian Genetic Algorithm was carried out to find the potent inhibitors for VP40 based on calculated ligand-protein pairwise interaction energies. The grid maps representing the protein were calculated using auto grid and grid size was set to 60*60*60 points with grid spacing of 0.375 Ǻ. Ten independent docking runs were carried out for each ligand and results were clustered according to the 1.0 Ǻ RMSD criteria. The post-docking analysis showed that binding energies ranged from -8.87 to 0.6 Kcal/mol. We report 7 molecules, which showed promising ADMET results, LD-50, as well as H-bond interaction in the binding pocket. The small molecules discovered could act as potential inhibitors for VP40 and could interfere with virus assembly and budding process.

  16. Docking and molecular dynamics simulations of the ternary complex nisin2:lipid II

    PubMed Central

    Mulholland, Sam; Turpin, Eleanor R.; Bonev, Boyan B.; Hirst, Jonathan D.

    2016-01-01

    Lanthionine antibiotics are an important class of naturally-occurring antimicrobial peptides. The best-known, nisin, is a commercial food preservative. However, structural and mechanistic details on nisin-lipid II membrane complexes are currently lacking. Recently, we have developed empirical force-field parameters to model lantibiotics. Docking and molecular dynamics (MD) simulations have been used to study the nisin2:lipid II complex in bacterial membranes, which has been put forward as the building block of nisin/lipid II binary membrane pores. An Ile1Trp mutation of the N-terminus of nisin has been modelled and docked onto lipid II models; the computed binding affinity increased compared to wild-type. Wild-type nisin was also docked onto three different lipid II structures and a stable 2:1 nisin:lipid II complex formed. This complex was inserted into a membrane. Six independent MD simulations revealed key interactions in the complex, specifically the N-terminal engagement of nisin with lipid II at the pyrophosphate and C-terminus of the pentapeptide chain. Nisin2 inserts into the membrane and we propose this as the first step in pore formation, mediated by the nisin N-terminus–lipid II pentapeptide hydrogen bond. The lipid II undecaprenyl chain adopted different conformations in the presence of nisin, which may also have implications for pore formation. PMID:26888784

  17. Molecular Docking Analysis of Steroid-based Copper Transporter 1 Inhibitors.

    PubMed

    Kadioglu, Onat; Serly, Julianna; Seo, Ean-Jeong; Vincze, Irén; Somlai, Csaba; Saeed, Mohamed E M; Molnár, József; Efferth, Thomas

    2015-12-01

    Copper transporter 1 (CTR1) represents an important determinant of cisplatin resistance. A series of 35 semi-substituted steroids were recently investigated on cisplatin-resistant CTR1-expressing A2780cis ovarian carcinoma cells as well as their parental sensitive counterparts regarding their cytotoxic and resistance-reversing features. In the present investigation, three compounds ( 4: , 5: , 25: ) were selected for molecular docking analysis on the homology-modelled human CTR1 transmembrane domain. Steroids 4: , 5: and 25: interacted with CTR1 at a similar docking pose and with even higher binding affinities than the known CTR1 inhibitor, cimetidine. Applying the defined docking mode, the binding energies were found to be -7.15±<0.001 kcal/mol (compound 4: ), -8.71±0.06 kcal/mol (compound 5: ), -7.63±0.01 kcal/mol (compound 25: ), and -5.05±0.02 kcal/mol (for cimetidine). These steroids have the potential for further development as CTR1 inhibitors overcoming cisplatin resistance.

  18. FIPSDock: a new molecular docking technique driven by fully informed swarm optimization algorithm.

    PubMed

    Liu, Yu; Zhao, Lei; Li, Wentao; Zhao, Dongyu; Song, Miao; Yang, Yongliang

    2013-01-05

    The accurate prediction of protein-ligand binding is of great importance for rational drug design. We present herein a novel docking algorithm called as FIPSDock, which implements a variant of the Fully Informed Particle Swarm (FIPS) optimization method and adopts the newly developed energy function of AutoDock 4.20 suite for solving flexible protein-ligand docking problems. The search ability and docking accuracy of FIPSDock were first evaluated by multiple cognate docking experiments. In a benchmarking test for 77 protein/ligand complex structures derived from GOLD benchmark set, FIPSDock has obtained a successful predicting rate of 93.5% and outperformed a few docking programs including particle swarm optimization (PSO)@AutoDock, SODOCK, AutoDock, DOCK, Glide, GOLD, FlexX, Surflex, and MolDock. More importantly, FIPSDock was evaluated against PSO@AutoDock, SODOCK, and AutoDock 4.20 suite by cross-docking experiments of 74 protein-ligand complexes among eight protein targets (CDK2, ESR1, F2, MAPK14, MMP8, MMP13, PDE4B, and PDE5A) derived from Sutherland-crossdock-set. Remarkably, FIPSDock is superior to PSO@AutoDock, SODOCK, and AutoDock in seven out of eight cross-docking experiments. The results reveal that FIPS algorithm might be more suitable than the conventional genetic algorithm-based algorithms in dealing with highly flexible docking problems.

  19. Kinetics and molecular docking studies of fucosterol and fucoxanthin, BACE1 inhibitors from brown algae Undaria pinnatifida and Ecklonia stolonifera.

    PubMed

    Jung, Hyun Ah; Ali, Md Yousof; Choi, Ran Joo; Jeong, Hyong Oh; Chung, Hae Young; Choi, Jae Sue

    2016-03-01

    Since the action of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is strongly correlated with the onset of Alzheimer's disease (AD), the development of BACE1 inhibitors as therapeutic agents is being vigorously pursued. In our ongoing research aimed at identifying anti-AD remedies derived from maritime plants, we evaluated the BACE1 inhibitory activities of fucosterol and fucoxanthin from Ecklonia stolonifera and Undaria pinnatifida. In vitro anti-AD activities were performed via BACE1 inhibition assays, as well as enzyme kinetic and molecular docking predictions. Based on enzyme-based assays, fucosterol and fucoxanthin showed noncompetitive and mixed-type inhibition, respectively, against BACE1. In addition, docking simulation results demonstrated that the Lys224 residue of BACE1 interacted with one hydroxyl group of fucosterol, while two additional BACE1 residues (Gly11 and Ala127) interacted with two hydroxyl groups of fucoxanthin. Moreover, the binding energy of fucosterol and fucoxanthin was negative (-10.1 and -7.0 kcal/mol), indicating that hydrogen bonding may stabilize the open form of the enzyme and potentiate tight binding of the active site of BACE1, resulting in more effective BACE1 inhibition. The results suggest that fucosterol and fucoxanthin may be used beneficially in the treatment of AD and provide potential guidelines for the design of new BACE1 inhibitors.

  20. Investigations on Binding Pattern of Kinase Inhibitors with PPARγ: Molecular Docking, Molecular Dynamic Simulations, and Free Energy Calculation Studies

    PubMed Central

    Mazumder, Mohit; Das, Umashankar; Gourinath, Samudrala

    2017-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential target for the treatment of several disorders. In view of several FDA approved kinase inhibitors, in the current study, we have investigated the interaction of selected kinase inhibitors with PPARγ using computational modeling, docking, and molecular dynamics simulations (MDS). The docked conformations and MDS studies suggest that the selected KIs interact with PPARγ in the ligand binding domain (LBD) with high positive predictive values. Hence, we have for the first time shown the plausible binding of KIs in the PPARγ ligand binding site. The results obtained from these in silico investigations warrant further evaluation of kinase inhibitors as PPARγ ligands in vitro and in vivo. PMID:28321247

  1. Studies of molecular docking between fibroblast growth factor and heparin using generalized simulated annealing

    NASA Astrophysics Data System (ADS)

    Pita, Samuel Silva Da Rocha; Fernandes, Tácio Vinício Amorim; Caffarena, Ernesto Raul; Pascutti, Pedro Geraldo

    Since the middle 70s, the main molecular docking problem consists in limitations to treat adequately the degrees of freedom of protein (or a receptor) due to the energy landscape roughness and the high computational cost. Until recently, only few algorithms considering flexible simultaneously both ligand and receptor at low computational cost were developed. As a recent proposed Statistical Mechanics, generalized simulated annealing (GSA) has been employed at diverse works concerning global optimization problems. In this work, we used this method exploring the molecular docking problem taking into account the FGF-2 and heparin complex. Since the requirements of an efficient docking algorithm are accuracy and velocity, we tested the influence of GSA parameters qA (new configuration acceptance index), qV (energy surface visiting index), and qT (temperature decreasing control) on the performance of GSADOCK program. Our simulations showed that as temperature parameter qT increases, qA parameter follows this behavior in the interval ranging from 1.1 to 2.3. We found that the GSA parameters have the best performance for the qA values ranging from 1.1 to 1.3, qV values from 1.3 to 1.5, and qT values from 1.1 to 1.7. Most of good qV values were equal or next the good qT values. Finally, the implemented algorithm is trustworthy and can be employed as a tool of molecular modeling methods. The final version of the program will be free of charge and will be accessible at our home-page or could be requested to the authors for e-mail.

  2. Interaction between 8-methoxypsoralen and trypsin: Monitoring by spectroscopic, chemometrics and molecular docking approaches

    NASA Astrophysics Data System (ADS)

    Liu, Yingying; Zhang, Guowen; Zeng, Ni; Hu, Song

    2017-02-01

    8-Methoxypsoralen (8-MOP) is a naturally occurring furanocoumarin with various biological activities. However, there is little information on the binding mechanism of 8-MOP with trypsin. Here, the interaction between 8-MOP and trypsin in vitro was determined by multi-spectroscopic methods combined with the multivariate curve resolution-alternating least squares (MCR-ALS) chemometrics approach. An expanded UV-vis spectral data matrix was analysed by MCR-ALS, the concentration profiles and pure spectra for the three reaction species (trypsin, 8-MOP and 8-MOP-trypsin) were obtained to monitor the interaction between 8-MOP and trypsin. The fluorescence data suggested that a static type of quenching mechanism occurred in the binding of 8-MOP to trypsin. Hydrophobic interaction dominated the formation of the 8-MOP-trypsin complex on account of the positive enthalpy and entropy changes, and trypsin had one high affinity binding site for 8-MOP with a binding constant of 3.81 × 104 L mol- 1 at 298 K. Analysis of three dimensional fluorescence, UV-vis absorption and circular dichroism spectra indicated that the addition of 8-MOP induced the rearrangement of the polypeptides carbonyl hydrogen-bonding network and the conformational changes in trypsin. The molecular docking predicted that 8-MOP interacted with the catalytic residues His57, Asp102 and Ser195 in trypsin. The binding patterns and trypsin conformational changes may result in the inhibition of trypsin activity. This study has provided insights into the binding mechanism of 8-MOP with trypsin.

  3. Structural investigations into the binding mode of novel neolignans Cmp10 and Cmp19 microtubule stabilizers by in silico molecular docking, molecular dynamics, and binding free energy calculations.

    PubMed

    Tripathi, Shubhandra; Kumar, Akhil; Kumar, B Sathish; Negi, Arvind S; Sharma, Ashok

    2016-06-01

    Microtubule stabilizers provide an important mode of treatment via mitotic cell arrest of cancer cells. Recently, we reported two novel neolignans derivatives Cmp10 and Cmp19 showing anticancer activity and working as microtubule stabilizers at micromolar concentrations. In this study, we have explored the binding site, mode of binding, and stabilization by two novel microtubule stabilizers Cmp10 and Cmp19 using in silico molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations. Molecular docking studies were performed to explore the β-tubulin binding site of Cmp10 and Cmp19. Further, MD simulations were used to probe the β-tubulin stabilization mechanism by Cmp10 and Cmp19. Binding affinity was also compared for Cmp10 and Cmp19 using binding free energy calculations. Our docking results revealed that both the compounds bind at Ptxl binding site in β-tubulin. MD simulation studies showed that Cmp10 and Cmp19 binding stabilizes M-loop (Phe272-Val288) residues of β-tubulin and prevent its dynamics, leading to a better packing between α and β subunits from adjacent tubulin dimers. In addition, His229, Ser280 and Gln281, and Arg278, Thr276, and Ser232 were found to be the key amino acid residues forming H-bonds with Cmp10 and Cmp19, respectively. Consequently, binding free energy calculations indicated that Cmp10 (-113.655 kJ/mol) had better binding compared to Cmp19 (-95.216 kJ/mol). This study provides useful insight for better understanding of the binding mechanism of Cmp10 and Cmp19 and will be helpful in designing novel microtubule stabilizers.

  4. Study of the Binding between Camptothecin Analogs and FTO by Spectroscopy and Molecular Docking.

    PubMed

    Ren, Ting; Wang, Zechun; Zhang, Lijiao; Wang, Ning; Han, Xinxin; Wang, Ruiyong; Chang, Junbiao

    2017-04-11

    In this work, the interaction between camptothecin (CPT) analogs and fat mass and obesity associated (FTO) was investigated using spectroscopy and molecular docking. From the experimental results, it was found that the CPT analogs caused the fluorescence quenching of FTO through a static quenching procedure. The binding constants and thermodynamic parameters at three different temperatures, the number of binding sites were obtained, which suggested that the hydrophobic interaction and electrostatic force played major role in the reaction between CPT analogs and FTO. Results revealed that 10-hydroxycamptothecin was the strongest quencher.

  5. Molecular docking studies and anti-tyrosinase activity of Thai mango seed kernel extract.

    PubMed

    Nithitanakool, Saruth; Pithayanukul, Pimolpan; Bavovada, Rapepol; Saparpakorn, Patchreenart

    2009-01-07

    The alcoholic extract from seed kernels of Thai mango (Mangifera indica L. cv. 'Fahlun') (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent, dose-dependent inhibitory effects on tyrosinase with respect to L-DOPA. Molecular docking studies revealed that the binding orientations of the phenolic principles were in the tyrosinase binding pocket and their orientations were located in the hydrophobic binding pocket surrounding the binuclear copper active site. The results indicated a possible mechanism for their anti-tyrosinase activity which may involve an ability to chelate the copper atoms which are required for the catalytic activity of tyrosinase.

  6. Synthesis of 2-acylated and sulfonated 4-hydroxycoumarins: In vitro urease inhibition and molecular docking studies.

    PubMed

    Rashid, Umer; Rahim, Fazal; Taha, Muhammad; Arshad, Muhammad; Ullah, Hayat; Mahmood, Tariq; Ali, Muhammad

    2016-06-01

    Sixteen 4-hydroxycoumarin derivatives were synthesized, characterized through EI-MS and (1)H NMR and screened for urease inhibitory potential. Three compounds exhibited better urease inhibition than the standard inhibitor thiourea (IC50=21±0.11μM) while other four compounds exhibited good to moderate inhibition with IC50 values between 29.45±1.1μM and 69.53±0.9μM. Structure activity relationship was established on the basis of molecular docking studies, which helped to predict the binding interactions of the most active compounds.

  7. Synthesis, biological evaluation and molecular docking of aryl hydrazines and hydrazides for anticancer activity.

    PubMed

    Gohil, Vikrantsinh M; Agrawal, Satyam K; Saxena, Ajit K; Garg, Divita; Gopimohan, C; Bhutani, Kamlesh K

    2010-03-01

    Aryl hydrazine and hydrazide analogues were synthesized based on p-tolyl hydrazine, isolated as a breakdown product of a secondary metabolite from the mushroom, Agaricus bisporus, and tested to be highly active molecule than 5-fluorouracil in in vitro anticancer studies. The synthesized analogues were tested for anticancer activity using NCI protocol. Anolgues 12 and 15 emerged as molecules with significant in vitro anticancer activity. Molecular docking study revealed the binding orientations of aryl hydrazines and hydrazides analogues in the active sites of thymidylate synthase.

  8. Implicit ligand theory: Rigorous binding free energies and thermodynamic expectations from molecular docking

    NASA Astrophysics Data System (ADS)

    Minh, David D. L.

    2012-09-01

    A rigorous formalism for estimating noncovalent binding free energies and thermodynamic expectations from calculations in which receptor configurations are sampled independently from the ligand is derived. Due to this separation, receptor configurations only need to be sampled once, facilitating the use of binding free energy calculations in virtual screening. Demonstrative calculations on a host-guest system yield good agreement with previous free energy calculations and isothermal titration calorimetry measurements. Implicit ligand theory provides guidance on how to improve existing molecular docking algorithms and insight into the concepts of induced fit and conformational selection in noncovalent macromolecular recognition.

  9. Effect of HIV-1 Subtype C integrase mutations implied using molecular modeling and docking data.

    PubMed

    Sachithanandham, Jaiprasath; Konda Reddy, Karnati; Solomon, King; David, Shoba; Kumar Singh, Sanjeev; Vadhini Ramalingam, Veena; Alexander Pulimood, Susanne; Cherian Abraham, Ooriyapadickal; Rupali, Pricilla; Sridharan, Gopalan; Kannangai, Rajesh

    2016-01-01

    The degree of sequence variation in HIV-1 integrase genes among infected patients and their impact on clinical response to Anti retroviral therapy (ART) is of interest. Therefore, we collected plasma samples from 161 HIV-1 infected individuals for subsequent integrase gene amplification (1087 bp). Thus, 102 complete integrase gene sequences identified as HIV-1 subtype-C was assembled. This sequence data was further used for sequence analysis and multiple sequence alignment (MSA) to assess position specific frequency of mutations within pol gene among infected individuals. We also used biophysical geometric optimization technique based molecular modeling and docking (Schrodinger suite) methods to infer differential function caused by position specific sequence mutations towards improved inhibitor selection. We thus identified accessory mutations (usually reduce susceptibility) leading to the resistance of some known integrase inhibitors in 14% of sequences in this data set. The Stanford HIV-1 drug resistance database provided complementary information on integrase resistance mutations to deduce molecular basis for such observation. Modeling and docking analysis show reduced binding by mutants for known compounds. The predicted binding values further reduced for models with combination of mutations among subtype C clinical strains. Thus, the molecular basis implied for the consequence of mutations in different variants of integrase genes of HIV-1 subtype C clinical strains from South India is reported. This data finds utility in the design, modification and development of a representative yet an improved inhibitor for HIV-1 integrase.

  10. Effect of HIV-1 Subtype C integrase mutations implied using molecular modeling and docking data

    PubMed Central

    Sachithanandham, Jaiprasath; Konda Reddy, Karnati; Solomon, King; David, Shoba; Kumar Singh, Sanjeev; Vadhini Ramalingam, Veena; Alexander Pulimood, Susanne; Cherian Abraham, Ooriyapadickal; Rupali, Pricilla; Sridharan, Gopalan; Kannangai, Rajesh

    2016-01-01

    The degree of sequence variation in HIV-1 integrase genes among infected patients and their impact on clinical response to Anti retroviral therapy (ART) is of interest. Therefore, we collected plasma samples from 161 HIV-1 infected individuals for subsequent integrase gene amplification (1087 bp). Thus, 102 complete integrase gene sequences identified as HIV-1 subtype-C was assembled. This sequence data was further used for sequence analysis and multiple sequence alignment (MSA) to assess position specific frequency of mutations within pol gene among infected individuals. We also used biophysical geometric optimization technique based molecular modeling and docking (Schrodinger suite) methods to infer differential function caused by position specific sequence mutations towards improved inhibitor selection. We thus identified accessory mutations (usually reduce susceptibility) leading to the resistance of some known integrase inhibitors in 14% of sequences in this data set. The Stanford HIV-1 drug resistance database provided complementary information on integrase resistance mutations to deduce molecular basis for such observation. Modeling and docking analysis show reduced binding by mutants for known compounds. The predicted binding values further reduced for models with combination of mutations among subtype C clinical strains. Thus, the molecular basis implied for the consequence of mutations in different variants of integrase genes of HIV-1 subtype C clinical strains from South India is reported. This data finds utility in the design, modification and development of a representative yet an improved inhibitor for HIV-1 integrase. PMID:28149058

  11. Molecular docking as a popular tool in drug design, an in silico travel

    PubMed Central

    de Ruyck, Jerome; Brysbaert, Guillaume; Blossey, Ralf; Lensink, Marc F

    2016-01-01

    New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism-or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents’ synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein–protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery. PMID:27390530

  12. Molecular modeling of methyl-α-Neu5Ac analogues docked against cholera toxin--a molecular dynamics study.

    PubMed

    Blessy, J Jino; Sharmila, D Jeya Sundara

    2015-02-01

    Molecular modeling of synthetic methyl-α-Neu5Ac analogues modified in C-9 position was investigated by molecular docking and molecular dynamics (MD) simulation methods. Methyl-α-Neu5Ac analogues were docked against cholera toxin (CT) B subunit protein and MD simulations were carried out for three Methyl-α-Neu5Ac analogue-CT complexes (30, 10 and 10 ns) to estimate the binding activity of cholera toxin-Methyl-α-Neu5Ac analogues using OPLS_2005 force field. In this study, direct and water mediated hydrogen bonds play a vital role that exist between the methyl-α-9-N-benzoyl-amino-9-deoxy-Neu5Ac (BENZ)-cholera toxin active site residues. The Energy plot, RMSD and RMSF explain that the simulation was stable throughout the simulation run. Transition of phi, psi and omega angle for the complex was calculated. Molecular docking studies could be able to identify the binding mode of methyl-α-Neu5Ac analogues in the binding site of cholera toxin B subunit protein. MD simulation for Methyl-α-9-N-benzoyl-amino-9-deoxy-Neu5Ac (BENZ), Methyl-α-9-N-acetyl-9-deoxy-9-amino-Neu5Ac and Methyl-α-9-N-biphenyl-4-acetyl-deoxy-amino-Neu5Ac complex with CT B subunit protein was carried out, which explains the stable nature of interaction. These methyl-α-Neu5Ac analogues that have computationally acceptable pharmacological properties may be used as novel candidates for drug design for cholera disease.

  13. Searching the conformational complexity and binding properties of HDAC6 through docking and molecular dynamic simulations.

    PubMed

    Sixto-López, Yudibeth; Bello, Martiniano; Rodríguez-Fonseca, Rolando Alberto; Rosales-Hernández, Martha Cecilia; Martínez-Archundia, Marlet; Gómez-Vidal, José Antonio; Correa-Basurto, José

    2016-09-23

    Histone deacetylases (HDACs) are a family of proteins involved in the deacetylation of histones and other non-histones substrates. HDAC6 belongs to class II and shares similar biological functions with others of its class. Nevertheless, its three-dimensional structure that involves the catalytic site remains unknown for exploring the ligand recognition properties. Therefore, in this contribution, homology modeling, 100-ns-long Molecular Dynamics (MD) simulation and docking calculations were combined to explore the conformational complexity and binding properties of the catalytic domain 2 from HDAC6 (DD2-HDAC6), for which activity and affinity toward five different ligands have been reported. Clustering analysis allowed identifying the most populated conformers present during the MD simulation, which were used as starting models to perform docking calculations with five DD2-HDAC6 inhibitors: Cay10603 (CAY), Rocilinostat (RCT), Tubastatin A (TBA), Tubacin (TBC), and Nexturastat (NXT), and then were also submitted to 100-ns-long MD simulations. Docking calculations revealed that the five inhibitors bind at the DD2-HDAC6 binding site with the lowest binding free energy, the same binding mode is maintained along the 100-ns-long MD simulations. Overall, our results provide structural information about the molecular flexibility of apo and holo DD2-HDAC6 states as well as insight of the map of interactions between DD2-HDAC6 and five well-known DD2-HDAC6 inhibitors allowing structural details to guide the drug design. Finally, we highlight the importance of combining different theoretical approaches to provide suitable structural models for structure-based drug design.

  14. Molecular docking study of the binding of aminopyridines within the K+ channel.

    PubMed

    Caballero, Norma Angélica; Meléndez, Francisco Javier; Niño, Alfonso; Muñoz-Caro, Camelia

    2007-05-01

    We present a molecular docking study aimed to identify the binding site of protonated aminopyridines for the blocking of voltage dependent K(+) channels. Several active aminopyridines are considered: 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 3,4-diaminopyridine, and 4-aminoquinoleine. We apply the AutoDock force field with a lamarckian genetic algorithm, using atomic charges for the ligands derived from the electrostatic potential obtained at the B3LYP/cc-pVDZ level. We find a zone in the alpha-subunit of the K(+) channel bearing common binding sites. This zone corresponds to five amino acids comprised between residuals Thr107 and Ala111, in the KcsA K(+) channel (1J95 pdb structure). The 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine bind to the carboxylic oxygens of Thr107 and Ala111. In all cases aminopyridines are perpendicular to the axis of the pore. 4-aminoquinoleine binds to the carboxylic oxygen of Ala111. Due to its large size, the molecular plane is parallel to the axis of the pore. The charge distributions and the structures of the binding complexes suggest that the interaction is driven by formation of several hydrogen bonds. We find 2-aminopyridine, 3-aminopyridine, 4-aminopyridine, and 3,4-diaminopyridine with similar binding energy. Considering the standard error of the estimate of the AutoDock force field, this energy should lie, as a rough estimation, in the interval 3-7 kcal mol(-1). On the other hand, 4-aminoquinoleine seems to have a smaller binding energy.

  15. Molecular docking and 3D-QSAR studies on gag peptide analogue inhibitors interacting with human cyclophilin A.

    PubMed

    Cui, Meng; Huang, Xiaoqin; Luo, Xiaomin; Briggs, James M; Ji, Ruyun; Chen, Kaixian; Shen, Jianhua; Jiang, Hualiang

    2002-11-21

    The interaction of a series gag peptide analogues with human cyclophilin A (hCypA) have been studied employing molecular docking and 3D-QSAR approaches. The Lamarckian Genetic Algorithm (LGA) and divide-and-conquer methods were applied to locate the binding orientations and conformations of the inhibitors interacting with hCypA. Good correlations between the calculated interaction free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. A novel interaction model was identified for inhibitors 11, 15, and 17 whose N-termini were modified by addition of the deaminovaline (Dav) group and the C-termini of 15 and 17 were modified by addition of a benzyl group. Accordingly, two new binding sites (sites A and D in Figure 1) were revealed, which show a strong correlation with inhibitor potency and thus can be used as a starting point for new inhibitor design. In addition, two predictive 3D-QSAR models were obtained by CoMFA and CoMSIA analyses based on the binding conformations derived from the molecular docking calculations. The reasonable r(cross)(2) (cross-validated) values 0.738 and 0.762 were obtained for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by four peptide analogues test set. The CoMFA and CoMSIA field distributions are in general agreement with the structural characteristics of the binding groove of hCypA. This indicates the reasonableness of the binding model of the inhibitors with hCypA. Considering all these results together with the valuable clues of binding from references published recently, reasonable pharmacophore elements have been suggested, demonstrating that the 3D-QSAR models about peptide analogue inhibitors are expected to be further employed in predicting activities of the novel compounds for inhibiting hCypA.

  16. Improved Accuracy in RNA-Protein Rigid Body Docking by Incorporating Force Field for Molecular Dynamics Simulation into the Scoring Function.

    PubMed

    Iwakiri, Junichi; Hamada, Michiaki; Asai, Kiyoshi; Kameda, Tomoshi

    2016-09-13

    RNA-protein interactions play fundamental roles in many biological processes. To understand these interactions, it is necessary to know the three-dimensional structures of RNA-protein complexes. However, determining the tertiary structure of these complexes is often difficult, suggesting that an accurate rigid body docking for RNA-protein complexes is needed. In general, the rigid body docking process is divided into two steps: generating candidate structures from the individual RNA and protein structures and then narrowing down the candidates. In this study, we focus on the former problem to improve the prediction accuracy in RNA-protein docking. Our method is based on the integration of physicochemical information about RNA into ZDOCK, which is known as one of the most successful computer programs for protein-protein docking. Because recent studies showed the current force field for molecular dynamics simulation of protein and nucleic acids is quite accurate, we modeled the physicochemical information about RNA by force fields such as AMBER and CHARMM. A comprehensive benchmark of RNA-protein docking, using three recently developed data sets, reveals the remarkable prediction accuracy of the proposed method compared with existing programs for docking: the highest success rate is 34.7% for the predicted structure of the RNA-protein complex with the best score and 79.2% for 3,600 predicted ones. Three full atomistic force fields for RNA (AMBER94, AMBER99, and CHARMM22) produced almost the same accurate result, which showed current force fields for nucleic acids are quite accurate. In addition, we found that the electrostatic interaction and the representation of shape complementary between protein and RNA plays the important roles for accurate prediction of the native structures of RNA-protein complexes.

  17. Molecular docking and QSAR studies on substituted acyl(thio)urea and thiadiazolo [2,3-alpha] pyrimidine derivatives as potent inhibitors of influenza virus neuraminidase.

    PubMed

    Sun, Jiaying; Cai, Shaoxi; Mei, Hu; Li, Jian; Yan, Ning; Wang, Qin; Lin, Zhihua; Huo, Danqun

    2010-09-01

    Surflex-Dock was employed to dock 36 thiourea and thiadiazolo [2,3-alpha] pyrimidine derivatives into neuraminidase 1a4g. Molecular docking results showed that hydrogen bonding, electrostatic, and hydrophobic features were important factors affecting inhibitory activities of these neuraminidase inhibitors. Moreover, there was a significant correlation between the predicted binding affinity (total scores) and experimental pIC50 values with correlation coefficient r=0.846 and p<0.0001. Hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis were used to develop quantitative structure-activity relationship models. Squared multiple correlation coefficients (r2) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.899, 0.878, and 0.865, respectively. Squared cross-validated correlation coefficient (q2) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models was in turn 0.628, 0.656, and 0.509. In addition, squared multiple correlation coefficients for test set (r2test) of hologram quantitative structure-activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.558, 0.667, and 0.566, respectively. The most active sample ID 2 was taken as a template molecule to design new molecules. Based on the comparative molecular field analysis model, new compounds were designed by LeapFrog. Seven new compounds with improved binding energy and predicted activities were finally obtained.

  18. Study on the interactions of mapenterol with serum albumins using multi-spectroscopy and molecular docking.

    PubMed

    Bi, Shuyun; Zhao, Tingting; Wang, Yu; Zhou, Huifeng

    2016-03-01

    The interactions of mapenterol with bovine serum albumin (BSA) and human serum albumin (HSA) have been investigated systematically using fluorescence spectroscopy, absorption spectroscopy, circular dichroism (CD) and molecular docking techniques. Mapenterol has a strong ability to quench the intrinsic fluorescence of BSA and HSA through static quenching procedures. At 291 K, the binding constants, Ka, were 1.93 × 10(3) and 2.73 × 10(3) L/mol for mapenterol-BSA and mapenterol-HAS, respectively. Electrostatic forces and hydrophobic interactions played important roles in stabilizing the mapenterol-BSA/has complex. Using site marker competitive studies, mapenterol was found to bind at Sudlow site I on BSA/HSA. There was little effect of K(+), Ca(2+), Cu(2+), Zn(2+) and Fe(3+) on the binding. The conformation of BSA/HSA was changed by mapenterol, as seen from the synchronous fluorescence spectra. The CD spectra showed that the binding of mapenterol to BSA/HSA changed the secondary structure of BSA/HSA. Molecular docking further confirmed that mapenterol could bind to Sudlow site I of BSA/HSA. According to Förster non-radiative energy transfer theory (FRET), the distances r0 between the donor and acceptor were calculated as 3.18 and 2.75 nm for mapenterol-BSA and mapenterol-HAS, respectively.

  19. Eco-friendly synthesis, physicochemical studies, biological assay and molecular docking of steroidal oxime-ethers

    PubMed Central

    Alam, Mahboob; Lee, Dong-Ung

    2015-01-01

    The aim of this study was to report the synthesis of biologically active compounds; 7-(2′-aminoethoxyimino)-cholest-5-ene (4), a steroidal oxime-ether and its derivatives (5, 6) via a facile microwave assisted solvent free reaction methodology. This new synthetic, eco-friendly, sustainable protocol resulted in a remarkable improvement in the synthetic efficiency (85-93 % yield) and high purity using basic alumina. The synthesized compounds were screened for their antibacterial against six bacterial strains by disc diffusion method and antioxidant potential by DPPH assay. The binding capabilities of a compound 6 exhibiting good antibacterial potential were assessed on the basis of molecular docking studies and four types of three-dimensional molecular field descriptors. Moreover the structure-antimicrobial activity relationships were studied using some physicochemical and quantum-chemical parameters with GAMESS interface as well as WebMO Job Manager by using the basic level of theory. Hence, this synthetic approach is believed to provide a better scope for the synthesis of steroidal oxime-ether analogues and will be a more practical alternative to the presently existing procedures. Moreover, detailed in silico docking studies suggested the plausible mechanism of steroidal oxime-ethers as effective antimicrobial agents. PMID:27330525

  20. Binding of mitomycin C to blood proteins: A spectroscopic analysis and molecular docking

    NASA Astrophysics Data System (ADS)

    Jang, Jongchol; Liu, Hui; Chen, Wei; Zou, Guolin

    2009-06-01

    Mitomycin C (MMC) was the first recognized bioreductive alkylating agent, and has been widely used clinically for antitumor therapy. The binding of MMC to two human blood proteins, human serum albumin (HSA) and human hemoglobin (HHb), have been investigated by fluorescence quenching, synchronous fluorescence, circular dichroism (CD) spectroscopy and molecular docking methods. The fluorescence data showed that binding of MMC to proteins caused strong fluorescence quenching of proteins through a static quenching way, and each protein had only one binding site for the drug. The binding constants of MMC to HSA and HHb at 298 K were 2.71 × 10 4 and 2.56 × 10 4 L mol -1, respectively. Thermodynamic analysis suggested that both hydrophobic interaction and hydrogen bonding played major roles in the binding of MMC to HSA or HHb. The CD spectroscopy indicated that the secondary structures of the two proteins were not changed in the presence of MMC. The study of molecular docking showed that MMC was located in the entrance of site I of HSA, and in the central cavity of HHb.

  1. Functionalized imidazolium and benzimidazolium salts as paraoxonase 1 inhibitors: Synthesis, characterization and molecular docking studies.

    PubMed

    Karataş, Mert Olgun; Uslu, Harun; Alıcı, Bülent; Gökçe, Başak; Gencer, Nahit; Arslan, Oktay; Arslan, N Burcu; Özdemir, Namık

    2016-03-15

    Paraoxonase (PON) is a key enzyme in metabolism of living organisms and decreased activity of PON1 was acknowledged as a risk for atherosclerosis and organophosphate toxicity. The present study describes the synthesis, characterization, PON1 inhibitory properties and molecular docking studies of functionalized imidazolium and benzimidazolium salts (1a-5g). The structures of all compounds were elucidated by IR, NMR, elemental analysis and structures of compounds 2b and 2c were characterized by single-crystal X-ray diffraction. Compound 1c, a coumarin substituted imidazolium salt showed the best inhibitory effect on the activity of PON1 with good IC50 value (6.37 μM). Kinetic investigation was evaluated for this compound and results showed that this compound is competitive inhibitor of PON1 with Ki value of 2.39 μM. Molecular docking studies were also performed for most active compound 1c and one of least active compound 2c in order to determine the probable binding model into active site of PON1 and validation of the experimental results.

  2. Study on the interaction of catalase with pesticides by flow injection chemiluminescence and molecular docking.

    PubMed

    Tan, Xijuan; Wang, Zhuming; Chen, Donghua; Luo, Kai; Xiong, Xunyu; Song, Zhenghua

    2014-08-01

    The interaction mechanisms of catalase (CAT) with pesticides (including organophosphates: disulfoton, isofenphos-methyl, malathion, isocarbophos, dimethoate, dipterex, methamidophos and acephate; carbamates: carbaryl and methomyl; pyrethroids: fenvalerate and deltamethrin) were first investigated by flow injection (FI) chemiluminescence (CL) analysis and molecular docking. By homemade FI-CL model of lg[(I0-I)/I]=lgK+nlg[D], it was found that the binding processes of pesticides to CAT were spontaneous with the apparent binding constants K of 10(3)-10(5) L mol(-1) and the numbers of binding sites about 1.0. The binding abilities of pesticides to CAT followed the order: fenvalerate>deltamethrin>disulfoton>isofenphos-methyl>carbaryl>malathion>isocarbophos>dimethoate>dipterex>acephate>methomyl>methamidophos, which was generally similar to the order of determination sensitivity of pesticides. The thermodynamic parameters revealed that CAT bound with hydrophobic pesticides by hydrophobic interaction force, and with hydrophilic pesticides by hydrogen bond and van der Waals force. The pesticides to CAT molecular docking study showed that pesticides could enter into the cavity locating among the four subdomains of CAT, giving the specific amino acid residues and hydrogen bonds involved in CAT-pesticides interaction. It was also found that the lgK values of pesticides to CAT increased regularly with increasing lgP, Mr, MR and MV, suggesting that the hydrophobicity and steric property of pesticide played essential roles in its binding to CAT.

  3. In vitro acetylcholinesterase inhibition by psoralen using molecular docking and enzymatic studies

    PubMed Central

    Somani, Gauresh; Kulkarni, Chinmay; Shinde, Prashant; Shelke, Rupesh; Laddha, Kirti; Sathaye, Sadhana

    2015-01-01

    Introduction: Alzheimer's disease (AD) has increased at an alarming rate and is now a worldwide health problem. Inhibitors of acetylcholinesterase (AChE) leading to inhibition of acetylcholine breakdown constitute the main therapeutic strategy for AD. Psoralen was investigated as inhibitor of AChE enzyme in an attempt to explore its potential for the management of AD. Materials and Methods: Psoralen was isolated from powdered Psoralea corylifolia fruits. AChE enzyme inhibitory activity of different concentrations of psoralen was investigated by use of in vitro enzymatic and molecular docking studies. Further, the enzyme kinetics were studied using Lineweaver-Burk plot. Results: Psoralen was found to inhibit AChE enzyme activity in a concentration-dependent manner. Kinetic studies showed psoralen inhibits AChE in a competitive manner. Molecular docking study revealed that psoralen binds well within the binding site of the enzyme showing interactions such as π-π stacking and hydrogen bonding with residues present therein. Conclusion: The result of AChE enzyme inhibitory activity of the psoralen in this study is promising. It could be further explored as a potential candidate for further development of new drugs against AD. PMID:25709334

  4. Structural and molecular docking studies of biologically active mercaptopyrimidine Schiff bases

    NASA Astrophysics Data System (ADS)

    Kirubavathy, S. Jone; Velmurugan, R.; Karvembu, R.; Bhuvanesh, N. S. P.; Enoch, Israel V. M. V.; Selvakumar, P. Mosae; Premnath, D.; Chitra, S.

    2017-01-01

    Novel Schiff bases derived from the treatment of mercapto-diamino pyrimidine with two different aldehydes are characterized using elemental analysis, single crystal X-ray diffraction and 1H NMR spectroscopy. The pharmacological action of the synthesized compounds viz., antimicrobial, anticancer and antitubercular activities is studied. The Schiff bases show a very good activity against various test pathogens. DNA and β-CD binding interactions of the compounds are studied using UV-Visible absorption and fluorescence spectral measurements. The binding constants of the compounds towards β-CD are in the order of 103 to 104. Molecular docking is done using MOE program on the 3D structure of the enzymes, viz., human thymidylate synthase complexed with dump and raltitrex, candida albicans N-myristoyltransferasepeptidic inhibitor, catalytic domain of protein kinase pKnb from mycobacterium tuberculosis in complex with mitoxantrone, pare, topoisomerase atpase inhibitor, E. coli and lactobacillus casdihydrofolatereductase. The MIC/IC50 values of the Schiff bases are compared with the glide scores from the molecular docking studies. The number of hydrogen bonding interactions between the Schiff bases and amino acid residues are also reported.

  5. Potential toxicity of sarafloxacin to catalase: spectroscopic, ITC and molecular docking descriptions.

    PubMed

    Cao, Zhaozhen; Liu, Rutao; Yang, Bingjun

    2013-11-01

    The interaction between sarafloxacin and catalase (CAT) was studied by fluorescence spectroscopy, UV-visible absorption spectroscopy, circular dichroism (CD) spectroscopy, isothermal titration microcalorimetry (ITC) and molecular docking method. After deducting the inner filter effect, the fluorescence of CAT was quenched regularly by different concentrations of sarafloxacin. The quenching mechanism was studied by lifetime measurement, and it was proved to be mostly due to static quenching. The formation of sarafloxacin-CAT complex alters the micro-environment of amide moieties and tryptophan (Trp) residues, reduces the α-helix content of the enzyme, changes the peripheral substituents on the porphyrin ring of heme and leads to the inhibition of the enzyme activity. Molecular docking study reveals that sarafloxacin is located between two α-helix of CAT near to Trp 182 and Trp 185 residues, which supports the experimental results and helps to have a more clear understanding about the interaction mechanism. The change in the relative position of His 74 to heme induced by the variation of secondary structure is considered to be the major reason for the reduction of CAT activity. Moreover, sarafloxacin binds into a hydrophobic area of CAT mainly through hydrophobic interactions, which is consistent with the ITC analysis.

  6. Potential toxicity of sarafloxacin to catalase: Spectroscopic, ITC and molecular docking descriptions

    NASA Astrophysics Data System (ADS)

    Cao, Zhaozhen; Liu, Rutao; Yang, Bingjun

    2013-11-01

    The interaction between sarafloxacin and catalase (CAT) was studied by fluorescence spectroscopy, UV-visible absorption spectroscopy, circular dichroism (CD) spectroscopy, isothermal titration microcalorimetry (ITC) and molecular docking method. After deducting the inner filter effect, the fluorescence of CAT was quenched regularly by different concentrations of sarafloxacin. The quenching mechanism was studied by lifetime measurement, and it was proved to be mostly due to static quenching. The formation of sarafloxacin-CAT complex alters the micro-environment of amide moieties and tryptophan (Trp) residues, reduces the α-helix content of the enzyme, changes the peripheral substituents on the porphyrin ring of heme and leads to the inhibition of the enzyme activity. Molecular docking study reveals that sarafloxacin is located between two α-helix of CAT near to Trp 182 and Trp 185 residues, which supports the experimental results and helps to have a more clear understanding about the interaction mechanism. The change in the relative position of His 74 to heme induced by the variation of secondary structure is considered to be the major reason for the reduction of CAT activity. Moreover, sarafloxacin binds into a hydrophobic area of CAT mainly through hydrophobic interactions, which is consistent with the ITC analysis.

  7. Trends in the Binding of Cell Penetrating Peptides to siRNA: A Molecular Docking Study

    PubMed Central

    Gunathunge, B. G. C. M.; Wimalasiri, P. N.; Karunaratne, D. N.

    2017-01-01

    The use of gene therapeutics, including short interfering RNA (siRNA), is limited by the lack of efficient delivery systems. An appealing approach to deliver gene therapeutics involves noncovalent complexation with cell penetrating peptides (CPPs) which are able to penetrate the cell membranes of mammals. Although a number of CPPs have been discovered, our understanding of their complexation and translocation of siRNA is as yet insufficient. Here, we report on computational studies comparing the binding affinities of CPPs with siRNA, considering a variety of CPPs. Specifically, seventeen CPPs from three different categories, cationic, amphipathic, and hydrophobic CPPs, were studied. Molecular mechanics were used to minimize structures, while molecular docking calculations were used to predict the orientation and favorability of sequentially binding multiple peptides to siRNA. Binding scores from docking calculations were highest for amphipathic peptides over cationic and hydrophobic peptides. Results indicate that initial complexation of peptides will likely occur along the major groove of the siRNA, driven by electrostatic interactions. Subsequent binding of CPPs is likely to occur in the minor groove and later on bind randomly, to siRNA or previously bound CPPs, through hydrophobic interactions. However, hydrophobic CPPs do not show this binding pattern. Ultimately binding yields a positively charged nanoparticle capable of noninvasive cellular import of therapeutic molecules. PMID:28321253

  8. Innovative interactive flexible docking method for multi-scale reconstruction elucidates dystrophin molecular assembly.

    PubMed

    Molza, A-E; Férey, N; Czjzek, M; Le Rumeur, E; Hubert, J-F; Tek, A; Laurent, B; Baaden, M; Delalande, O

    2014-01-01

    At present, our molecular knowledge of dystrophin, the protein encoded by the DMD gene and mutated in myopathy patients, remains limited. To get around the absence of its atomic structure, we have developed an innovative interactive docking method based on the BioSpring software in combination with Small-angle X-ray Scattering (SAXS) data. BioSpring allows interactive handling of biological macromolecules thanks to an augmented Elastic Network Model (aENM) that combines the spring network with non-bonded terms between atoms or pseudo-atoms. This approach can be used for building molecular assemblies even on a desktop or a laptop computer thanks to code optimizations including parallel computing and GPU programming. By combining atomistic and coarse-grained models, the approach significantly simplifies the set-up of multi-scale scenarios. BioSpring is remarkably efficient for the preparation of numeric simulations or for the design of biomolecular models integrating qualitative experimental data restraints. The combination of this program and SAXS allowed us to propose the first high-resolution models of the filamentous central domain of dystrophin, covering repeats 11 to 17. Low-resolution interactive docking experiments driven by a potential grid enabled us to propose how dystrophin may associate with F-actin and nNOS. This information provides an insight into medically relevant discoveries to come.

  9. 3D-QSAR and molecular docking studies on HIV protease inhibitors

    NASA Astrophysics Data System (ADS)

    Tong, Jianbo; Wu, Yingji; Bai, Min; Zhan, Pei

    2017-02-01

    In order to well understand the chemical-biological interactions governing their activities toward HIV protease activity, QSAR models of 34 cyclic-urea derivatives with inhibitory HIV were developed. The quantitative structure activity relationship (QSAR) model was built by using comparative molecular similarity indices analysis (CoMSIA) technique. And the best CoMSIA model has rcv2, rncv2 values of 0.586 and 0.931 for cross-validated and non-cross-validated. The predictive ability of CoMSIA model was further validated by a test set of 7 compounds, giving rpred2 value of 0.973. Docking studies were used to find the actual conformations of chemicals in active site of HIV protease, as well as the binding mode pattern to the binding site in protease enzyme. The information provided by 3D-QSAR model and molecular docking may lead to a better understanding of the structural requirements of 34 cyclic-urea derivatives and help to design potential anti-HIV protease molecules.

  10. Inhibitory effects of daidzein and genistein on trypsin: Insights from spectroscopic and molecular docking studies.

    PubMed

    Zeng, Hua-Jin; Wang, Ya-Ping; Yang, Ran; You, Jing; Qu, Ling-Bo

    2016-08-01

    In this work, the inhibitory effect of two isoflavonoids including daidzein and genistein on trypsin and their binding mechanism were determined by spectroscopic and molecular docking approaches. The results indicated that both daidzein and genistein reversibly inhibited trypsin in a competitive manner with IC50 values of 68.01×10(-6)molL(-1) and 64.70×10(-6)molL(-1) and Ki values of 62.12×10(-6)molL(-1) and 59.83×10(-6)molL(-1), respectively. They could spontaneously bind with trypsin mainly through hydrophobic force and electrostatic interactions with a single binding site. Analysis of circular dichrosim spectra and molecular docking revealed that both isoflavonoids bound directly into the catalytic cavity and the microenvironment and secondary structure of trypsin were changed in this process, which caused the inhibition of trypsin activity. All these experimental results and theoretical data in this work would be help in understanding the mechanism of inhibitory effects of daidzein and genistein against trypsin and the potential of isoflavonoid to relieve symptoms of pancreatitis.

  11. In silico analysis and molecular docking studies of potential angiotensin-converting enzyme inhibitor using quercetin glycosides

    PubMed Central

    Muhammad, Syed Aun; Fatima, Nighat

    2015-01-01

    The purpose of this study was to analyze the inhibitory action of quercetin glycosides by computational docking studies. For this, natural metabolite quercetin glycosides isolated from buckwheat and onions were used as ligand for molecular interaction. The crystallographic structure of molecular target angiotensin-converting enzyme (ACE) (peptidyl-dipeptidase A) was obtained from PDB database (PDB ID: 1O86). Enalapril, a well-known brand of ACE inhibitor was taken as the standard for comparative analysis. Computational docking analysis was performed using PyRx, AutoDock Vina option based on scoring functions. The quercetin showed optimum binding affinity with a molecular target (angiotensin-converting-enzyme) with the binding energy of −8.5 kcal/mol as compared to the standard (−7.0 kcal/mol). These results indicated that quercetin glycosides could be one of the potential ligands to treat hypertension, myocardial infarction, and congestive heart failure. PMID:26109757

  12. Identification of critical chemical features for Aurora kinase-B inhibitors using Hip-Hop, virtual screening and molecular docking

    NASA Astrophysics Data System (ADS)

    Sakkiah, Sugunadevi; Thangapandian, Sundarapandian; John, Shalini; Lee, Keun Woo

    2011-01-01

    This study was performed to find the selective chemical features for Aurora kinase-B inhibitors using the potent methods like Hip-Hop, virtual screening, homology modeling, molecular dynamics and docking. The best hypothesis, Hypo1 was validated toward a wide range of test set containing the selective inhibitors of Aurora kinase-B. Homology modeling and molecular dynamics studies were carried out to perform the molecular docking studies. The best hypothesis Hypo1 was used as a 3D query to screen the chemical databases. The screened molecules from the databases were sorted based on ADME and drug like properties. The selective hit compounds were docked and the hydrogen bond interactions with the critical amino acids present in Aurora kinase-B were compared with the chemical features present in the Hypo1. Finally, we suggest that the chemical features present in the Hypo1 are vital for a molecule to inhibit the Aurora kinase-B activity.

  13. 3D-QSAR and molecular docking studies on designing inhibitors of the hepatitis C virus NS5B polymerase

    NASA Astrophysics Data System (ADS)

    Li, Wenlian; Si, Hongzong; Li, Yang; Ge, Cuizhu; Song, Fucheng; Ma, Xiuting; Duan, Yunbo; Zhai, Honglin

    2016-08-01

    Viral hepatitis C infection is one of the main causes of the hepatitis after blood transfusion and hepatitis C virus (HCV) infection is a global health threat. The HCV NS5B polymerase, an RNA dependent RNA polymerase (RdRp) and an essential role in the replication of the virus, has no functional equivalent in mammalian cells. So the research and development of efficient NS5B polymerase inhibitors provides a great strategy for antiviral therapy against HCV. A combined three-dimensional quantitative structure-activity relationship (QSAR) modeling was accomplished to profoundly understand the structure-activity correlation of a train of indole-based inhibitors of the HCV NS5B polymerase to against HCV. A comparative molecular similarity indices analysis (COMSIA) model as the foundation of the maximum common substructure alignment was developed. The optimum model exhibited statistically significant results: the cross-validated correlation coefficient q2 was 0.627 and non-cross-validated r2 value was 0.943. In addition, the results of internal validations of bootstrapping and Y-randomization confirmed the rationality and good predictive ability of the model, as well as external validation (the external predictive correlation coefficient rext2 = 0.629). The information obtained from the COMSIA contour maps enables the interpretation of their structure-activity relationship. Furthermore, the molecular docking study of the compounds for 3TYV as the protein target revealed important interactions between active compounds and amino acids, and several new potential inhibitors with higher activity predicted were designed basis on our analyses and supported by the simulation of molecular docking. Meanwhile, the OSIRIS Property Explorer was introduced to help select more satisfactory compounds. The satisfactory results from this study may lay a reliable theoretical base for drug development of hepatitis C virus NS5B polymerase inhibitors.

  14. Furoquinoline Alkaloids from the Leaves of Evodia lepta as Potential Cholinesterase Inhibitors and their Molecular Docking.

    PubMed

    Sichaem, Jirapast; Rojpitikul, Thanawan; Sawasdee, Pattara; Lugsannangarm, Kiattisak; Santi, Tip-pyang

    2015-08-01

    Nine furoquinoline alkaloids (1-9) were isolated from the leaves of Evodia lepta based on bioassay-guided fractionation and chromatographic techniques. All isolates were evaluated for their cholinesterase (ChEs) inhibitory activities, in which kokusaginine (7) and melineurine (5) exhibited the highest activity toward AChE and BChE, respectively. Lineweaver-Burk plots indicated that 5 and 7 were mixed mode inhibitors of both ChE enzymes. Molecular docking studies on the binding sites of AChE and BChE were performed in order to afford a molecular insight into the mode of action of these active compounds. From this study these compounds have emerged as promising molecules for Alzheimer's disease therapy.

  15. Synthesis, crystal structure, and in vitro and in silico molecular docking of novel acyl thiourea derivatives

    NASA Astrophysics Data System (ADS)

    Haribabu, Jebiti; Subhashree, Govindarajulu Rangabashyam; Saranya, Sivaraj; Gomathi, Kannayiram; Karvembu, Ramasamy; Gayathri, Dasararaju

    2015-08-01

    In the present study, a series of six biologically active substituted acyl thiourea compounds (1-6) has been synthesized from cyclohexanecarbonyl isothiocyanate and various primary amines (2-methyl aniline, aniline, 4-methoxy aniline, 4-ethoxy aniline, benzyl amine and 2-methoxy aniline). The synthesized compounds were characterized by elemental analyses, UV-Visible, FT-IR, 1H & 13C NMR and mass spectroscopic techniques. Three dimensional molecular structure of two compounds (1 and 5) was determined by single crystal X-ray crystallography. All the synthesized compounds show good anti-oxidant and anti-haemolytic activities. In silico molecular docking studies were performed to screen against DprE1 and HSP90 enzymes targeting tuberculosis and cancer respectively.

  16. Nitromethylene neonicotinoids analogues with tetrahydropyrimidine fixed cis-configuration: synthesis, insecticidal activities, and molecular docking studies.

    PubMed

    Sun, Chuanwen; Yang, Dingrong; Xing, Jiahua; Wang, Haifeng; Jin, Jia; Zhu, Jun

    2010-03-24

    Two series of new nitromethylene neonicotinoid analogues (2a-2h and 3a-3h) were designed and prepared, with the cis-configuration confirmed by X-ray diffraction. Preliminary bioassays showed that most analogues exhibited excellent insecticidal activities at 500 mg/L, and analogues with optical activity (2c-2g) were highly potent at 100 mg/L, while compound 2d had >90% mortality at 20 mg/L, which suggested that it could be used as a lead for future insecticides development. Modeling the ligand-receptor complexes by molecular docking study explained the structure-activity relationships observed in vitro and revealed an intriguing molecular binding mode at the active site of the nAChR model, thereby possibly providing some useful information for future receptor structure-based designs of novel insecticidal compounds.

  17. Indazoles as potential c-Met inhibitors: design, synthesis and molecular docking studies.

    PubMed

    Ye, Lianbao; Ou, Xiaomin; Tian, Yuanxin; Yu, Bangwei; Luo, Yan; Feng, Binghong; Lin, Hansen; Zhang, Jiajie; Wu, Shuguang

    2013-07-01

    Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of indazoles were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibition on c-Met and compound 4d showed highest activity against c-Met with IC50 value of 0.17 μM in TR-FRET-based assay and IC50 value of 5.45 μM in cell-based assay as compared to other tested compounds. Molecular docking experiments verified the results and explained the molecular mechanism of pretty activities to c-Met.

  18. Active site binding modes of inhibitors of Staphylococcus aureus mevalonate diphosphate decarboxylase from docking and molecular dynamics simulations.

    PubMed

    Addo, James K; Skaff, D Andrew; Miziorko, Henry M

    2016-01-01

    Bacterial mevalonate diphosphate decarboxylase (MDD) is an attractive therapeutic target for antibacterial drug development. In this work, we discuss a combined docking and molecular dynamics strategy toward inhibitor binding to bacterial MDD. The docking parameters utilized in this study were first validated with observations for the inhibitors 6-fluoromevalonate diphosphate (FMVAPP) and diphosphoglycolylproline (DPGP) using existing structures for the Staphylococcus epidermidis enzyme. The validated docking protocol was then used to predict structures of the inhibitors bound to Staphylococcus aureus MDD using the unliganded crystal structure of Staphylococcus aureus MDD. We also investigated a possible interactions improvement by combining this docking method with molecular dynamics simulations. Thus, the predicted docking structures were analyzed in a molecular dynamics trajectory to generate dynamic models and reinforce the predicted binding modes. FMVAPP is predicted to make more extensive contacts with S. aureus MDD, forming stable hydrogen bonds with Arg144, Arg193, Lys21, Ser107, and Tyr18, as well as making stable hydrophobic interactions with Tyr18, Trp19, and Met196. The differences in predicted binding are supported by experimentally determined Ki values of 0.23 ± 0.02 and 34 ± 8 μM, for FMVAPP and DPGP, respectively. The structural information coupled with the kinetic characterization obtained from this study should be useful in defining the requirements for inhibition as well as in guiding the selection of active compounds for inhibitor optimization.

  19. Molecular Docking Studies of Catechin and Its Derivatives as Anti-bacterial Inhibitor for Glucosamine-6-Phosphate Synthase

    NASA Astrophysics Data System (ADS)

    Fikrika, H.; Ambarsari, L.; Sumaryada, T.

    2016-01-01

    Molecular docking simulation of catechin and its derivatives on Glucosamine-6- Phosphate Synthase (GlmS) has been performed in this research. GlmS inhibition by a particular ligand will suppress the production of bacterial cell wall and significantly reduce the population of invading bacteria. In this study, catechin derivatives i.e epicatechin, galloatechin and epigalloatechin were found to have stronger binding affinities as compared to natural ligand of GlmS, Fructose-6-Phosphate (F6P). Those three ligands were docked on the same pocket in GlmS target as F6P, with 70% binding sites similarity. Based on the docking results, gallocatechin turns out to be the most potent ligand for anti-bacterial agent with ΔG= -8.00 kcal/mol. The docking between GlmS and catechin derivatives are characterized by a constant present of a strong hydrogen bond between functional group O3 and Ser-349. This hydrogen bond most likely plays a significant role in the docking mechanism and binding modes selection. The surprising result is catechin itself exhibited a quite strong binding with GlmS (ΔG= -7.80 kcal.mol), but docked on a completely different pocket compared to other ligands. This results suggest that catechin might still have a curing effect but with a completely different pathway and mechanism as compared to its derivatives.

  20. Protein-peptide molecular docking with large-scale conformational changes: the p53-MDM2 interaction

    NASA Astrophysics Data System (ADS)

    Ciemny, Maciej Pawel; Debinski, Aleksander; Paczkowska, Marta; Kolinski, Andrzej; Kurcinski, Mateusz; Kmiecik, Sebastian

    2016-12-01

    Protein-peptide interactions are often associated with large-scale conformational changes that are difficult to study either by classical molecular modeling or by experiment. Recently, we have developed the CABS-dock method for flexible protein-peptide docking that enables large-scale rearrangements of the protein chain. In this study, we use CABS-dock to investigate the binding of the p53-MDM2 complex, an element of the cell cycle regulation system crucial for anti-cancer drug design. Experimental data suggest that p53-MDM2 binding is affected by significant rearrangements of a lid region - the N-terminal highly flexible MDM2 fragment; however, the details are not clear. The large size of the highly flexible MDM2 fragments makes p53-MDM2 intractable for exhaustive binding dynamics studies using atomistic models. We performed extensive dynamics simulations using the CABS-dock method, including large-scale structural rearrangements of MDM2 flexible regions. Without a priori knowledge of the p53 peptide structure or its binding site, we obtained near-native models of the p53-MDM2 complex. The simulation results match well the experimental data and provide new insights into the possible role of the lid fragment in p53 binding. The presented case study demonstrates that CABS-dock methodology opens up new opportunities for protein-peptide docking with large-scale changes of the protein receptor structure.

  1. Molecular docking and structure-based virtual screening studies of potential drug target, CAAX prenyl proteases, of Leishmania donovani.

    PubMed

    Singh, Shalini; Vijaya Prabhu, Sitrarasu; Suryanarayanan, Venkatesan; Bhardwaj, Ruchika; Singh, Sanjeev Kumar; Dubey, Vikash Kumar

    2016-11-01

    Targeting CAAX prenyl proteases of Leishmania donovani can be a good approach towards developing a drug molecule against Leishmaniasis. We have modeled the structure of CAAX prenyl protease I and II of L. donovani, using homology modeling approach. The structures were further validated using Ramachandran plot and ProSA. Active site prediction has shown difference in the amino acid residues present at the active site of CAAX prenyl protease I and CAAX prenyl protease II. The electrostatic potential surface of the CAAX prenyl protease I and II has revealed that CAAX prenyl protease I has more electropositive and electronegative potentials as compared CAAX prenyl protease II suggesting significant difference in their activity. Molecular docking with known bisubstrate analog inhibitors of protein farnesyl transferase and peptidyl (acyloxy) methyl ketones reveals significant binding of these molecules with CAAX prenyl protease I, but comparatively less binding with CAAX prenyl protease II. New and potent inhibitors were also found using structure-based virtual screening. The best docked compounds obtained from virtual screening were subjected to induced fit docking to get best docked configurations. Prediction of drug-like characteristics has revealed that the best docked compounds are in line with Lipinski's rule. Moreover, best docked protein-ligand complexes of CAAX prenyl protease I and II are found to be stable throughout 20 ns simulation. Overall, the study has identified potent drug molecules targeting CAAX prenyl protease I and II of L. donovani whose drug candidature can be verified further using biochemical and cellular studies.

  2. Message passing interface and multithreading hybrid for parallel molecular docking of large databases on petascale high performance computing machines.

    PubMed

    Zhang, Xiaohua; Wong, Sergio E; Lightstone, Felice C

    2013-04-30

    A mixed parallel scheme that combines message passing interface (MPI) and multithreading was implemented in the AutoDock Vina molecular docking program. The resulting program, named VinaLC, was tested on the petascale high performance computing (HPC) machines at Lawrence Livermore National Laboratory. To exploit the typical cluster-type supercomputers, thousands of docking calculations were dispatched by the master process to run simultaneously on thousands of slave processes, where each docking calculation takes one slave process on one node, and within the node each docking calculation runs via multithreading on multiple CPU cores and shared memory. Input and output of the program and the data handling within the program were carefully designed to deal with large databases and ultimately achieve HPC on a large number of CPU cores. Parallel performance analysis of the VinaLC program shows that the code scales up to more than 15K CPUs with a very low overhead cost of 3.94%. One million flexible compound docking calculations took only 1.4 h to finish on about 15K CPUs. The docking accuracy of VinaLC has been validated against the DUD data set by the re-docking of X-ray ligands and an enrichment study, 64.4% of the top scoring poses have RMSD values under 2.0 Å. The program has been demonstrated to have good enrichment performance on 70% of the targets in the DUD data set. An analysis of the enrichment factors calculated at various percentages of the screening database indicates VinaLC has very good early recovery of actives.

  3. Hologram quantitative structure activity relationship, docking, and molecular dynamics studies of inhibitors for CXCR4.

    PubMed

    Zhang, Chongqian; Du, Chunmiao; Feng, Zhiwei; Zhu, Jingyu; Li, Youyong

    2015-02-01

    CXCR4 plays a crucial role as a co-receptor with CCR5 for HIV-1 anchoring to mammalian cell membrane and is implicated in cancer metastasis and inflammation. In the current work, we study the relationship of structure and activity of AMD11070 derivatives and other inhibitors of CXCR4 using HQSAR, docking and molecular dynamics (MD) simulations. We obtain an HQSAR model (q(2) = 0.779), and the HQSAR result illustrates that AMD11070 shows a high antiretroviral activity. As HQSAR only provides 2D information, we perform docking and MD to study the interaction of It1t, AMD3100, and AMD3465 with CXCR4. Our results illustrate that the binding are affected by two crucial residues Asp97 and Glu288. The butyl amine moiety of AMD11070 contributes to its high antiretroviral activity. Without a butyl amine moiety, (2,7a-Dihydro-1H-benzoimidazol-2-ylmethyl)-methyl-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (compound 5a) shows low antiretroviral activity. Our results provide structural details about the interactions between the inhibitors and CXCR4, which are useful for rational drug design of CXCR4.

  4. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking.

    PubMed

    Islam, Barira; Sharma, Charu; Adem, Abdu; Aburawi, Elhadi; Ojha, Shreesh

    2015-01-01

    Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP(+)). We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (-)-epigallocatechin-3-gallate (EGCG) and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure-function relationship studies.

  5. Binding interaction between sorafenib and calf thymus DNA: Spectroscopic methodology, viscosity measurement and molecular docking

    NASA Astrophysics Data System (ADS)

    Shi, Jie-Hua; Chen, Jun; Wang, Jing; Zhu, Ying-Yao

    2015-02-01

    The binding interaction of sorafenib with calf thymus DNA (ct-DNA) was studied using UV-vis absorption spectroscopy, fluorescence emission spectroscopy, circular dichroism (CD), viscosity measurement and molecular docking methods. The experimental results revealed that there was obvious binding interaction between sorafenib and ct-DNA. The binding constant (Kb) of sorafenib with ct-DNA was 5.6 × 103 M-1 at 298 K. The enthalpy and entropy changes (ΔH0 and ΔS0) in the binding process of sorafenib with ct-DNA were -27.66 KJ mol-1 and -21.02 J mol-1 K-1, respectively, indicating that the main binding interaction forces were van der Waals force and hydrogen bonding. The docking results suggested that sorafenib preferred to bind on the minor groove of A-T rich DNA and the binding site of sorafenib was 4 base pairs long. The conformation change of sorafenib in the sorafenib-DNA complex was obviously observed and the change was close relation with the structure of DNA, implying that the flexibility of sorafenib molecule played an important role in the formation of the stable sorafenib-ct-DNA complex.

  6. DNA topoisomerase-directed anticancerous alkaloids: ADMET-based screening, molecular docking, and dynamics simulation.

    PubMed

    Singh, Swati; Das, Tamal; Awasthi, Manika; Pandey, Veda P; Pandey, Brijesh; Dwivedi, Upendra N

    2016-01-01

    Topoisomerases (Topo I and II) have been looked as crucial targets against various types of cancers. In the present paper, 100 anticancerous alkaloids were subjected to in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses to investigate their pharmacokinetic properties. Out of 100 alkaloids, only 18 were found to fulfill all the ADMET descriptors and obeyed the Lipinski's rule of five. All the 18 alkaloids were found to dock successfully within the active site of both Topo I and II. A comparison of the inhibitory potential of 18 screened alkaloids with those of selected drugs revealed that four alkaloids (oliveroline, coptisine, aristolactam, and piperine) inhibited Topo I, whereas six alkaloids (oliveroline, aristolactam, anonaine, piperine, coptisine, and liriodenine) inhibited Topo II more strongly than those of their corresponding drugs, topotecan and etoposide, respectively, with oliveroline being the outstanding. The stability of the complexes of Topo I and II with the best docked alkaloid, oliveroline, was further analyzed using 10 nSec molecular dynamics simulation and compared with those of the respective drugs, namely, topotecan and etoposide, which revealed stabilization of these complexes within 5 nSec of simulation with better stability of Topo II complex than that of Topo I.

  7. Insight into the mechanism of polyphenols on the activity of HMGR by molecular docking

    PubMed Central

    Islam, Barira; Sharma, Charu; Adem, Abdu; Aburawi, Elhadi; Ojha, Shreesh

    2015-01-01

    Statins are hypolipidemic drugs that are effective in the treatment of hypercholesterolemia by attenuating cholesterol synthesis in the liver via competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Recently, dietary changes associated with drug therapy have garnered attention as novel drugs to mitigate or ameliorate hypercholesterolemia. The present study was undertaken to observe different dietary polyphenols that can bind to the active site of HMGR and inhibit it. Results from the 12 dietary polyphenols tested reveal that polyphenols can bind to HMGR and block the binding of nicotinamide adenine dinucleotide phosphate (NADP+). We observed that the rigidity of phenolic rings prevents the polyphenols from docking to the enzyme activity site. The presence of an ester linkage between the phenolic rings in (–)-epigallocatechin-3-gallate (EGCG) and the alkyl chain in curcumin allows them to orient in the active site of the HMGR and bind to the catalytic residues. EGCG and curcumin showed binding to the active site residues with a low GRID score, which may be a potential inhibitor of HMGR. Kaempferol showed binding to HMG-CoA, but with low binding affinity. These observations provide a rationale for the consistent hypolipidemic effect of EGCG and curcumin, which has been previously reported in several epidemiological and animal studies. Therefore, this study substantiates the mechanism of polyphenols on the activity of HMGR by molecular docking and provides the impetus for drug design involving further structure–function relationship studies. PMID:26357462

  8. In Silico Design of Human IMPDH Inhibitors Using Pharmacophore Mapping and Molecular Docking Approaches

    PubMed Central

    Li, Rui-Juan; Wang, Ya-Li; Wang, Qing-He; Wang, Jian; Cheng, Mao-Sheng

    2015-01-01

    Inosine 5′-monophosphate dehydrogenase (IMPDH) is one of the crucial enzymes in the de novo biosynthesis of guanosine nucleotides. It has served as an attractive target in immunosuppressive, anticancer, antiviral, and antiparasitic therapeutic strategies. In this study, pharmacophore mapping and molecular docking approaches were employed to discover novel Homo sapiens IMPDH (hIMPDH) inhibitors. The Güner-Henry (GH) scoring method was used to evaluate the quality of generated pharmacophore hypotheses. One of the generated pharmacophore hypotheses was found to possess a GH score of 0.67. Ten potential compounds were selected from the ZINC database using a pharmacophore mapping approach and docked into the IMPDH active site. We find two hits (i.e., ZINC02090792 and ZINC00048033) that match well the optimal pharmacophore features used in this investigation, and it is found that they form interactions with key residues of IMPDH. We propose that these two hits are lead compounds for the development of novel hIMPDH inhibitors. PMID:25784957

  9. Alphavirus protease inhibitors from natural sources: A homology modeling and molecular docking investigation.

    PubMed

    Byler, Kendall G; Collins, Jasmine T; Ogungbe, Ifedayo Victor; Setzer, William N

    2016-10-01

    Alphaviruses such as Chikungunya virus (CHIKV), O'Nyong-Nyong virus (ONNV), Ross River virus (RRV), Eastern equine encephalitis virus (EEEV), Venezuelan equine encephalitis virus (VEEV), and Western equine encephalitis virus (WEEV), are mosquito-transmitted viruses that can cause fevers, rash, and rheumatic diseases (CHIKV, ONNV, RRV) or potentially fatal encephalitis (EEEV, VEEV, WEEV) in humans. These diseases are considered neglected tropical diseases for which there are no current antiviral therapies or vaccines available. The alphavirus non-structural protein 2 (nsP2) contains a papain-like protease, which is considered to be a promising target for antiviral drug discovery. In this work, molecular docking analyses have been carried out on a library of 2174 plant-derived natural products (290 alkaloids, 664 terpenoids, 1060 polyphenolics, and 160 miscellaneous phytochemicals) with the nsP2 proteases of CHIKV, ONNV, RRV, EEEV, VEEV, WEEV, as well as Aura virus (AURV), Barmah Forest Virus (BFV), Semliki Forest virus (SFV), and Sindbis virus (SINV) in order to identity structural scaffolds for inhibitor design or discovery. Of the 2174 phytochemicals examined, a total of 127 showed promising docking affinities and poses to one or more of the nsP2 proteases, and this knowledge can be used to guide experimental investigation of potential inhibitors.

  10. Synthesis, Evaluation of Pharmacological Activity, and Molecular Docking of 1,4-Dihydropyridines as Calcium Antagonists.

    PubMed

    Shaldam, Moataz Ahmed; El-Hamamsy, Mervat Hamed; Saleh, Dalia Osama; El-Moselhy, Tarek Fathy

    2016-01-01

    1,4-Dihydropyridine (DHP) is an important class of calcium antagonist. It inhibits the influx of extracellular Ca(2+) through L-type voltage-dependent calcium channels. Two series of nifedipine analogues were synthesized and evaluated as calcium antagonists. The ortho-nitrophenyl ring of nifedipine was replaced with an ortho- or a meta-chlorophenyl substituent. The IC50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution with groups of suitable bulkiness, such as ethyl ester, at the 3- and 5-positions of the DHP ring gave 3h, which is approximately three-fold more active than nifedipine as a calcium antagonist. A docking study with the DHP receptor model was performed to interpret the differences in calcium antagonist activities. The molecular docking study demonstrated that the lipophilicity of the substituted phenyl group at the 4-position of the DHP ring is an important factor that could increase the activity of the calcium antagonist taking the steric factor into consideration. Bulky groups interfere with ring-to-ring hydrophobic interaction with Tyr(1460) and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increase activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring may ensure strong binding to the receptor and hence stabilization of the closed-channel conformation.

  11. DNA-binding study of anticancer drug cytarabine by spectroscopic and molecular docking techniques.

    PubMed

    Shahabadi, Nahid; Falsafi, Monireh; Maghsudi, Maryam

    2017-01-02

    The interaction of anticancer drug cytarabine with calf thymus DNA (CT-DNA) was investigated in vitro under simulated physiological conditions by multispectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated drug interacted with CT-DNA in a groove-binding mode, while the binding constant of UV-vis and the number of binding sites were 4.0 ± 0.2 × 10(4) L mol(-1) and 1.39, respectively. The fluorimetric studies showed that the reaction between the drugs with CT-DNA is exothermic. Circular dichroism spectroscopy was employed to measure the conformational change of DNA in the presence of cytarabine. Furthermore, the drug induces detectable changes in its viscosity for DNA interaction. The molecular modeling results illustrated that cytarabine strongly binds to groove of DNA by relative binding energy of docked structure -20.61 KJ mol(-1). This combination of multiple spectroscopic techniques and molecular modeling methods can be widely used in the investigation on the interaction of small molecular pollutants and drugs with biomacromolecules for clarifying the molecular mechanism of toxicity or side effect in vivo.

  12. Vibrational spectroscopic, molecular docking and quantum chemical studies on 6-aminonicotinamide

    NASA Astrophysics Data System (ADS)

    Mohamed Asath, R.; Premkumar, S.; Mathavan, T.; Milton Franklin Benial, A.

    2017-04-01

    The most stable molecular structure of 6-aminonicotinamide (ANA) molecule was predicted by conformational analysis and vibrational spectral analysis was carried out by experimental and theoretical methods. The calculated and experimentally observed vibrational frequencies were assigned and compared. The π→π* electronic transition of the molecule was predicted by theoretically calculated ultraviolet-visible spectra in gas and liquid phase and further validated experimentally using ethanol as a solvent. Frontier molecular orbitals analysis was carried out to probe the reactive nature of the ANA molecule and further the site selectivity to specific chemical reactions were effectively analyzed by Fukui function calculation. The molecular electrostatic potential surface was simulated to confirm the reactive sites of the molecule. The natural bond orbital analysis was also performed to understand the intra molecular interactions, which confirms the bioactivity of the ANA molecule. Neuroprotective nature of the ANA molecule was analyzed by molecular docking analysis and the ANA molecule was identified as a good inhibitor against Alzheimer's disease.

  13. Mechanism evaluation of the interactions between flavonoids and bovine serum albumin based on multi-spectroscopy, molecular docking and Q-TOF HR-MS analyses.

    PubMed

    Fu, Ling; Sun, Yiqun; Ding, Lina; Wang, Yangyang; Gao, Zhen; Wu, Zhen; Wang, Shaomin; Li, Wen; Bi, Yuefeng

    2016-07-15

    The mechanism of interactions between a flavonoid glycoside (linarin) and 6 flavonoids with various hydroxyl and methoxyl substituents (luteolin, apigenin, acacetin, tricin, 5,3',4'-trihydroxy-6,7-dimethoxyflavone, and 5,7,4'-trihydroxy-6,3',5'-trimethoxyflavone) and bovine serum albumin (BSA) were investigated by multi-spectroscopy, molecular docking, and quadrupole (Q)-time of flight (TOF) high resolution (HR) mass spectrometry (MS). Fluorescence spectra and molecular docking predicted that each of the flavonoids had only one probable binding site inside the hydrophobic cleft of BSA. The binding constants appeared to correlate positively with the number of hydroxyl groups, and negatively with the number of methoxyl groups. In addition, hydroxyls on ring B bound more easily with BSA than those on ring A. The change in conformation of BSA after binding suggested that the quenching mechanism was static quenching combined with nonradiative energy transfer. The results of Q-TOF HR-MS were consistent with fluorescence quenching and molecular docking.

  14. Molecular interaction of a kinase inhibitor midostaurin with anticancer drug targets, S100A8 and EGFR: transcriptional profiling and molecular docking study for kidney cancer therapeutics.

    PubMed

    Mirza, Zeenat; Schulten, Hans-Juergen; Farsi, Hasan Ma; Al-Maghrabi, Jaudah A; Gari, Mamdooh A; Chaudhary, Adeel Ga; Abuzenadah, Adel M; Al-Qahtani, Mohammed H; Karim, Sajjad

    2015-01-01

    The S100A8 and epidermal growth factor receptor (EGFR) proteins are proto-oncogenes that are strongly expressed in a number of cancer types. EGFR promotes cellular proliferation, differentiation, migration and survival by activating molecular pathways. Involvement of proinflammatory S100A8 in tumor cell differentiation and progression is largely unclear and not studied in kidney cancer (KC). S100A8 and EGFR are potential therapeutic biomarkers and anticancer drug targets for KC. In this study, we explored molecular mechanisms of interaction profiles of both molecules with potential anticancer drugs. We undertook transcriptional profiling in Saudi KCs using Affymetrix HuGene 1.0 ST arrays. We identified 1478 significantly expressed genes, including S100A8 and EGFR overexpression, using cut-off p value <0.05 and fold change ≥2. Additionally, we compared and confirmed our findings with expression data available at NCBI's GEO database. A significant number of genes associated with cancer showed involvement in cell cycle progression, DNA repair, tumor morphology, tissue development, and cell survival. Atherosclerosis signaling, leukocyte extravasation signaling, notch signaling, and IL-12 signaling were the most significantly disrupted signaling pathways. The present study provides an initial transcriptional profiling of Saudi KC patients. Our analysis suggests distinct transcriptomic signatures and pathways underlying molecular mechanisms of KC progression. Molecular docking analysis revealed that the kinase inhibitor "midostaurin" has amongst the selected drug targets, the best ligand properties to S100A8 and EGFR, with the implication that its binding inhibits downstream signaling in KC. This is the first structure-based docking study for the selected protein targets and anticancer drug, and the results indicate S100A8 and EGFR as attractive anticancer targets and midostaurin with effective drug properties for therapeutic intervention in KC.

  15. Hybrid benzothiazole analogs as antiurease agent: Synthesis and molecular docking studies.

    PubMed

    Taha, Muhammad; Ismail, Nor Hadiani; Imran, Syahrul; Wadood, Abdul; Rahim, Fazal; Khan, Khalid Muhammad; Riaz, Muhammad

    2016-06-01

    Benzothiazole analogs (1-20) have been synthesized, characterized by EI-MS and (1)H NMR, and evaluated for urease inhibition activity. All compounds showed excellent urease inhibitory potential varying from 1.4±0.10 to 34.43±2.10μM when compared with standard thiourea (IC50 19.46±1.20μM). Among the series seventeen (17) analogs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, and 18 showed outstanding urease inhibitory potential. Analogs 15 and 19 also showed good urease inhibition activity. When we compare the activity of N-phenylthiourea 20 with all substituted phenyl derivatives (1-18) we found that compound 15 showed less activity than compound 20 having 3-methoxy substituent. The binding interactions of these active analogs were confirmed through molecular docking.

  16. Synthesis, antimalarial evaluation and molecular docking studies of some thiolactone derivatives

    NASA Astrophysics Data System (ADS)

    Sainy, Jitendra; Sharma, Rajesh

    2017-04-01

    In present study novel thiolactone derivatives were designed, synthesized and characterized by various analytical techniques such as IR, 1H NMR, 13C NMR, mass spectral data and elemental analysis. All synthesized compounds were evaluated for in vitro antimalarial activity against Dd2 and 3d7 strain of P. falciparum. All synthesized compounds were also subjected for molecular docking study with pf KASI/II enzyme to analyze their binding orientation in the active site of the enzyme. Compounds 5d, 5e, and 5i found to be most potent with IC50 in the range of 0.09-0.19 μM and 0.03-0.04 μM against the Dd2 strain and 3D7 strain respectively as well as they showed good binding affinities with the residues of the active site of pf KASI/II.

  17. Synthesis, molecular docking and biological evaluation of coumarin derivatives containing piperazine skeleton as potential antibacterial agents.

    PubMed

    Wang, She-Feng; Yin, Yong; Wu, Xun; Qiao, Fang; Sha, Shao; Lv, Peng-Cheng; Zhao, Jing; Zhu, Hai-Liang

    2014-11-01

    A series of 4-hydroxycoumarin derivatives were designed and synthesized in order to find some more potent antibacterial drugs. Their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4 g represented the most potent antibacterial activity against Bacillus subtilis and S. aureus with MIC of 0.236, 0.355 μg/mL, respectively. What's more, it showed the most potent activity against SaFabI with IC50 of 0.57 μM. Molecular docking of 4 g into S. aureus Enoyl-ACP-reductase active site were performed to determine the probable binding mode, while the QSAR model was built to check the previous work as well as to introduce new directions.

  18. Molecular docking studies and anti-snake venom metalloproteinase activity of Thai mango seed kernel extract.

    PubMed

    Pithayanukul, Pimolpan; Leanpolchareanchai, Jiraporn; Saparpakorn, Patchreenart

    2009-08-27

    Snakebite envenomations cause severe local tissue necrosis and the venom metalloproteinases are thought to be the key toxins involved. In this study, the ethanolic extract from seed kernels of Thai mango (Mangifera indica L. cv. 'Fahlun') (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent and dose-dependent inhibitory effects on the caseinolytic and fibrinogenolytic activities of Malayan pit viper and Thai cobra venoms in in vitro tests. molecular docking studies revealed that the binding orientations of the phenolic principles were in the binding pockets of snake venom metalloproteinases (SVMPs). The phenolic principles could form hydrogen bonds with the three histidine residues in the conserved zinc-binding motif and could chelate the Zn(2+) atom of the SVMPs, which could potentially result in inhibition of the venom enzymatic activities and thereby inhibit tissue necrosis.

  19. Molecular dynamic and docking interaction study of Heterodera glycines serine proteinase with Vigna mungo proteinase inhibitor.

    PubMed

    Prasad, C V S Siva; Gupta, Saurabh; Gaponenko, Alex; Tiwari, Murlidhar

    2013-08-01

    Many plants do produce various defense proteins like proteinase inhibitors (PIs) to protect them against various pests. PIs function as pseudosubstrates of digestive proteinase, which inhibits proteolysis in pests and leads to amino acid deficiency-based mortality. This work reports the structural interaction studies of serine proteinase of Heterodera glycines (SPHG) with Vigna mungo proteinase inhibitor (VMPI). 3D protein structure modeling, validation of SPHG and VMPI, and their putative protein-protein binding sites were predicted. Protein-protein docking followed by molecular dynamic simulation was performed to find the reliable confirmation of SPHG-VMPI complex. Trajectory analysis of each successive conformation concludes better interaction of first loop in comparison with second loop. Lysine residues of first loop were actively participating in complex formation. Overall, this study discloses the structural aspects and interaction mechanisms of VMPI with SPHG, and it would be helpful in the development of pest-resistant genetically modified crops.

  20. Homology modeling, substrate docking, and molecular simulation studies of mycobacteriophage Che12 lysin A.

    PubMed

    Saadhali, Shainaba A; Hassan, Sameer; Hanna, Luke Elizabeth; Ranganathan, Uma Devi; Kumar, Vanaja

    2016-08-01

    Mycobacteriophages produce lysins that break down the host cell wall at the end of lytic cycle to release their progenies. The ability to lyse mycobacterial cells makes the lysins significant. Mycobacteriophage Che12 is the first reported temperate phage capable of infecting and lysogenising Mycobacterium tuberculosis. Gp11 of Che12 was found to have Chitinase domain that serves as endolysin (lysin A) for Che12. Structure of gp11 was modeled and evaluated using Ramachandran plot in which 98 % of the residues are in the favored and allowed regions. Che12 lysin A was predicted to act on NAG-NAM-NAG molecules in the peptidoglycan of cell wall. The tautomers of NAG-NAM-NAG molecule were generated and docked with lysin A. The stability and binding affinity of lysin A - NAG-NAM-NAG tautomers were studied using molecular dynamics simulations.

  1. Synthesis, molecular docking and biological evaluation of metronidazole derivatives containing piperazine skeleton as potential antibacterial agents.

    PubMed

    Wang, She-Feng; Yin, Yong; Qiao, Fang; Wu, Xun; Sha, Shao; Zhang, Li; Zhu, Hai-Liang

    2014-04-15

    Metronidazole has a broad-spectrum antibacterial activity. Hereby a series of novel metronidazole derivatives were designed and synthesized based on nitroimidazole scaffold in order to find some more potent antibacterial drugs. For these compounds which were reported for the first time, their antibacterial activities against Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus were tested. These compounds showed good antibacterial activities against Gram-positive strains. Compound 4m represented the most potent antibacterial activity against S. aureus ATCC 25923 with MIC of 0.003 μg/mL and it showed the most potent activity against S. aureus TyrRS with IC50 of 0.0024 μM. Molecular docking of 4m into S. aureus tyrosyl-tRNA synthetase active site were also performed to determine the probable binding mode.

  2. Molecular docking sites designed for the generation of highly crystalline covalent organic frameworks

    NASA Astrophysics Data System (ADS)

    Ascherl, Laura; Sick, Torben; Margraf, Johannes T.; Lapidus, Saul H.; Calik, Mona; Hettstedt, Christina; Karaghiosoff, Konstantin; Döblinger, Markus; Clark, Timothy; Chapman, Karena W.; Auras, Florian; Bein, Thomas

    2016-04-01

    Covalent organic frameworks (COFs) formed by connecting multidentate organic building blocks through covalent bonds provide a platform for designing multifunctional porous materials with atomic precision. As they are promising materials for applications in optoelectronics, they would benefit from a maximum degree of long-range order within the framework, which has remained a major challenge. We have developed a synthetic concept to allow consecutive COF sheets to lock in position during crystal growth, and thus minimize the occurrence of stacking faults and dislocations. Hereby, the three-dimensional conformation of propeller-shaped molecular building units was used to generate well-defined periodic docking sites, which guided the attachment of successive building blocks that, in turn, promoted long-range order during COF formation. This approach enables us to achieve a very high crystallinity for a series of COFs that comprise tri- and tetradentate central building blocks. We expect this strategy to be transferable to a broad range of customized COFs.

  3. Molecular modeling of Mycobacterium tuberculosis dUTpase: docking and catalytic mechanism studies.

    PubMed

    Ramalho, Teodorico C; Caetano, Melissa S; Josa, Daniela; Luz, Gustavo P; Freitas, Elisangela A; da Cunha, Elaine F F

    2011-06-01

    Mycobacterium tuberculosis is a leading cause of infectious disease in the world today. This outlook is aggravated by a growing number of M. tuberculosis infections in individuals who are immunocompromised as a result of HIV infections. Thus, new and more potent anti-TB agents are necessary. Therefore, dUTpase was selected as a target enzyme to combat M. tuberculosis. In this work, molecular modeling methods involving docking and QM/MM calculations were carried out to investigate the binding orientation and predict binding affinities of some potential dUTpase inhibitors. Our results suggest that the best potential inhibitor investigated, among the compounds studied in this work, is the compound dUPNPP. Regarding the reaction mechanism, we concluded that the decisive stage for the reaction is the stage 1. Furthermore, it was also observed that the compounds with a -1 electrostatic charge presented lower activation energy in relation to the compounds with a -2 charge.

  4. Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations.

    PubMed

    Shamim, Amen; Abbasi, Sumra Wajid; Azam, Syed Sikander

    2015-07-01

    β-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG. Current study aims to gain in silico insights into the structural and dynamical aspect of S. gordonii FabH via molecular docking and molecular dynamics (MD) simulations. The FabH protein is catalytically active in dimerization while it can lock in monomeric state. Current study highlights two residues Pro88 and Leu315 that are close to each other by dimerization. The active site of FabH is composed of the catalytic triad formed by residues Cys112, His249, and Asn279 in which Cys112 is involved in acetyl transfer, while His249 and Asn279 play an active role in decarboxylation. Docking analysis revealed that among the studied compounds, methyl-CoA disulfide has highest GOLD score (82.75), binding affinity (-11 kcal/mol) and exhibited consistently better interactions. During MD simulations, the FabH structure remained stable with the average RMSD value of 1.7 Å and 1.6 Å for undocked protein and docked complex, respectively. Further, crucial hydrogen bonding of the conserved catalytic triad for exhibiting high affinity between the FabH protein and ligand is observed by RDF analysis. The MD simulation results clearly demonstrated that binding of the inhibitor with S. gordonii FabH enhanced the structure and stabilized the dimeric FabH protein. Therefore, the inhibitor has the potential to become

  5. Spectroscopic investigation, vibrational assignments, HOMO-LUMO, NBO, MEP analysis and molecular docking studies of oxoaporphine alkaloid liriodenine

    NASA Astrophysics Data System (ADS)

    Costa, Renyer A.; Pitt, Priscilla Olliveira; Pinheiro, Maria Lucia B.; Oliveira, Kelson M. T.; Salomé, Kahlil Schwanka; Barison, Andersson; Costa, Emmanoel Vilaça

    2017-03-01

    A combined experimental and theoretical DFT study of the structural, vibrational and electronic properties of liriodenine is presented using B3LYP function with 6-311G (2d, p) basis set. The theoretical geometry optimization data were compared with the X-ray data for a similar structure in the associated literature, showing similar values. In addition, natural bond orbitals (NBOs), HOMO-LUMO energy gap, mapped molecular Electrostatic Potential (MEP) surface calculation, first and second order hyperpolarizabilities were also performed with the same calculation level. Theoretical UV spectrum agreed well with the measured experimental data, with transitions assigned. The molecular electrostatic potential map shows opposite potentials regions that forms hydrogen bonds that stabilize the dimeric form, which were confirmed by the close values related to the C dbnd O bond stretching between the dimeric form and the experimental IR spectra (1654 cm- 1 for the experimental, 1700 cm- 1 for the dimer form). Calculated HOMO/LUMO gaps shows the excitation energy for Liriodenine, justifying its stability and kinetics reaction. Molecular docking studies with Candida albicans dihydrofolate reductase (DHFR) and Candida albicans secreted aspartic protease (SAP) showed binding free energies values of - 8.5 and - 8.3 kcal/mol, suggesting good affinity between the liriodenine and the target macromolecules.

  6. Interaction between phillygenin and human serum albumin based on spectroscopic and molecular docking

    NASA Astrophysics Data System (ADS)

    Song, W.; Ao, M. Z.; Shi, Y.; Yuan, L. F.; Yuan, X. X.; Yu, L. J.

    2012-01-01

    In this paper, the interaction of human serum albumin (HSA) with phillygenin was investigated by fluorescence, circular dichroism (CD), UV-vis spectroscopic and molecular docking methods under physiological conditions. The Stern-Volmer analysis indicated that the fluorescence quenching of HSA by phillygenin resulted from static mechanism, and the binding constants were 1.71 × 10 5, 1.61 × 10 5 and 1.47 × 10 4 at 300, 305 and 310 K, respectively. The results of UV-vis spectra show that the secondary structure of the protein has been changed in the presence of phillygenin. The CD spectra showed that HSA conformation was altered by phillygenin with a major reduction of α-helix and an increase in β-sheet and random coil structures, indicating a partial protein unfolding. The distance between donor (HSA) and acceptor (phillygenin) was calculated to be 3.52 nm and the results of synchronous fluorescence spectra showed that binding of phillygenin to HSA can induce conformational changes in HSA. Molecular docking experiments found that phillygenin binds with HSA at IIIA domain of hydrophobic pocket with hydrogen bond interactions. The ionic bonds were formed with the O (4), O (5) and O (6) of phillygenin with nitrogen of ASN109, ARG186 and LEU115, respectively. The hydrogen bonds are formed between O (2) of phillygenin and SER419. In the presence of copper (II), iron (III) and alcohol, the apparent association constant KA and the number of binding sites of phillygenin on HSA were both decreased in the range of 88.84-91.97% and 16.09-18.85%, respectively. In view of the evidence presented, it is expected to enrich our knowledge of the interaction dynamics of phillygenin to the important plasma protein HSA, and it is also expected to provide important information of designs of new inspired drugs.

  7. Quorum sensing inhibitory potential and molecular docking studies of sesquiterpene lactones from Vernonia blumeoides.

    PubMed

    Aliyu, Abubakar Babando; Koorbanally, Neil Anthony; Moodley, Brenda; Singh, Parvesh; Chenia, Hafizah Yousuf

    2016-06-01

    The increasing incidence of multidrug-resistant Gram-negative bacterial pathogens has focused research on the suppression of bacterial virulence via quorum sensing inhibition strategies, rather than the conventional antimicrobial approach. The anti-virulence potential of eudesmanolide sesquiterpene lactones previously isolated from Vernonia blumeoides was assessed by inhibition of quorum sensing and in silico molecular docking. Inhibition of quorum sensing-controlled violacein production in Chromobacterium violaceum was quantified using violacein inhibition assays. Qualitative modulation of quorum sensing activity and signal synthesis was investigated using agar diffusion double ring assays and C. violaceum and Agrobacterium tumefaciens biosensor systems. Inhibition of violacein production was concentration-dependent, with ⩾90% inhibition being obtained with ⩾2.4 mg ml(-1) of crude extracts. Violacein inhibition was significant for the ethyl acetate extract with decreasing inhibition being observed with dichloromethane, hexane and methanol extracts. Violacein inhibition ⩾80% was obtained with 0.071 mg ml(-1) of blumeoidolide B in comparison with ⩾3.6 mg ml(-1) of blumeoidolide A. Agar diffusion double ring assays indicated that only the activity of the LuxI synthase homologue, CviI, was modulated by blumeoidolides A and B, and V. blumeoides crude extracts, suggesting that quorum sensing signal synthesis was down-regulated or competitively inhibited. Finally, molecular docking was conducted to explore the binding conformations of sesquiterpene lactones into the binding sites of quorum sensing regulator proteins, CviR and CviR'. The computed binding energy data suggested that the blumeoidolides have a tendency to inhibit both CviR and CviR' with varying binding affinities. Vernonia eudesmanolide sesquiterpene lactones have the potential to be novel therapeutic agents, which might be important in reducing virulence and pathogenicity of drug-resistant bacteria

  8. A comparative modeling and molecular docking study on Mycobacterium tuberculosis targets involved in peptidoglycan biosynthesis.

    PubMed

    Fakhar, Zeynab; Naiker, Suhashni; Alves, Claudio N; Govender, Thavendran; Maguire, Glenn E M; Lameira, Jeronimo; Lamichhane, Gyanu; Kruger, Hendrik G; Honarparvar, Bahareh

    2016-11-01

    An alarming rise of multidrug-resistant Mycobacterium tuberculosis strains and the continuous high global morbidity of tuberculosis have reinvigorated the need to identify novel targets to combat the disease. The enzymes that catalyze the biosynthesis of peptidoglycan in M. tuberculosis are essential and noteworthy therapeutic targets. In this study, the biochemical function and homology modeling of MurI, MurG, MraY, DapE, DapA, Alr, and Ddl enzymes of the CDC1551 M. tuberculosis strain involved in the biosynthesis of peptidoglycan cell wall are reported. Generation of the 3D structures was achieved with Modeller 9.13. To assess the structural quality of the obtained homology modeled targets, the models were validated using PROCHECK, PDBsum, QMEAN, and ERRAT scores. Molecular dynamics simulations were performed to calculate root mean square deviation (RMSD) and radius of gyration (Rg) of MurI and MurG target proteins and their corresponding templates. For further model validation, RMSD and Rg for selected targets/templates were investigated to compare the close proximity of their dynamic behavior in terms of protein stability and average distances. To identify the potential binding mode required for molecular docking, binding site information of all modeled targets was obtained using two prediction algorithms. A docking study was performed for MurI to determine the potential mode of interaction between the inhibitor and the active site residues. This study presents the first accounts of the 3D structural information for the selected M. tuberculosis targets involved in peptidoglycan biosynthesis.

  9. In silico evaluation, molecular docking and QSAR analysis of quinazoline-based EGFR-T790M inhibitors.

    PubMed

    Asadollahi-Baboli, M

    2016-08-01

    Mutated epidermal growth factor receptor (EGFR-T790M) inhibitors hold promise as new agents against cancer. Molecular docking and QSAR analysis were performed based on a series of fifty-three quinazoline derivatives to elucidate key structural and physicochemical properties affecting inhibitory activity. Molecular docking analysis identified the true conformations of ligands in the receptor's active pocket. The structural features of the ligands, expressed as molecular descriptors, were derived from the obtained docked conformations. Non-linear and spline QSAR models were developed through novel genetic algorithm and artificial neural network (GA-ANN) and multivariate adaptive regression spline techniques, respectively. The former technique was employed to consider non-linear relation between molecular descriptors and inhibitory activity of quinazoline derivatives. The later technique was also used to describe the non-linearity using basis functions and sub-region equations for each descriptor. Our QSAR model gave a high predictive performance [Formula: see text] and [Formula: see text]) using diverse validation techniques. Eight new compounds were designed using our QSAR model as potent EGFR-T790M inhibitors. Overall, the proposed in silico strategy based on docked derived descriptor and non-linear descriptor subset selection may help design novel quinazoline derivatives with improved EGFR-T790M inhibitory activity.

  10. Docking and Migration of Carbon Monoxide in Nitrogenase: The Case for Gated Pockets from IR Spectroscopy and Molecular Dynamics

    PubMed Central

    Gee, Leland B.; Leontyev, Igor; Stuchebrukhov, Alexei; Scott, Aubrey D.; Pelmenschikov, Vladimir; Cramer, Stephen P.

    2015-01-01

    Evidence for a CO docking site near the FeMo-cofactor in nitrogenase has been obtained by FT-IR monitored low temperature photolysis. We investigated the possible migration paths for CO from this docking site using molecular dynamics calculations. The simulations support the notion of a gas channel with multiple internal pockets from the active site to the protein exterior. Travel between pockets is gated by motion of protein residues. Implications for the mechanism of nitrogenase reactions with CO and N2 are discussed. PMID:25919807

  11. Docking and molecular dynamics studies of peripheral site ligand-oximes as reactivators of sarin-inhibited human acetylcholinesterase.

    PubMed

    de Almeida, Joyce S F D; Cuya Guizado, Teobaldo R; Guimarães, Ana P; Ramalho, Teodorico C; Gonçalves, Arlan S; de Koning, Martijn C; França, Tanos C C

    2016-12-01

    In the present work, we performed docking and molecular dynamics simulations studies on two groups of long-tailored oximes designed as peripheral site binders of acetylcholinesterase (AChE) and potential penetrators on the blood brain barrier. Our studies permitted to determine how the tails anchor in the peripheral site of sarin-inhibited human AChE, and which aminoacids are important to their stabilization. Also the energy values obtained in the docking studies corroborated quite well with the experimental results obtained before for these oximes.

  12. Investigating the Interaction of Fe Nanoparticles with Lysozyme by Biophysical and Molecular Docking Studies

    PubMed Central

    Aghili, Zahra; Taheri, Saba; Zeinabad, Hojjat Alizadeh; Pishkar, Leila; Saboury, Ali Akbar; Rahimi, Arash; Falahati, Mojtaba

    2016-01-01

    Herein, the interaction of hen egg white lysozyme (HEWL) with iron nanoparticle (Fe NP) was investigated by spectroscopic and docking studies. The zeta potential analysis revealed that addition of Fe NP (6.45±1.03 mV) to HEWL (8.57±0.54 mV) can cause to greater charge distribution of nanoparticle-protein system (17.33±1.84 mV). In addition, dynamic light scattering (DLS) study revealed that addition of Fe NP (92.95±6.11 nm) to HEWL (2.68±0.37 nm) increases suspension potential of protein/nanoparticle system (51.17±3.19 nm). Fluorescence quenching studies reveled that both static and dynamic quenching mechanism occur and hydrogen bond and van der Waals interaction give rise to protein-NP system. Synchronous fluorescence spectroscopy of HEWL in the presence of Fe NP showed that the emission maximum wavelength of tryptophan (Trp) residues undergoes a red-shift. ANS fluorescence data indicated a dramatic exposure of hydrophobic residues to the solvent. The considerable reduction in melting temperature (T(m)) of HEWL after addition of Fe NP determines an unfavorable interaction system. Furthermore circular dichoroism (CD) experiments demonstrated that, the secondary structure of HEWL has not changed with increasing Fe NP concentrations; however, some conformational changes occur in tertiary structure of HEWL. Moreover, protein–ligand docking study confirmed that the Fe NP forms hydrogen bond contacts with HEWL. PMID:27776180

  13. A combined spectroscopic, molecular docking and molecular dynamic simulation study on the interaction of quercetin with β-casein nanoparticles.

    PubMed

    Mehranfar, Fahimeh; Bordbar, Abdol-Khalegh; Parastar, Hadi

    2013-10-05

    The interaction of quercetin with β-casein nanoparticle micelle was studied at various temperatures in order to do a complete thermodynamic and molecular analysis on the binding process. The results of fluorescence studies showed the possibility of fluorescence energy transfer between excited tryptophan and quercetin. The determined values of critical transfers distance and the mean distance of ligand from Trp-143 residues in β-casein micelle represents a non-radiative energy transfer mechanism for quenching and the existence of a significant interaction between this flavonoid and β-casein nanoparticle. The equilibrium binding of quercetin with β-casein micelle at different temperatures was studied by using UV-Vis absorption spectroscopy. The chemometric analysis (principal component analysis (PCA) and multivariate curve resolution-alternating least squares (MCR-ALS) methods) on spectrophotometric data revealed the existence of two components in solution (quercetin and β-casein-quercetin complex) and resolved their pure concentration and spectral profiles. This information let us to calculate the equilibrium binding constant at various temperatures and the relevant thermodynamic parameters of interaction (enthalpy, entropy and Gibbs free energy) with low uncertainty. The negative values of entropy and enthalpy changes represent the predominate role of hydrogen binding and van der Waals interactions in the binding process. Docking calculations showed the probable binding site of quercetin is located in the hydrophobic core of β-casein where the quercetin molecule is lined by hydrophobic residues and make five hydrogen bonds and several van der Waals contacts with them. Moreover, molecular dynamic (MD) simulation results suggested that this flavonoid can interact with β-casein, without affecting the secondary structure of β-casein. Simulations, molecular docking and experimental data reciprocally supported each other.

  14. Theory of atomic additivity in molecular hyperpolizabilities

    NASA Technical Reports Server (NTRS)

    Baird, James K.

    1987-01-01

    Hyperpolarizability is a function of frequency. This is called dispersion. Because of the Kramers-Kronig relations, researchers expect that a material that is dispersing light is also absorbing it. Where there is both dispersion and absorption, the molecular polarizabilities are complex functions of the frequency. This led researchers to consider atomic additivity in both the real and imaginary parts of the ordinary and hyperpolarizabilities. This effort is desirable not only from a theoretical point of view, but also because of the existence of a large body of complex refractive index data, which may be used to test the additivity principle with the complex valued ordinary dipole polarizability.

  15. QSAR, molecular docking studies of thiophene and imidazopyridine derivatives as polo-like kinase 1 inhibitors

    NASA Astrophysics Data System (ADS)

    Cao, Shandong

    2012-08-01

    The purpose of the present study was to develop in silico models allowing for a reliable prediction of polo-like kinase inhibitors based on a large diverse dataset of 136 compounds. As an effective method, quantitative structure activity relationship (QSAR) was applied using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The proposed QSAR models showed reasonable predictivity of thiophene analogs (Rcv2=0.533, Rpred2=0.845) and included four molecular descriptors, namely IC3, RDF075m, Mor02m and R4e+. The optimal model for imidazopyridine derivatives (Rcv2=0.776, Rpred2=0.876) was shown to perform good in prediction accuracy, using GATS2m and BEHe1 descriptors. Analysis of the contour maps helped to identify structural requirements for the inhibitors and served as a basis for the design of the next generation of the inhibitor analogues. Docking studies were also employed to position the inhibitors into the polo-like kinase active site to determine the most probable binding mode. These studies may help to understand the factors influencing the binding affinity of chemicals and to develop alternative methods for prescreening and designing of polo-like kinase inhibitors.

  16. Docking and Molecular Dynamics of Steviol Glycoside-Human Bitter Receptor Interactions.

    PubMed

    Acevedo, Waldo; González-Nilo, Fernando; Agosin, Eduardo

    2016-10-12

    Stevia is one of the sweeteners with the greatest consumer demand because of its natural origin and minimal calorie content. Steviol glycosides (SG) are the main active compounds present in the leaves of Stevia rebaudiana and are responsible for its sweetness. However, recent in vitro studies in HEK 293 cells revealed that SG specifically activate the hT2R4 and hT2R14 bitter taste receptors, triggering this mouth feel. The objective of this study was to characterize the interaction of SG with these two receptors at the molecular level. The results showed that SG have only one site for orthosteric binding to these receptors. The binding free energy (ΔGbinding) between the receptor and SG was negatively correlated with SG bitterness intensity, for both hT2R4 (r = -0.95) and hT2R14 (r = -0.89). We also determined, by steered molecular dynamics simulations, that the force required to extract stevioside from the receptors was greater than that required for rebaudioside A, in accordance with the ΔG values obtained by molecular docking. Finally, we identified the loop responsible for the activation by SG of both receptors. As a whole, these results contribute to a better understanding of the resulting off-flavor perception of these natural sweeteners in foods and beverages, allowing for better prediction, and control, of the resulting bitterness.

  17. Investigation on critical structural motifs of ligands for triggering glucocorticoid receptor nuclear migration through molecular docking simulations.

    PubMed

    Liu, Ya-Lin; Jang, Soonmin; Wang, Shih-Min; Chen, Chiu-Hao; Li, Feng-Yin

    2016-06-01

    The glucocorticoid receptor (GR), a transcription factor regulating gene expression in a ligand-dependent fashion, is known for flexibility in adapting various ligands with their structures ranging from steroid to non-steroid. However, in our previous study, GR shows a stringent discrimination against a set of steroid ligands with highly similar structures for triggering its nuclear migration. In order to resolve this puzzle, we employed molecular docking simulations to investigate the origin of this structural discrimination. By analyzing the docking orientations and the related ligand-GR interaction patterns, we found that the hydrophilicity mismatch between the docking ligand and the GR ligand-binding site is the main cause combined with the steric hindrance and structural rigidness of these steroid ligands. Furthermore, we utilized this knowledge to rationalize how the structure-binding interaction of non-steroid ligands triggers GR nuclear migration with their structures available in Protein Data Bank.

  18. A structure-activity relationship study of catechol- O-methyltransferase inhibitors combining molecular docking and 3D QSAR methods

    NASA Astrophysics Data System (ADS)

    Tervo, Anu J.; Nyrönen, Tommi H.; Rönkkö, Toni; Poso, Antti

    2003-12-01

    A panel of 92 catechol- O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity.

  19. Design, synthesis, cytotoxic activity and molecular docking studies of new 20(S)-sulfonylamidine camptothecin derivatives.

    PubMed

    Song, Zi-Long; Wang, Mei-Juan; Li, Lanlan; Wu, Dan; Wang, Yu-Han; Yan, Li-Ting; Morris-Natschke, Susan L; Liu, Ying-Qian; Zhao, Yong-Long; Wang, Chih-Ya; Liu, Huanxiang; Goto, Masuo; Liu, Heng; Zhu, Gao-Xiang; Lee, Kuo-Hsiung

    2016-06-10

    In an ongoing investigation of 20-sulfonylamidine derivatives (9, YQL-9a) of camptothecin (1) as potential anticancer agents directly and selectively inhibiting topoisomerase (Topo) I, the sulfonylamidine pharmacophore was held constant, and a camptothecin derivatives with various substitution patterns were synthesized. The new compounds were evaluated for antiproliferative activity against three human tumor cell lines, A-549, KB, and multidrug resistant (MDR) KB subline (KBvin). Several analogs showed comparable or superior antiproliferative activity compared to the clinically prescribed 1 and irinotecan (3). Significantly, the 20-sulfonylamidine derivatives exhibited comparable cytotoxicity against KBvin, while 1 and 3 were less active against this cell line. Among them, compound 15c displayed much better cytotoxic activity than the controls 1, 3, and 9. Novel key structural features related to the antiproliferative activities were identified by structure-activity relationship (SAR) analysis. In a molecular docking model, compounds 9 and 15c interacted with Topo I-DNA through a different binding mode from 1 and 3. The sulfonylamidine side chains of 9 and 15c could likely form direct hydrogen bonds with Topo I, while hydrophobic interaction with Topo I and π-π stacking with double strand DNA were also confirmed as binding driving forces. The results from docking models were consistent with the SAR conclusions. The introduction of bulky substituents at the 20-position contributed to the altered binding mode of the compound by allowing them to form new interactions with Topo I residues. The information obtained in this study will be helpful for the design of new derivatives of 1 with most promising anticancer activity.

  20. Design, synthesis, anticancer, antimicrobial activities and molecular docking studies of novel quinoline bearing dihydropyridines.

    PubMed

    Nkosi, S'busiso Mfan'vele; Anand, Krishnan; Anandakumar, S; Singh, Sanil; Chuturgoon, Anil Amichund; Gengan, Robert Moonsamy

    2016-12-01

    A new series of eight quinoline bearing dihydropyridine derivatives (A1-A8) were synthesized in high yield and in short reaction time by a four component reaction of 2-chloro-3-fomyl quinoline, malononitrile, arylamines and dimethyl acetylenedicarboxylate in the presence of a catalytic amount of triethylamine. The compounds were fully characterized by IR, NMR and GC-MS. These compounds were screened for potential biological activity in an A549 lung cancer cell line and were also evaluated for their antibacterial activities against Pseudomonas aeruginosa ATCC 27853, Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 29213 whilst their molecular docking properties in an enzymatic system were also determined. Compounds A2, A3, A4 and A8 showed anti-proliferative activity; with A4 having the highest toxicity at 250μg/mL and A8 has high toxicity at 125, 250 and 500μg/mL, respectively. Antibacterial results indicated that A4 have significant activity against tested microorganisms at the minimum inhibitory concentration (MIC) values of 32μg/mL against Pseudomonas aeruginosa and Escherichia coli, and 16μg/mL against Staphylococcus aureus. Docking of A1 with human mdm2 indicated the lowest binding energy (-6.111Kcal/mol) thereby showing strong affinity of the ligand molecule with the receptor which has been stabilized by strong hydrogen bond interactions in the binding pocket. This confirms that A1 is a better inhibitor for E3 ubiquitin-protein ligase mdm2.

  1. Molecular recognition and binding of beta-lactamase II from Bacillus cereus with penicillin V and sulbactam by spectroscopic analysis in combination with docking simulation.

    PubMed

    Zhang, Yeli; Qiao, Pan; Li, Shuaihua; Feng, Xuan; Bian, Liujiao

    2017-02-10

    The molecular recognition and binding interaction of beta-lactamase II from Bacillus cereus (Bc II) with penicillin V (PV) and sulbactam (Sul) at 277 K were studied by spectroscopic analysis and molecular docking. The results showed that a non-fluorescence static complex was separately formed between Bc II and two ligands, the molecular ratio of Bc II to PV or Sul was both 1:1 in the binding and the binding constants were 2.00 × 10(6) and 3.98 × 10(5) (L/mol), respectively. The negative free energy changes and apparent activation energies indicated that both the binding processes were spontaneous. Molecular docking showed that in the binding process, the whole Sul molecule entered into the binding pocket of Bc II while only part of the whole PV molecule entered into the pocket due to a long side chain, and electrostatic interactions were the major contribution to the binding processes. In addition, a weak conformational change of Bc II was also observed in the molecular recognition and binding process of Bc II with PV or Sul. This study may provide some valuable information for exploring the recognition and binding of proteins with ligands in the binding process and for the design of novel super-antibiotics.

  2. Theoretical approach to the innovative mutation of naphthalene 1,2-dioxygenase: a molecular dynamics and docking study.

    PubMed

    Librando, Vito; Pappalardo, Matteo

    2014-08-01

    Polycyclic aromatic hydrocarbons are a family of ubiquitous pollutants whose environmental behavior has been widely studied. Different bacterial species are able to decompose hydrocarbons by using them as a food source. One of the best-studied enzymes is naphthalene 1,2-dioxygenase (NDO). A practical way to optimize the degradation process is by mutating the protein involved, increasing both the degradation capacity of the enzyme and its ability to work under extreme environmental conditions of high temperature and low pH. Herein, we describe the study of NDO using molecular dynamics and docking calculations to discover new mutants with high degrading capabilities. We modeled eleven new mutants of NDO. The results indicate that increasing the size of the active site cavity in the mutants allowed for the insertion of high molecular weight PAHs. Additionally, the physicochemical properties of the NDO active sites make the sites well suited to interactions with PAHs, so most amino-acid modifications should not result in significantly altered behavior of NDO.

  3. RNA-Seq and molecular docking reveal multi-level pesticide resistance in the bed bug

    PubMed Central

    2012-01-01

    Background Bed bugs (Cimex lectularius) are hematophagous nocturnal parasites of humans that have attained high impact status due to their worldwide resurgence. The sudden and rampant resurgence of C. lectularius has been attributed to numerous factors including frequent international travel, narrower pest management practices, and insecticide resistance. Results We performed a next-generation RNA sequencing (RNA-Seq) experiment to find differentially expressed genes between pesticide-resistant (PR) and pesticide-susceptible (PS) strains of C. lectularius. A reference transcriptome database of 51,492 expressed sequence tags (ESTs) was created by combining the databases derived from de novo assembled mRNA-Seq tags (30,404 ESTs) and our previous 454 pyrosequenced database (21,088 ESTs). The two-way GLMseq analysis revealed ~15,000 highly significant differentially expressed ESTs between the PR and PS strains. Among the top 5,000 differentially expressed ESTs, 109 putative defense genes (cuticular proteins, cytochrome P450s, antioxidant genes, ABC transporters, glutathione S-transferases, carboxylesterases and acetyl cholinesterase) involved in penetration resistance and metabolic resistance were identified. Tissue and development-specific expression of P450 CYP3 clan members showed high mRNA levels in the cuticle, Malpighian tubules, and midgut; and in early instar nymphs, respectively. Lastly, molecular modeling and docking of a candidate cytochrome P450 (CYP397A1V2) revealed the flexibility of the deduced protein to metabolize a broad range of insecticide substrates including DDT, deltamethrin, permethrin, and imidacloprid. Conclusions We developed significant molecular resources for C. lectularius putatively involved in metabolic resistance as well as those participating in other modes of insecticide resistance. RNA-Seq profiles of PR strains combined with tissue-specific profiles and molecular docking revealed multi-level insecticide resistance in C. lectularius

  4. Identification of promising DNA GyrB inhibitors for Tuberculosis using pharmacophore-based virtual screening, molecular docking and molecular dynamics studies.

    PubMed

    Islam, Md Ataul; Pillay, Tahir S

    2017-01-21

    In this study, we searched for potential DNA GyrB inhibitors using pharmacophore-based virtual screening followed by molecular docking and molecular dynamics simulation approaches. For this purpose, a set of 248 DNA GyrB inhibitors was collected from the literature and a well-validated pharmacophore model was generated. The best pharmacophore model explained that two each of hydrogen bond acceptors and hydrophobicity regions were critical for inhibition of DNA GyrB. Good statistical results of the pharmacophore model indicated that the model was robust in nature. Virtual screening of molecular databases revealed three molecules as potential antimycobacterial agents. The final screened promising compounds were evaluated in molecular docking and molecular dynamics simulation studies. In the molecular dynamics studies, RMSD and RMSF values undoubtedly explained that the screened compounds formed stable complexes with DNA GyrB. Therefore, it can be concluded that the compounds identified may have potential for the treatment of TB.

  5. Template engineered biopotent macrocyclic complexes involving furan moiety: Molecular modeling and molecular docking

    NASA Astrophysics Data System (ADS)

    Rathi, Parveen; Singh, D. P.

    2015-08-01

    Bioactive cobalt(II), nickel(II), copper(II) and zinc(II) complexes of octaazamacrocycle, 19, 20-dioxa-2,3,5,6,11,12,14,15-octaazatricyclo[14.2.1.1]icosa-1,6,8,10,15,17-hexaene-4,13-dithione, derived from furan-2,5-dione and thiocarbonohydrazide in the mole ratio 2:2:1 have been engineered via template methodology. The synthesized metal complexes have also been structurally characterized in the light of various physicochemical techniques and evaluated for antimicrobial and antioxidant activities. All these studies point toward the formation of divalent macrocyclic complexes possessing distorted octahedral geometry and having significant antimicrobial and antioxidant properties as compared to the starting precursors. Virtual screening of a representative complex was done through docking to the binding site of COX-2 to evaluate the anti-inflammatory activity of the series. Non-electrolytic nature of the complexes has been predicted on the basis of low value of molar conductivity in DMSO. All the complexes were having notable activities against pathogenic microbes as compared to precursors-thiocarbonohydrazide and furan-2,5-dione however, the complex 5, [Ni (C10H8N8O2S2) (NO3)2], shows the best antimicrobial activity.

  6. Investigate the Binding of Catechins to Trypsin Using Docking and Molecular Dynamics Simulation

    PubMed Central

    Cui, Fengchao; Yang, Kecheng; Li, Yunqi

    2015-01-01

    To explore the inhibitory mechanism of catechins for digestive enzymes, we investigated the binding mode of catechins to a typical digestive enzyme-trypsin and analyzed the structure-activity relationship of catechins, using an integration of molecular docking, molecular dynamics simulation and binding free energy calculation. We found that catechins with different structures bound to a conservative pocket S1 of trypsin, which is comprised of residues 189–195, 214–220 and 225–228. In the trypsin-catechin complexes, Asp189 by forming strong hydrogen bonding, and Gln192, Trp215 and Gly216 through hydrophobic interactions, all significantly contribute to the binding of catechins. The number and the position of hydroxyl and aromatic groups, the structure of stereoisomers, and the orientation of catechins in the binding pocket S1 of trypsin all affect the binding affinity. The binding affinity is in the order of Epigallocatechin gallate (EGCG) > Epicatechin gallate (ECG) > Epicatechin (EC) > Epigallocatechin (EGC), and 2R-3R EGCG shows the strongest binding affinity out of other stereoisomers. Meanwhile, the synergic conformational changes of residues and catechins were also analyzed. These findings will be helpful in understanding the knowledge of interactions between catechins and trypsin and referable for the design of novel polyphenol based functional food and nutriceutical formulas. PMID:25938485

  7. Structure and functional features of olive pollen pectin methylesterase using homology modeling and molecular docking methods.

    PubMed

    Jimenez-Lopez, Jose C; Kotchoni, Simeon O; Rodríguez-García, María I; Alché, Juan D

    2012-12-01

    Pectin methylesterases (PMEs), a multigene family of proteins with multiple differentially regulated isoforms, are key enzymes implicated in the carbohydrates (pectin) metabolism of cell walls. Olive pollen PME has been identified as a new allergen (Ole e 11) of potential relevance in allergy amelioration, since it exhibits high prevalence among atopic patients. In this work, the structural and functional characterization of two olive pollen PME isoforms and their comparison with other PME plants was performed by using different approaches: (1) the physicochemical properties and functional-regulatory motifs characterization, (2) primary sequence analysis, 2D and 3D comparative structural features study, (3) conservation and evolutionary analysis, (4) catalytic activity and regulation based on molecular docking analysis of a homologue PME inhibitor, and (5) B-cell epitopes prediction by sequence and structural based methods and protein-protein interaction tools, while T-cell epitopes by inhibitory concentration and binding score methods. Our results indicate that the structural differences and low conservation of residues, together with differences in physicochemical and posttranslational motifs might be a mechanism for PME isovariants generation, regulation, and differential surface epitopes generation. Olive PMEs perform a processive catalytic mechanism, and a differential molecular interaction with specific PME inhibitor, opening new possibilities for PME activity regulation. Despite the common function of PMEs, differential features found in this study will lead to a better understanding of the structural and functional characterization of plant PMEs and help to improve the component-resolving diagnosis and immunotherapy of olive pollen allergy by epitopes identification.

  8. Study on the binding of chlorogenic acid to pepsin by spectral and molecular docking.

    PubMed

    Zeng, Hua-jin; Liang, Hui-li; You, Jing; Qu, Ling-bo

    2014-11-01

    The interaction of pepsin with chlorogenic acid (CHA) was investigated using fluorescence, UV/vis spectroscopy and molecular modeling methods. Stern-Volmer analysis indicated that the fluorescence quenching of pepsin by CHA resulted from a static mechanism, and the binding constant was 1.1846 × 10(5) and 1.1587 × 10(5) L/mol at 288 and 310 K, respectively. The distance between donor (pepsin) and acceptor (CHA) was calculated to be 2.39 nm and the number of binding sites for CHA binding on pepsin was ~ 1. The results of synchronous fluorescence and three-dimensional fluorescence showed that binding of CHA to pepsin could induce conformational changes in pepsin. Molecular docking experiments found that CHA bonded with pepsin in the area of the hydrophobic cavity with Van der Waals' forces or hydrogen bonding interaction, which were consistent with the results obtained from the thermodynamic parameter analysis. Furthermore, the binding of CHA can inhibit pepsin activity in vitro.

  9. Synthesis of novel derivatives of oxindole, their urease inhibition and molecular docking studies.

    PubMed

    Taha, Muhammad; Ismail, Nor Hadiani; Khan, Ajmal; Shah, Syed Adnan Ali; Anwar, Ammarah; Halim, Sobia Ahsan; Fatmi, M Qaiser; Imran, Syahrul; Rahim, Fazal; Khan, Khalid Mohammed

    2015-08-15

    We synthesized a series of novel 5-24 derivatives of oxindole. The synthesis started from 5-chlorooxindole, which was condensed with methyl 4-carboxybezoate and result in the formation of benzolyester derivatives of oxindole which was then treated with hydrazine hydrate. The oxindole benzoylhydrazide was treated with aryl acetophenones and aldehydes to get target compounds 5-24. The synthesized compounds were evaluated for urease inhibition; the compound 5 (IC50 = 13.00 ± 0.35 μM) and 11 (IC50 = 19.20 ± 0.50 μM) showed potent activity as compared to the standard drug thiourea (IC50 = 21.00 ± 0.01 μM). Other compounds showed moderate to weak activity. All synthetic compounds were characterized by different spectroscopic techniques including (1)H NMR, (13)C NMR, IR and EI MS. The molecular interactions of the active compounds within the binding site of urease enzyme were studied through molecular docking simulations.

  10. Towards better modelling of drug-loading in solid lipid nanoparticles: Molecular dynamics, docking experiments and Gaussian Processes machine learning.

    PubMed

    Hathout, Rania M; Metwally, Abdelkader A

    2016-11-01

    This study represents one of the series applying computer-oriented processes and tools in digging for information, analysing data and finally extracting correlations and meaningful outcomes. In this context, binding energies could be used to model and predict the mass of loaded drugs in solid lipid nanoparticles after molecular docking of literature-gathered drugs using MOE® software package on molecularly simulated tripalmitin matrices using GROMACS®. Consequently, Gaussian processes as a supervised machine learning artificial intelligence technique were used to correlate the drugs' descriptors (e.g. M.W., xLogP, TPSA and fragment complexity) with their molecular docking binding energies. Lower percentage bias was obtained compared to previous studies which allows the accurate estimation of the loaded mass of any drug in the investigated solid lipid nanoparticles by just projecting its chemical structure to its main features (descriptors).

  11. GPU.proton.DOCK: Genuine Protein Ultrafast proton equilibria consistent DOCKing

    PubMed Central

    Kantardjiev, Alexander A.

    2011-01-01

    GPU.proton.DOCK (Genuine Protein Ultrafast proton equilibria consistent DOCKing) is a state of the art service for in silico prediction of protein–protein interactions via rigorous and ultrafast docking code. It is unique in providing stringent account of electrostatic interactions self-consistency and proton equilibria mutual effects of docking partners. GPU.proton.DOCK is the first server offering such a crucial supplement to protein docking algorithms—a step toward more reliable and high accuracy docking results. The code (especially the Fast Fourier Transform bottleneck and electrostatic fields computation) is parallelized to run on a GPU supercomputer. The high performance will be of use for large-scale structural bioinformatics and systems biology projects, thus bridging physics of the interactions with analysis of molecular networks. We propose workflows for exploring in silico charge mutagenesis effects. Special emphasis is given to the interface-intuitive and user-friendly. The input is comprised of the atomic coordinate files in PDB format. The advanced user is provided with a special input section for addition of non-polypeptide charges, extra ionogenic groups with intrinsic pKa values or fixed ions. The output is comprised of docked complexes in PDB format as well as interactive visualization in a molecular viewer. GPU.proton.DOCK server can be accessed at http://gpudock.orgchm.bas.bg/. PMID:21666258

  12. Screening of Toxic Effects of Bisphenol A and Products of Its Degradation: Zebrafish (Danio rerio) Embryo Test and Molecular Docking.

    PubMed

    Makarova, Katerina; Siudem, Pawel; Zawada, Katarzyna; Kurkowiak, Justyna

    2016-10-01

    Bisphenol A (BPA) acts as an endocrine-disrupting compound even at a low concentration. Degradation of BPA could lead to the formation of toxic products. In this study, we compare the toxicity of BPA and seven intermediate products of its degradation. The accuracy of three molecular docking programs (Surflex, Autodock, and Autodock Vina) in predicting the binding affinities of selected compounds to human (ERα, ERβ, and ERRγ) and zebrafish (ERα, ERRγA, and ERRγB) estrogen and estrogen-related receptors was evaluated. The docking experiments showed that 4-isopropylphenol could have similar toxicity to that of BPA due to its high affinity to ERRγ and ERRγB and high octanol-water partitioning coefficient. The least toxic compounds were hydroquinone and phenol. Those compounds as well as BPA were screened in the zebrafish (Danio rerio) embryo test. 4-isopropylphenol had the strongest toxic effect on zebrafish embryos and caused 100% lethality shortly after exposure. BPA caused the delay in development, multiple deformations, and low heartbeats (30 bps), whereas hydroquinone had no impact on the development of the zebrafish embryo. Thus, the results of zebrafish screening are in good agreement with our docking experiment. The molecular docking could be used to screen the toxicity of other xenoestrogens and their products of degradation.

  13. Exploring the selectivity of auto-inducer complex with LuxR using molecular docking, mutational studies and molecular dynamics simulations

    NASA Astrophysics Data System (ADS)

    Rajamanikandan, Sundaraj; Srinivasan, Pappu

    2017-03-01

    Bacteria communicate with one another using extracellular signaling molecules called auto-inducers (AHLs), a process termed as quorum sensing. The quorum sensing process allows bacteria to regulate various physiological activities. In this regard, quorum sensing master regulator LuxR from Vibrio harveyi represents an attractive therapeutic target for the development of novel anti-quorum sensing agents. Eventhough the binding of AHL complex with LuxR is evidenced in earlier reports, but their mode of binding is not clearly determined. Therefore, in the present work, molecular docking, in silico mutational studies, molecular dynamics simulations and free energy calculations were performed to understand the selectivity of AHL into the binding site of LuxR. The results revealed that Asn133 and Gln137 residues play a crucial role in recognizing AHL more effectively into the binding site of LuxR with good binding free energy. In addition to that, the carbonyl group presents in the lactone ring and amide group of AHL plays a vital role in the formation of hydrogen bond interactions with the protein. Further, structure based virtual screening was performed using ChemBridge database to screen potent lead molecules against LuxR. 4-benzyl-2-pyrrolidinone and N-[2(1-cyclohexen-1-yl) enthyl]-N'(2-ethoxyphenyl) were selected based on dock score, binding affinity and mode of interactions with the receptor. Furthermore, binding free energy, density functional theory and ADME prediction were performed to rank the lead molecules. Thus, the identified lead molecules can be used for the development of anti-quorum sensing drugs.

  14. Synthesis, characterization, crystal structure, in-vitro antimicrobial evaluation and molecular docking studies of 1-(furan-2-carbonyl)-3-alkyl-2,6-diphenylpiperidin-4-one derivatives

    NASA Astrophysics Data System (ADS)

    Srikanth, R.; Sivarajan, A.; Venkatesan, C. S.; Maheshwaran, V.; Sugumar, P.; Rajitha, G.; Varalakshmi, J. C.; Ponnuswamy, M. N.

    2016-12-01

    A new class of various furoyl derivatives of 2,6-disubstituted piperidin-4-ones were synthesized and characterized by FTIR, NMR, mass and single crystal X-ray diffraction methods. The synthesized compounds were subjected to in-vitro antibacterial and antifungal activities against pathogenic microbial strains. The results pointed out that compounds 11, 12 & 14 displayed pronounced activity towards gram positive bacteria, whereas the compounds 9, 13 & 14 showed a superior inhibition activity against gram negative bacteria. The compound 9 showed a moderate activity towards the fungi. In addition, molecular docking experiments were also carried out.

  15. Investigation of the Interaction of Naringin Palmitate with Bovine Serum Albumin: Spectroscopic Analysis and Molecular Docking

    PubMed Central

    Zhang, Xia; Li, Lin; Xu, Zhenbo; Liang, Zhili; Su, Jianyu; Huang, Jianrong; Li, Bing

    2013-01-01

    Background Bovine serum albumin (BSA) contains high affinity binding sites for several endogenous and exogenous compounds and has been used to replace human serum albumin (HSA), as these two compounds share a similar structure. Naringin palmitate is a modified product of naringin that is produced by an acylation reaction with palmitic acid, which is considered to be an effective substance for enhancing naringin lipophilicity. In this study, the interaction of naringin palmitate with BSA was characterised by spectroscopic and molecular docking techniques. Methodology/Principal Findings The goal of this study was to investigate the interactions between naringin palmitate and BSA under physiological conditions, and differences in naringin and naringin palmitate affinities for BSA were further compared and analysed. The formation of naringin palmitate-BSA was revealed by fluorescence quenching, and the Stern-Volmer quenching constant (KSV) was found to decrease with increasing temperature, suggesting that a static quenching mechanism was involved. The changes in enthalpy (ΔH) and entropy (ΔS) for the interaction were detected at −4.11±0.18 kJ·mol−1 and −76.59±0.32 J·mol−1·K−1, respectively, which indicated that the naringin palmitate-BSA interaction occurred mainly through van der Waals forces and hydrogen bond formation. The negative free energy change (ΔG) values of naringin palmitate at different temperatures suggested a spontaneous interaction. Circular dichroism studies revealed that the α-helical content of BSA decreased after interacting with naringin palmitate. Displacement studies suggested that naringin palmitate was partially bound to site I (subdomain IIA) of the BSA, which was also substantiated by the molecular docking studies. Conclusions/Significance In conclusion, naringin palmitate was transported by BSA and was easily removed afterwards. As a consequence, an extension of naringin applications for use in food, cosmetic and medicinal

  16. Structure-based virtual screening, molecular docking, ADMET and molecular simulations to develop benzoxaborole analogs as potential inhibitor against Leishmania donovani trypanothione reductase.

    PubMed

    Pandey, Rajan Kumar; Kumbhar, Bajarang Vasant; Sundar, Shyam; Kunwar, Ambarish; Prajapati, Vijay Kumar

    2017-02-01

    Visceral leishmaniasis (VL) is the most fatal form of leishmaniasis and it affects 70 countries worldwide. Increasing drug resistant for antileishmanial drugs such as miltefosine, sodium stibogluconate and pentamidine has been reported in the VL endemic region. Amphotericin B has shown potential antileishmanial activity in different formulations but its cost of treatment and associated nephrotoxicity have limited its use by affected people living in the endemic zone. To control the VL infection in the affected countries, it is necessary to develop new antileishmanial compounds with high efficacy and negligible toxicity. Computer aided programs such as binding free energy estimation; ADMET prediction and molecular dynamics simulation can be used to investigate novel antileishmanial molecules in shorter duration. To develop antileishmanial lead molecule, we performed standard precision (SP) docking for 1160 benzoxaborole analogs along with reference inhibitors against trypanothione reductase of Leishmania parasite. Furthermore, extra precision (XP) docking, ADMET prediction, prime MM-GBSA was conducted over 115 ligands, showing better docking score than reference inhibitors to get potential antileishmanial compounds. Simultaneously, area under the curve (AUC) was estimated using ROC plot to validate the SP and XP docking protocol. Later on, two benzoxaborole analogs with best MM-GBSA ΔG-bind were subjected to molecular simulation and docking confirmation to ensure the ligand interaction with TR. The presented drug discovery based on computational study confirms that BOB27 can be used as a potential drug candidate and warrants further experimental investigation to fight against VL in endemic areas.

  17. Exploration of Novel Human Tyrosinase Inhibitors by Molecular Modeling, Docking and Simulation Studies.

    PubMed

    Hassan, Mubashir; Ashraf, Zaman; Abbas, Qamar; Raza, Hussain; Seo, Sung-Yum

    2016-04-21

    Research studies on human tyrosinase inhibitors and exploration for better cytotoxic agents remain an important line in drug discovery and development at the present time. Recently, multiple inhibitors are being used to cure melanogenesis by targeting human tyrosinase. A series of coumarin (C1-C9)-, thymol (T1-T8)- and vanillin (V1-V8)-based derivatives have been theoretically analyzed for their inhibitory effects against human tyrosinase. The crystal structure of human tyrosinase is not available in Protein Data Bank. Therefore, homology modeling approach was used to predict three-dimensional (3D) crystal structure of human tyrosinase. The reliability and efficacy of predicted 3D structure were validated by using Ramachandran plots which indicate that 95.01 % residues are present in favored regions. Moreover, multiple computational approaches such as molecular docking and molecular dynamic (MD) simulation along with various online tools were employed to screen the best inhibitor against melanogenesis. The results revealed that V7 and C9 compounds showed significant binding energy values (-7.79 and -7.40 kcal/mol, respectively) compared with the standard drugs such as kojic acid (-4.21 kcal/mol) and arbutin (-4.62 kcal/mol). Moreover, MD simulation results also justified that V7 showed little fluctuations throughout the simulation period as depicted by the root mean square deviation and root mean square fluctuation graphs. Thus, the present in silico study provides a deeper insight into the structural attributes of V7 compound and its overall molecular interactions against human tyrosinase and gives a hypothetical gateway to use this compound as a potential inhibitor against melanogenesis.

  18. Computational modeling on the recognition of the HRE motif by HIF-1: molecular docking and molecular dynamics studies.

    PubMed

    Sokkar, Pandian; Sathis, Vani; Ramachandran, Murugesan

    2012-05-01

    Hypoxia inducible factor-1 (HIF-1) is a bHLH-family transcription factor that controls genes involved in glycolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a heterodimer of HIF-1α and HIF-1β, binds to the hypoxia responsive element (HRE) present in the promoter regions of hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). Neither the structure of free HIF-1 nor that of its complex with HRE is available. Computational modeling of the transcription factor-DNA complex has always been challenging due to their inherent flexibility and large conformational space. The present study aims to model the interaction between the DNA-binding domain of HIF-1 and HRE. Experiments showed that rigid macromolecular docking programs (HEX and GRAMM-X) failed to predict the optimal dimerization of individually modeled HIF-1 subunits. Hence, the HIF-1 heterodimer was modeled based on the phosphate system positive regulatory protein (PHO4) homodimer. The duplex VEGF-DNA segment containing HRE with flanking nucleotides was modeled in the B form and equilibrated via molecular dynamics (MD) simulation. A rigid docking approach was used to predict the crude binding mode of HIF-1 dimer with HRE, in which the putative contacts were found to be present. An MD simulation (5 ns) of the HIF-1-HRE complex in explicit water was performed to account for its flexibility and to optimize its interactions. All of the conserved amino acid residues were found to play roles in the recognition of HRE. The present work, which sheds light on the recognition of HRE by HIF-1, could be beneficial in the design of peptide or small molecule therapeutics that can mimic HIF-1 and bind with the HRE sequence.

  19. Receptor- and ligand-based study of fullerene analogues: comprehensive computational approach including quantum-chemical, QSAR and molecular docking simulations.

    PubMed

    Ahmed, Lucky; Rasulev, Bakhtiyor; Turabekova, Malakhat; Leszczynska, Danuta; Leszczynski, Jerzy

    2013-09-21

    Fullerene and its derivatives have potential antiviral activity due to their specific binding interactions with biological molecules. In this study fullerene derivatives were investigated by the synergic combination of three approaches: quantum-mechanical calculations, protein-ligand docking and quantitative structure-activity relationship methods. The protein-ligand docking studies and improved structure-activity models have been able both to predict binding affinities for the set of fullerene-C60 derivatives and to help in finding mechanisms of fullerene derivative interactions with human immunodeficiency virus type 1 aspartic protease, HIV-1 PR. Protein-ligand docking revealed several important molecular fragments that are responsible for the interaction with HIV-1 PR. In addition, a density functional theory method has been utilized to identify the optimal geometries and predict physico-chemical parameters of the studied compounds. The 5-variable GA-MLRA based model showed the best predictive ability (r(2)training = 0.882 and r(2)test = 0.738), with high internal and external correlation coefficients.

  20. Inhibition of MMP-9 by green tea catechins and prediction of their interaction by molecular docking analysis.

    PubMed

    Sarkar, Jaganmay; Nandy, Suman Kumar; Chowdhury, Animesh; Chakraborti, Tapati; Chakraborti, Sajal

    2016-12-01

    Green tea polyphenolic catechins have been shown to prevent various types of diseases such as pulmonary hypertension (PAH), cancer and cardiac and neurological disorders. Matrix metalloproteinases (MMPs) play an important role in the development of PAH. The present study demonstrated that among the four green tea catechins (EGCG, ECG, EC and EGC), EGCG and ECG inhibit pro-/active MMP-9 activities in pulmonary artery smooth muscle cell culture supernatant. Based on the above, we investigated the interactions of pro-/active MMP-9 with the green tea catechins by computational methods. In silico molecular docking analysis revealed a strong interaction between pro-/active MMP-9 and EGCG/ECG, and galloyl group appears to be responsible for this enhanced interaction. The molecular docking studies corroborate our experimental observation that EGCG and ECG are mainly active in preventing both the proMMP-9 and MMP-9 activities.

  1. Connecting simulated, bioanalytical, and molecular docking data on the stereoselective binding of (±)-catechin to human serum albumin.

    PubMed

    Sabela, Myalowenkosy I; Gumede, Njabulo J; Escuder-Gilabert, Laura; Martín-Biosca, Yolanda; Bisetty, Khirsna; Medina-Hernández, María-Jose; Sagrado, Salvador

    2012-02-01

    The stereoselective binding of the frequently ingested nutraceutical (±)-catechin, with demonstrated differential biological activity between enantiomers, to human serum albumin (HSA), with the largest complexation and enantioselectivity potential among the plasmatic proteins, is studied by combining simulations to optimize the experimental design, robust in vitro electrokinetic chromatographic data, and molecular docking-chiral recognition estimates. Methodological and mathematical drawbacks in previous reports on (±)-catechin-HSA are detected and eliminated. Recent and novel direct equations extracted from the classical interaction model allows advantageous univariate mathematical data treatment, providing the first evidence of quantitative (±)-catechin-HSA enantioselectivity. Also, the binding site in HSA of the enantiomers is approached, and both the experimental enantioselectivity and the main binding site information are contrasted with a molecular docking approach.

  2. Molecular docking studies of Traditional Chinese Medicinal compounds against known protein targets to treat non-small cell lung carcinomas

    PubMed Central

    Zhao, Guo-Fang; Huang, Zuo-An; Du, Xue-Kui; Yang, Ming-Lei; Huang, Dan-Dan; Zhang, Shun

    2016-01-01

    In silico drug design using virtual screening, absorption, distribution, metabolism and excretion (ADME)/Tox data analysis, automated docking and molecular dynamics simulations for the determination of lead compounds for further in vitro analysis is a cost effective strategy. The present study used this strategy to discover novel lead compounds from an in-house database of Traditional Chinese Medicinal (TCM) compounds against epithelial growth factor receptor (EGFR) protein for targeting non-small cell lung cancer (NSCLC). After virtual screening of an initial dataset of 2,242 TCM compounds, leads were identified based on binding energy and ADME/Tox data and subjected to automated docking followed by molecular dynamics simulation. Triptolide, a top compound identified by this vigorous in silico screening, was then tested in vitro on the H2347 cell line carrying wild-type EGFR, revealing an anti-proliferative potency similar to that of known drugs against NSCLC. PMID:27279494

  3. Molecular Docking Studies with Rabies Virus Glycoprotein to Design Viral Therapeutics

    PubMed Central

    Tomar, N. R.; Singh, V.; Marla, S. S.; Chandra, R.; Kumar, R.; Kumar, A.

    2010-01-01

    The genome of rabies virus encodes five proteins; the nucleoprotein, the phosphoprotein, the matrix protein, the glycoprotein, and the RNA-dependent RNA polymerase. Among these, the glycoprotein is the most important as it is the major contributor to pathogenicity and virus neutralizing antibody response. Keeping in mind that glycoprotein is the only protein exposed on the surface of virus and is thought to be responsible for the interaction with the cell membrane, it was attempted to target glycoprotein by a ligand polyethylene glycol 4000, which blocks its active site, as seen by molecular operating environment software, so that it may be possible to prevent the spread of virus into the host. The ligand polyethylene glycol 4000 was retrieved from Research Collaboratory for Structural Bioinformatics protein data bank by providing the glycoprotein sequence to the databank. In this study it was observed that the ligand was successfully docked on a major portion of antigenic site II of glycoprotein by mimicking the virus neutralizing antibodies. This knowledge may be important for the development of novel therapies for the treatment of rabies and other viral diseases in the future. PMID:21218060

  4. Coumarin or benzoxazinone based novel carbonic anhydrase inhibitors: synthesis, molecular docking and anticonvulsant studies.

    PubMed

    Karataş, Mert Olgun; Uslu, Harun; Sarı, Suat; Alagöz, Mehmet Abdullah; Karakurt, Arzu; Alıcı, Bülent; Bilen, Cigdem; Yavuz, Emre; Gencer, Nahit; Arslan, Oktay

    2016-10-01

    Among many others, coumarin derivatives are known to show human carbonic anhydrase (hCA) inhibitory activity. Since hCA inhibition is one of the underlying mechanisms that account for the activities of some antiepileptic drugs (AEDs), hCA inhibitors are expected to have anti-seizure properties. There are also several studies reporting compounds with an imidazole and/or benzimidazole moiety which exert these pharmacological properties. In this study, we prepared fifteen novel coumarin-bearing imidazolium and benzimidazolium chloride, nine novel benzoxazinone-bearing imidazolium and benzimidazolium chloride derivatives and evaluated their hCA inhibitory activities and along with fourteen previously synthesized derivatives we scanned their anticonvulsant effects. As all compounds inhibited purified hCA isoforms I and II, some of them also proved protective against Maximal electroshock seizure (MES) and ScMet induced seizures in mice. Molecular docking studies with selected coumarin derivatives have revealed that these compounds bind to the active pocket of the enzyme in a similar fashion to that previously described for coumarin derivatives.

  5. Resistance Mechanisms and Molecular Docking Studies of Four Novel QoI Fungicides in Peronophythora litchii.

    PubMed

    Zhou, Yuxin; Chen, Lei; Hu, Jian; Duan, Hongxia; Lin, Dong; Liu, Pengfei; Meng, Qingxiao; Li, Bin; Si, Naiguo; Liu, Changling; Liu, Xili

    2015-12-14

    Peronophythora litchii is the causal agent of litchi downy blight. Enestroburin, SYP-1620, SYP-2815 and ZJ0712 are four novel QoI fungicides developed by China. Eight mutants of P. litchii resistant to these QoI fungicides and azoxystrobin (as a known QoI fungicide) were obtained in our preliminary work. In this study, the full length of the cytochrome b gene in P. litchii, which has a full length of 382 amino acids, was cloned from both sensitive isolates and resistant mutants, and single-site mutations G142A, G142S, Y131C, or F128S were found in resistant mutants. Molecular docking was used to predict how the mutations alter the binding of the five QoI fungicides to the Qo-binding pockets. The results have increased our understanding of QoI fungicide-resistance mechanisms and may help in the development of more potent inhibitors against plant diseases in the fields.

  6. Development of Dual Inhibitors against Alzheimer's Disease Using Fragment-Based QSAR and Molecular Docking

    PubMed Central

    Goyal, Manisha; Dhanjal, Jaspreet Kaur; Goyal, Sukriti; Tyagi, Chetna; Hamid, Rabia; Grover, Abhinav

    2014-01-01

    Alzheimer's (AD) is the leading cause of dementia among elderly people. Considering the complex heterogeneous etiology of AD, there is an urgent need to develop multitargeted drugs for its suppression. β-amyloid cleavage enzyme (BACE-1) and acetylcholinesterase (AChE), being important for AD progression, have been considered as promising drug targets. In this study, a robust and highly predictive group-based QSAR (GQSAR) model has been developed based on the descriptors calculated for the fragments of 20 1,4-dihydropyridine (DHP) derivatives. A large combinatorial library of DHP analogues was created, the activity of each compound was predicted, and the top compounds were analyzed using refined molecular docking. A detailed interaction analysis was carried out for the top two compounds (EDC and FDC) which showed significant binding affinity for BACE-1 and AChE. This study paves way for consideration of these lead molecules as prospective drugs for the effective dual inhibition of BACE-1 and AChE. The GQSAR model provides site-specific clues about the molecules where certain modifications can result in increased biological activity. This information could be of high value for design and development of multifunctional drugs for combating AD. PMID:25019089

  7. A machine learning approach to predicting protein-ligand binding affinity with applications to molecular docking

    PubMed Central

    Ballester, Pedro J.; Mitchell, John B.O.

    2012-01-01

    Motivation Accurately predicting the binding affinities of large sets of diverse protein-ligand complexes is an extremely challenging task. The scoring functions that attempt such computational prediction are essential for analysing the outputs of Molecular Docking, which is in turn an important technique for drug discovery, chemical biology and structural biology. Each scoring function assumes a predetermined theory-inspired functional form for the relationship between the variables that characterise the complex, which also include parameters fitted to experimental or simulation data, and its predicted binding affinity. The inherent problem of this rigid approach is that it leads to poor predictivity for those complexes that do not conform to the modelling assumptions. Moreover, resampling strategies, such as cross-validation or bootstrapping, are still not systematically used to guard against the overfitting of calibration data in parameter estimation for scoring functions. Results We propose a novel scoring function (RF-Score) that circumvents the need for problematic modelling assumptions via non-parametric machine learning. In particular, Random Forest was used to implicitly capture binding effects that are hard to model explicitly. RF-Score is compared with the state of the art on the demanding PDBbind benchmark. Results show that RF-Score is a very competitive scoring function. Importantly, RF-Score’s performance was shown to improve dramatically with training set size and hence the future availability of more high quality structural and interaction data is expected to lead to improved versions of RF-Score. PMID:20236947

  8. Synthesis and spectroscopic characterization of fluorescent 4-aminoantipyrine analogues: Molecular docking and in vitro cytotoxicity studies

    NASA Astrophysics Data System (ADS)

    Premnath, D.; Mosae Selvakumar, P.; Ravichandiran, P.; Tamil Selvan, G.; Indiraleka, M.; Jannet Vennila, J.

    2016-01-01

    Two substituted aromatic carbonyl compounds (compounds 1 and 2) of 4-aminoantipyrine were synthesized by condensation of fluorine substituted benzoyl chlorides and 4-aminoantipyrine. The structures of synthesized derivatives were established on the basis of UV-Vis, IR, and Mass, 1H, 13C NMR and Fluorescence spectroscopy. Both compounds showed significant fluorescence emission and two broad emission bands were observed in the region at 340 nm and 450 nm on excitation at 280 nm. Theoretically to prove that the molecule has anticancer activity against cervical cancer cells, the compounds were analyzed for molecular docking interactions with HPV16-E7 target protein by Glide protocol. Furthermore, 4-aminoantipyrine derivatives were evaluated for their in vitro cytotoxic activity against human cervical cancer cells (SiHa) by MTT assay. Compound 1 showed two fold higher activity (IC50 = 0.912 μM) over compound 2, and its activity was similar to that of Pazopanib, suggesting that although the two compounds were chemically very similar the difference in substituent on the phenyl moiety caused changes in properties.

  9. Synthesis, alkaline phosphatase inhibition studies and molecular docking of novel derivatives of 4-quinolones.

    PubMed

    Miliutina, Mariia; Ejaz, Syeda Abida; Khan, Shafi Ullah; Iaroshenko, Viktor O; Villinger, Alexander; Iqbal, Jamshed; Langer, Peter

    2017-01-27

    New and convenient methods for the functionalization of the 4-quinolone scaffold at positions C-1, C-3 and C-6 were developed. The 4-quinolone derivatives were evaluated for their inhibitory potential on alkaline phosphatase isozymes. Most of the compounds exhibit excellent inhibitory activity and moderate selectivity. The IC50 values on tissue non-specific alkaline phosphatase (TNAP) were in the range of 1.34 ± 0.11 to 44.80 ± 2.34 μM, while the values on intestinal alkaline phosphatase (IAP) were in the range of 1.06 ± 0.32 to 192.10 ± 3.78 μM. The most active derivative exhibits a potent inhibition on IAP with a ≈14 fold higher selectivity as compared to TNAP. Furthermore, molecular docking calculations were performed for the most potent inhibitors to show their binding interactions within the active site of the respective enzymes.

  10. Novel biphenyl ester derivatives as tyrosinase inhibitors: Synthesis, crystallographic, spectral analysis and molecular docking studies

    PubMed Central

    Kwong, Huey Chong; Chidan Kumar, C. S.; Mah, Siau Hui; Chia, Tze Shyang; Loh, Zi Han; Chandraju, Siddegowda; Lim, Gin Keat

    2017-01-01

    Biphenyl-based compounds are clinically important for the treatments of hypertension and inflammatory, while many more are under development for pharmaceutical uses. In the present study, a series of 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl benzoates, 2(a-q), and 2-([1,1'-biphenyl]-4-yl)-2-oxoethyl pyridinecarboxylate, 2(r-s) were synthesized by reacting 1-([1,1'-biphenyl]-4-yl)-2-bromoethan-1-one with various carboxylic acids using potassium carbonate in dimethylformamide at ambient temperature. Single-crystal X-ray diffraction studies revealed a more closely packed crystal structure can be produced by introduction of biphenyl moiety. Five of the compounds among the reported series exhibited significant anti-tyrosinase activities, in which 2p, 2r and 2s displayed good inhibitions which are comparable to standard inhibitor kojic acid at concentrations of 100 and 250 μg/mL. The inhibitory effects of these active compounds were further confirmed by computational molecular docking studies and the results revealed the primary binding site is active-site entrance instead of inner copper binding site which acted as the secondary binding site. PMID:28241010

  11. Resistance Mechanisms and Molecular Docking Studies of Four Novel QoI Fungicides in Peronophythora litchii

    PubMed Central

    Zhou, Yuxin; Chen, Lei; Hu, Jian; Duan, Hongxia; Lin, Dong; Liu, Pengfei; Meng, Qingxiao; Li, Bin; Si, Naiguo; Liu, Changling; Liu, Xili

    2015-01-01

    Peronophythora litchii is the causal agent of litchi downy blight. Enestroburin, SYP-1620, SYP-2815 and ZJ0712 are four novel QoI fungicides developed by China. Eight mutants of P. litchii resistant to these QoI fungicides and azoxystrobin (as a known QoI fungicide) were obtained in our preliminary work. In this study, the full length of the cytochrome b gene in P. litchii, which has a full length of 382 amino acids, was cloned from both sensitive isolates and resistant mutants, and single-site mutations G142A, G142S, Y131C, or F128S were found in resistant mutants. Molecular docking was used to predict how the mutations alter the binding of the five QoI fungicides to the Qo-binding pockets. The results have increased our understanding of QoI fungicide-resistance mechanisms and may help in the development of more potent inhibitors against plant diseases in the fields. PMID:26657349

  12. The crystal structure of sulfamethoxazole, interaction with DNA, DFT calculation, and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Das, Dipankar; Sahu, Nilima; Roy, Suman; Dutta, Paramita; Mondal, Sudipa; Torres, Elena L.; Sinha, Chittaranjan

    2015-02-01

    Sulfamethoxazole (SMX) [4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide] is structurally established by single crystal X-ray diffraction measurement. The crystal packing shows H-bonded 2D polymer through N(7)sbnd H(7A)---O(2), N(7)sbnd H(7B)---O(3), N(1)sbnd H(1)---N(2), C(5)sbnd H(5)---O(3)sbnd S(1) and N(7)sbnd (H7A)---O(2)sbnd S(1). Density Functional Theory (DFT) and Time Dependent-DFT (TD-DFT) computations of optimized structure of SMX determine the electronic structure and has explained the electronic spectral transitions. The interaction of SMX with CT-DNA has been studied by absorption spectroscopy and the binding constant (Kb) is 4.37 × 104 M-1. The in silico test of SMX with DHPS from Escherichia coli and Streptococcus pneumoniae helps to understand drug metabolism and accounts the drug-molecule interactions. The molecular docking of SMX-DNA also helps to predict the interaction feature.

  13. The crystal structure of sulfamethoxazole, interaction with DNA, DFT calculation, and molecular docking studies.

    PubMed

    Das, Dipankar; Sahu, Nilima; Roy, Suman; Dutta, Paramita; Mondal, Sudipa; Torres, Elena L; Sinha, Chittaranjan

    2015-02-25

    Sulfamethoxazole (SMX) [4-amino-N-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide] is structurally established by single crystal X-ray diffraction measurement. The crystal packing shows H-bonded 2D polymer through N(7)-H(7A)-O(2), N(7)-H(7B)-O(3), N(1)-H(1)-N(2), C(5)-H(5)-O(3)-S(1) and N(7)-(H7A)-O(2)-S(1). Density Functional Theory (DFT) and Time Dependent-DFT (TD-DFT) computations of optimized structure of SMX determine the electronic structure and has explained the electronic spectral transitions. The interaction of SMX with CT-DNA has been studied by absorption spectroscopy and the binding constant (Kb) is 4.37×10(4)M(-1). The in silico test of SMX with DHPS from Escherichia coli and Streptococcus pneumoniae helps to understand drug metabolism and accounts the drug-molecule interactions. The molecular docking of SMX-DNA also helps to predict the interaction feature.

  14. Binding interaction of atorvastatin with bovine serum albumin: Spectroscopic methods and molecular docking.

    PubMed

    Wang, Qi; Huang, Chuan-ren; Jiang, Min; Zhu, Ying-yao; Wang, Jing; Chen, Jun; Shi, Jie-hua

    2016-03-05

    The interaction of atorvastatin with bovine serum albumin (BSA) was investigated using multi-spectroscopic methods and molecular docking technique for providing important insight into further elucidating the store and transport process of atorvastatin in the body and the mechanism of action and pharmacokinetics. The experimental results revealed that the fluorescence quenching mechanism of BSA induced atorvastatin was a combined dynamic and static quenching. The binding constant and number of binding site of atorvastatin with BSA under simulated physiological conditions (pH=7.4) were 1.41 × 10(5) M(-1) and about 1 at 310K, respectively. The values of the enthalpic change (ΔH(0)), entropic change (ΔS(0)) and Gibbs free energy (ΔG(0)) in the binding process of atorvastatin with BSA at 310K were negative, suggesting that the binding process of atorvastatin and BSA was spontaneous and the main interaction forces were van der Waals force and hydrogen bonding interaction. Moreover, atorvastatin was bound into the subdomain IIA (site I) of BSA, resulting in a slight change of the conformation of BSA.

  15. Binding interaction of atorvastatin with bovine serum albumin: Spectroscopic methods and molecular docking

    NASA Astrophysics Data System (ADS)

    Wang, Qi; Huang, Chuan-ren; Jiang, Min; Zhu, Ying-yao; Wang, Jing; Chen, Jun; Shi, Jie-hua

    2016-03-01

    The interaction of atorvastatin with bovine serum albumin (BSA) was investigated using multi-spectroscopic methods and molecular docking technique for providing important insight into further elucidating the store and transport process of atorvastatin in the body and the mechanism of action and pharmacokinetics. The experimental results revealed that the fluorescence quenching mechanism of BSA induced atorvastatin was a combined dynamic and static quenching. The binding constant and number of binding site of atorvastatin with BSA under simulated physiological conditions (pH = 7.4) were 1.41 × 105 M- 1 and about 1 at 310 K, respectively. The values of the enthalpic change (ΔH0), entropic change (ΔS0) and Gibbs free energy (ΔG0) in the binding process of atorvastatin with BSA at 310 K were negative, suggesting that the binding process of atorvastatin and BSA was spontaneous and the main interaction forces were van der Waals force and hydrogen bonding interaction. Moreover, atorvastatin was bound into the subdomain IIA (site I) of BSA, resulting in a slight change of the conformation of BSA.

  16. Part I: Synthesis, cancer chemopreventive activity and molecular docking study of novel quinoxaline derivatives.

    PubMed

    Galal, Shadia A; Abdelsamie, Ahmed S; Tokuda, Harukuni; Suzuki, Nobutaka; Lida, Akira; Elhefnawi, Mahmoud M; Ramadan, Raghda A; Atta, Mona H E; El Diwani, Hoda I

    2011-01-01

    The reaction of o-phenylene diamine and ethyl oxamate is reinvestigated and led to 3-aminoquinoxalin-2(1H)-one rather than benzimidazole-2-carboxamide as was previously reported. The structure of the obtained quinoxaline has been confirmed by X-ray. The anti-tumor activity of synthesized quinoxalines 1-21 has been evaluated by studying their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the studied compounds 1-21, compounds 12, 8, 13, 18, 17 and 19, respectively, demonstrated strong inhibitory effects on the EBV-EA activation without showing any cytotoxicity and their effects being stronger than that of a representative control, oleanolic acid. Furthermore, compound 12 exhibited a remarkable inhibitory effect on skin tumor promotion in an in vivo two-stage mouse skin carcinogenesis test using 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter. The result of the present investigation indicated that compound 12 might be valuable as a potent cancer chemopreventive agent. Moreover, the molecular docking into PTK (PDB: 1t46) has been done for lead optimization of the aforementioned compounds as potential PTK inhibitors.

  17. Synthesis, molecular docking studies of hybrid benzimidazole as α-glucosidase inhibitor.

    PubMed

    Zawawi, Nik Khairunissa Nik Abdullah; Taha, Muhammad; Ahmat, Norizan; Ismail, Nor Hadiani; Wadood, Abdul; Rahim, Fazal

    2017-02-01

    Thiourea derivatives having benzimidazole 1-17 have been synthesized, characterized by (1)H NMR, (13)C NMR and EI-MS and evaluated for α-glucosidase inhibition. Identification of potential α-glucosidase inhibitors were done by in vitro screening of 17 thiourea bearing benzimidazole derivatives using Baker's yeast α-glucosidase enzyme. Compounds 1-17 exhibited a varying degree of α-glucosidase inhibitory activity with IC50 values between 35.83±0.66 and 297.99±1.20μM which are more better than the standard acarbose (IC50=774.5±1.94μM). Compound 10 and 14 showed significant inhibitory effects with IC50 value 50.57±0.81 and 35.83±0.66μM, respectively better than the rest of the series. Structure activity relationships were established. Molecular docking studies were performed to understand the binding interaction of the compounds.

  18. An efficient and accurate molecular alignment and docking technique using ab initio quality scoring

    PubMed Central

    Füsti-Molnár, László; Merz, Kenneth M.

    2008-01-01

    An accurate and efficient molecular alignment technique is presented based on first principle electronic structure calculations. This new scheme maximizes quantum similarity matrices in the relative orientation of the molecules and uses Fourier transform techniques for two purposes. First, building up the numerical representation of true ab initio electronic densities and their Coulomb potentials is accelerated by the previously described Fourier transform Coulomb method. Second, the Fourier convolution technique is applied for accelerating optimizations in the translational coordinates. In order to avoid any interpolation error, the necessary analytical formulas are derived for the transformation of the ab initio wavefunctions in rotational coordinates. The results of our first implementation for a small test set are analyzed in detail and compared with published results of the literature. A new way of refinement of existing shape based alignments is also proposed by using Fourier convolutions of ab initio or other approximate electron densities. This new alignment technique is generally applicable for overlap, Coulomb, kinetic energy, etc., quantum similarity measures and can be extended to a genuine docking solution with ab initio scoring. PMID:18624561

  19. Structural Elucidation and Molecular Docking of a Novel Antibiotic Compound from Cyanobacterium Nostoc sp. MGL001

    PubMed Central

    Niveshika; Verma, Ekta; Mishra, Arun K.; Singh, Angad K.; Singh, Vinay K.

    2016-01-01

    Cyanobacteria are rich source of array of bioactive compounds. The present study reports a novel antibacterial bioactive compound purified from cyanobacterium Nostoc sp. MGL001 using various chromatographic techniques viz. thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). Further characterization was done using electrospray ionization mass spectroscopy (ESIMS) and nuclear magnetic resonance (NMR) and predicted structure of bioactive compound was 9-Ethyliminomethyl-12-(morpholin - 4 - ylmethoxy) -5, 8, 13, 16–tetraaza–hexacene - 2, 3 dicarboxylic acid (EMTAHDCA). Structure of EMTAHDCA clearly indicated that it is a novel compound that was not reported in literature or natural product database. The compound exhibited growth inhibiting effects mainly against the gram negative bacterial strains and produced maximum zone of inhibition at 150 μg/mL concentration. The compound was evaluated through in silico studies for its ability to bind 30S ribosomal fragment (PDB ID: 1YRJ, 1MWL, 1J7T, and 1LC4) and OmpF porin protein (4GCP, 4GCQ, and 4GCS) which are the common targets of various antibiotic drugs. Comparative molecular docking study revealed that EMTAHDCA has strong binding affinity for these selected targets in comparison to a number of most commonly used antibiotics. The ability of EMTAHDCA to bind the active sites on the proteins and 30S ribosomal fragments where the antibiotic drugs generally bind indicated that it is functionally similar to the commercially available drugs. PMID:27965634

  20. Structural Elucidation and Molecular Docking of a Novel Antibiotic Compound from Cyanobacterium Nostoc sp. MGL001.

    PubMed

    Niveshika; Verma, Ekta; Mishra, Arun K; Singh, Angad K; Singh, Vinay K

    2016-01-01

    Cyanobacteria are rich source of array of bioactive compounds. The present study reports a novel antibacterial bioactive compound purified from cyanobacterium Nostoc sp. MGL001 using various chromatographic techniques viz. thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). Further characterization was done using electrospray ionization mass spectroscopy (ESIMS) and nuclear magnetic resonance (NMR) and predicted structure of bioactive compound was 9-Ethyliminomethyl-12-(morpholin - 4 - ylmethoxy) -5, 8, 13, 16-tetraaza-hexacene - 2, 3 dicarboxylic acid (EMTAHDCA). Structure of EMTAHDCA clearly indicated that it is a novel compound that was not reported in literature or natural product database. The compound exhibited growth inhibiting effects mainly against the gram negative bacterial strains and produced maximum zone of inhibition at 150 μg/mL concentration. The compound was evaluated through in silico studies for its ability to bind 30S ribosomal fragment (PDB ID: 1YRJ, 1MWL, 1J7T, and 1LC4) and OmpF porin protein (4GCP, 4GCQ, and 4GCS) which are the common targets of various antibiotic drugs. Comparative molecular docking study revealed that EMTAHDCA has strong binding affinity for these selected targets in comparison to a number of most commonly used antibiotics. The ability of EMTAHDCA to bind the active sites on the proteins and 30S ribosomal fragments where the antibiotic drugs generally bind indicated that it is functionally similar to the commercially available drugs.

  1. 20(S)-Protopanaxadiol Phospholipid Complex: Process Optimization, Characterization, In Vitro Dissolution and Molecular Docking Studies.

    PubMed

    Pu, Yiqiong; Zhang, Xitong; Zhang, Qi; Wang, Bing; Chen, Yuxi; Zang, Chuanqi; Wang, Yuqin; Dong, Tina Ting-Xia; Zhang, Tong

    2016-10-19

    20(S)-Protopanaxadiol (PPD), a bioactive compound extracted from ginseng, possesses cardioprotective, neuroprotective, anti-inflammatory, antiestrogenic, anticancer and anxiolytic effects. However, the clinical application of PPD is limited by its weak aqueous solubility. In this study, we optimized an efficient method of preparing its phospholipid complex (PPD-PLC) using a central composite design and response surface analysis. The prepared PPD-PLC was characterized by differential scanning calorimetric, powder X-ray diffraction, Fourier-transformed infrared spectroscopy and nuclear magnetic resonance analyses associated with molecular docking calculation. The equilibrium solubility of PPD-PLC in water and n-octanol increased 6.53- and 1.53-times, respectively. Afterwards, using PPD-PLC as the intermediate, the PPD-PLC-loaded dry suspension (PPD-PLC-SU) was prepared with our previous method. In vitro evaluations were conducted on PPD-PLC and PPD-PLC-SU, including dissolution behaviors and stability properties under different conditions. Results of in vitro dissolution behavior revealed the improved dissolution extents and rates of PPD-PLC and PPD-PLC-SU (p < 0.05). Results of the formulation stability investigation also exposed the better stability of PPD-PLC-SU compared with free PPD. Therefore, phospholipid complex technology is a useful formulation strategy for BCS II drugs, as it could effectively improve their hydrophilicity and lipophilicity.

  2. DESIGN, SYNTHESIS, MOLECULAR DOCKING AND ANTI-BREAST CANCER ACTIVITY OF NOVEL QUINAZOLINONES TARGETING ESTROGEN RECEPTOR α.

    PubMed

    Ahmed, Marwa F; Youns, Mahmoud; Belal, Amany

    2016-01-01

    A new series of 6,8-dibromo-2-(4-chlorophenyl)-4-oxo-4H-quinazoline derivatives II-VI were syn- thesized, their chemical structures were confirmed by spectroscopic means and elemental analyses. All these compounds were tested in vitro against human breast cancer cell line (MCF-7) using resazurin reduction assay method and doxorubicin as a reference drug. Most of the tested compounds showed better activity than dox- orubicin. Compound IVh was the best active one, its IC₅₀ is 8.52 µg/mL. Molecular docking studies for the best active compounds IVb, IVc, IVf, IVh and Va were performed on the active site of estrogen receptor α (ERα) subtype to explore the estrogen receptor binding ability of these compounds. All the docked compounds showed good fitting score energy with the active site of ERα subtype and compound IVh showed the best docking score energy(-25.3 kcal/mol). Estrogen binding evaluation assay was performed for the docked compounds to ensure that their activity against MCF7 go through inhibition of ERα, they showed ERα inhibition at 41-85% and compound IVh was the most active one (85%).

  3. Analysis and Ranking of Protein-Protein Docking Models Using Inter-Residue Contacts and Inter-Molecular Contact Maps.

    PubMed

    Oliva, Romina; Chermak, Edrisse; Cavallo, Luigi

    2015-07-01

    In view of the increasing interest both in inhibitors of protein-protein interactions and in protein drugs themselves, analysis of the three-dimensional structure of protein-protein complexes is assuming greater relevance in drug design. In the many cases where an experimental structure is not available, protein-protein docking becomes the method of choice for predicting the arrangement of the complex. However, reliably scoring protein-protein docking poses is still an unsolved problem. As a consequence, the screening of many docking models is usually required in the analysis step, to possibly single out the correct ones. Here, making use of exemplary cases, we review our recently introduced methods for the analysis of protein complex structures and for the scoring of protein docking poses, based on the use of inter-residue contacts and their visualization in inter-molecular contact maps. We also show that the ensemble of tools we developed can be used in the context of rational drug design targeting protein-protein interactions.

  4. Pharmacophore modeling, in silico screening, molecular docking and molecular dynamics approaches for potential alpha-delta bungarotoxin-4 inhibitors discovery

    PubMed Central

    Kumar, R. Barani; Suresh, M. Xavier; Priya, B. Shanmuga

    2015-01-01

    Background: The alpha-delta bungartoxin-4 (α-δ-Bgt-4) is a potent neurotoxin produced by highly venomous snake species, Bungarus caeruleus, mainly targeting neuronal acetylcholine receptors (nAchRs) and producing adverse biological malfunctions leading to respiratory paralysis and mortality. Objective: In this study, we predicted the three-dimensional structure of α-δ-Bgt-4 using homology modeling and investigated the conformational changes and the key residues responsible for nAchRs inhibiting activity. Materials and Methods: From the selected plants, which are traditionally used for snake bites, the active compounds are taken and performed molecular interaction studies and also used for modern techniques like pharmacophore modeling and mapping and absorption, distribution, metabolism, elimination and toxicity analysis which may increase the possibility of success. Results: Moreover, 100's of drug-like compounds were retrieved and analyzed through computational virtual screening and allowed for pharmacokinetic profiling, molecular docking and dynamics simulation. Conclusion: Finally the top five drug-like compounds having competing level of inhibition toward α-δ-Bgt-4 toxin were suggested based on their interaction with α-δ-Bgt-4 toxin. PMID:26109766

  5. Studies on molecular structure, vibrational spectra and molecular docking analysis of 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate.

    PubMed

    Suresh, D M; Amalanathan, M; Joe, I Hubert; Jothy, V Bena; Diao, Yun-Peng

    2014-09-15

    The molecular structure, vibrational analysis and molecular docking analysis of the 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate (MDDNAB) molecule have been carried out using FT-IR and FT-Raman spectroscopic techniques and DFT method. The equilibrium geometry, harmonic vibrational wave numbers, various bonding features have been computed using density functional method. The calculated molecular geometry has been compared with experimental data. The detailed interpretation of the vibrational spectra has been carried out by using VEDA program. The hyper-conjugative interactions and charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The simulated FT-IR and FT-Raman spectra satisfactorily coincide with the experimental spectra. The PES and charge analysis have been made. The molecular docking was done to identify the binding energy and the Hydrogen bonding with the cancer protein molecule.

  6. Studies on molecular structure, vibrational spectra and molecular docking analysis of 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate

    NASA Astrophysics Data System (ADS)

    Suresh, D. M.; Amalanathan, M.; Hubert Joe, I.; Bena Jothy, V.; Diao, Yun-Peng

    2014-09-01

    The molecular structure, vibrational analysis and molecular docking analysis of the 3-Methyl-1,4-dioxo-1,4-dihydronaphthalen-2-yl 4-aminobenzoate (MDDNAB) molecule have been carried out using FT-IR and FT-Raman spectroscopic techniques and DFT method. The equilibrium geometry, harmonic vibrational wave numbers, various bonding features have been computed using density functional method. The calculated molecular geometry has been compared with experimental data. The detailed interpretation of the vibrational spectra has been carried out by using VEDA program. The hyper-conjugative interactions and charge delocalization have been analyzed using natural bond orbital (NBO) analysis. The simulated FT-IR and FT-Raman spectra satisfactorily coincide with the experimental spectra. The PES and charge analysis have been made. The molecular docking was done to identify the binding energy and the Hydrogen bonding with the cancer protein molecule.

  7. Characterization of intermolecular interaction between cyanidin-3-glucoside and bovine serum albumin: spectroscopic and molecular docking methods.

    PubMed

    Shi, Jie-hua; Wang, Jing; Zhu, Ying-yao; Chen, Jun

    2014-08-01

    The intermolecular interaction between cyanidin-3-glucoside (Cy-3-G) and bovine serum albumin (BSA) was investigated using fluorescence, circular dichroism and molecular docking methods. The experimental results revealed that the fluorescence quenching of BSA at 338 nm by Cy-3-G resulted from the formation of Cy-3-G-BSA complex. The number of binding sites (n) for Cy-3-G binding on BSA was approximately equal to 1. The experimental and molecular docking results revealed that after binding Cy-3-G to BSA, Cy-3-G is closer to the Tyr residue than the Trp residue, the secondary structure of BSA almost not change, the binding process of Cy-3-G with BSA is spontaneous, and Cy-3-G can be inserted into the hydrophobic cavity of BSA (site II') in the binding process of Cy-3-G with BSA. Moreover, based on the sign and magnitude of the enthalpy and entropy changes (ΔH(0)  = - 29.64 kcal/mol and ΔS(0)  = - 69.51 cal/mol K) and the molecular docking results, it can be suggested that the main interaction forces of Cy-3-G with BSA are Van der Waals and hydrogen bonding interactions.

  8. Binding interaction of ramipril with bovine serum albumin (BSA): Insights from multi-spectroscopy and molecular docking methods.

    PubMed

    Shi, Jie-Hua; Pan, Dong-Qi; Jiang, Min; Liu, Ting-Ting; Wang, Qi

    2016-11-01

    The binding interaction between a typical angiotensin-converting enzyme inhibitor (ACEI), ramipril, and a transport protein, bovine serum albumin (BSA), was studied in vitro using UV-vis absorption spectroscopy, steady-state fluorescence spectroscopic titration, synchronous fluorescence spectroscopy, three dimensional fluorescence spectroscopy, circular dichroism and molecular docking under the imitated physiological conditions (pH=7.4). The experimental results suggested that the intrinsic fluorescence of BSA was quenched by ramipril thought a static quenching mechanism, indicating that the stable ramipril-BSA complex was formed by the intermolecular interaction. The number of binding sites (n) and binding constant of ramipril-BSA complex were about 1 and 3.50×10(4)M(-1) at 298K, respectively, suggesting that there was stronger binding interaction of ramipril with BSA. The thermodynamic parameters together with molecular docking study revealed that both van der Waal's forces and hydrogen bonding interaction dominated the formation of the ramipril-BSA complex and the binding interaction of BSA with ramipril is enthalpy-driven processes due to |ΔH°|>|TΔS°| and ΔG°<0. The spatial distance between ramipril and BSA was calculated to be 3.56nm based on Förster's non-radiative energy transfer theory. The results of the competitive displacement experiments and molecular docking confirmed that ramipril inserted into the subdomain IIA (site I) of BSA, resulting in a slight change in the conformation of BSA but BSA still retained its secondary structure α-helicity.

  9. Synthesis, characterization, biological studies (DNA binding, cleavage, antibacterial and topoisomerase I) and molecular docking of copper(II) benzimidazole complexes.

    PubMed

    Arjmand, Farukh; Parveen, Shazia; Afzal, Mohd; Shahid, Mohd

    2012-09-03

    To explore the therapeutic potential of copper-based benzimidazole complexes, tetranuclear Cu(II) complex 1 and dinuclear ternary amino acid complexes 2 and 3 {L-trp and L-val, respectively} were synthesized and thoroughly characterized. In vitro DNA binding studies of complexes 1-3 were carried out employing UV-vis titrations, fluorescence, circular dichroic and viscosity measurements which revealed that the complexes 1-3 bind to CT DNA preferably via groove binding. Complex 1 cleaved pBR322 DNA via hydrolytic pathway (validated by T4 DNA ligase assay), accessible to major groove while 2 followed oxidative mechanism, binding to minor groove of DNA double helix; binding events were further validated by molecular docking studies. Additionally, the complexes 1 and 2 exhibit high Topo-I inhibitory activity at different concentrations. The complexes 1-3 were evaluated for antibacterial activity against Escherichia coli and Staphylococcus aureus, and 2 was found to be most effective against Gram-positive bacteria.

  10. Binding mode of triazole derivatives as aromatase inhibitors based on docking, protein ligand interaction fingerprinting, and molecular dynamics simulation studies

    PubMed Central

    Mojaddami, Ayyub; Sakhteman, Amirhossein; Fereidoonnezhad, Masood; Faghih, Zeinab; Najdian, Atena; Khabnadideh, Soghra; Sadeghpour, Hossein; Rezaei, Zahra

    2017-01-01

    Aromatase inhibitors (AIs) as effective candidates have been used in the treatment of hormone-dependent breast cancer. In this study, we have proposed 300 structures as potential AIs and filtered them by Lipinski's rule of five using DrugLito software. Subsequently, they were subjected to docking simulation studies to select the top 20 compounds based on their Gibbs free energy changes and also to perform more studies on the protein-ligand interaction fingerprint by AuposSOM software. In this stage, anastrozole and letrozole were used as positive control to compare their interaction fingerprint patterns with our proposed structures. Finally, based on the binding energy values, one active structure (ligand 15) was selected for molecular dynamic simulation in order to get information for the binding mode of these ligands within the enzyme cavity. The triazole of ligand 15 pointed to HEM group in aromatase active site and coordinated to Fe of HEM through its N4 atom. In addition, two π-cation interactions was also observed, one interaction between triazole and porphyrin of HEM group, and the other was 4-chloro phenyl moiety of this ligand with Arg115 residue. PMID:28255310

  11. Crystal structure analysis, covalent docking and molecular dynamics calculations reveal a conformational switch in PhaZ7 PHB depolymerase.

    PubMed

    Kellici, Tahsin F; Mavromoustakos, Thomas; Jendrossek, Dieter; Papageorgiou, Anastassios C

    2017-04-03

    An open and a closed conformation of a surface loop in PhaZ7 extracellular poly(3-hydroxybutyrate) depolymerase were identified in two high resolution crystal structures of a PhaZ7 Y105E mutant. Molecular dynamics (MD) simulations revealed high root mean square fluctuations (RMSF) of the 281-295 loop, in particular at residue Asp289 (RMSF 7.62 Å). Covalent docking between a 3-hydroxybutyric acid trimer and the catalytic residue Ser136 showed that the binding energy of the substrate is significantly more favourable in the open loop conformation compared to that in the closed loop conformation. MD simulations with the substrate covalently bound depicted 1 Å RMSF higher values for the residues 281-295 in comparison to the apo (substrate-free) form. In addition, the presence of the substrate in the active site enhanced the ability of the loop to adopt a closed form. Taken together, the analysis suggests that the flexible loop 281-295 of PhaZ7 depolymerase can act as a lid domain to control substrate access to the active site of the enzyme. This article is protected by copyright. All rights reserved.

  12. Looking for inhibitors of the dengue virus NS5 RNA-dependent RNA-polymerase using a molecular docking approach

    PubMed Central

    Galiano, Vicente; Garcia-Valtanen, Pablo; Micol, Vicente; Encinar, José Antonio

    2016-01-01

    The dengue virus (DENV) nonstructural protein 5 (NS5) contains both an N-terminal methyltransferase domain and a C-terminal RNA-dependent RNA polymerase domain. Polymerase activity is responsible for viral RNA synthesis by a de novo initiation mechanism and represents an attractive target for antiviral therapy. The incidence of DENV has grown rapidly and it is now estimated that half of the human population is at risk of becoming infected with this virus. Despite this, there are no effective drugs to treat DENV infections. The present in silico study aimed at finding new inhibitors of the NS5 RNA-dependent RNA polymerase of the four serotypes of DENV. We used a chemical library comprising 372,792 nonnucleotide compounds (around 325,319 natural compounds) to perform molecular docking experiments against a binding site of the RNA template tunnel of the virus polymerase. Compounds with high negative free energy variation (ΔG <−10.5 kcal/mol) were selected as putative inhibitors. Additional filters for favorable druggability and good absorption, distribution, metabolism, excretion, and toxicity were applied. Finally, after the screening process was completed, we identified 39 compounds as lead DENV polymerase inhibitor candidates. Potentially, these compounds could act as efficient DENV polymerase inhibitors in vitro and in vivo. PMID:27784988

  13. Probing the origins of aromatase inhibitory activity of disubstituted coumarins via QSAR and molecular docking.

    PubMed

    Worachartcheewan, Apilak; Suvannang, Naravut; Prachayasittikul, Supaluk; Prachayasittikul, Virapong; Nantasenamat, Chanin

    2014-01-01

    This study investigated the quantitative structure-activity relationship (QSAR) of imidazole derivatives of 4,7-disubstituted coumarins as inhibitors of aromatase, a potential therapeutic protein target for the treatment of breast cancer. Herein, a series of 3,7- and 4,7-disubstituted coumarin derivatives (1-34) with R1 and R2 substituents bearing aromatase inhibitory activity were modeled as a function of molecular and quantum chemical descriptors derived from low-energy conformer geometrically optimized at B3LYP/6-31G(d) level of theory. Insights on origins of aromatase inhibitory activity was afforded by the computed set of 7 descriptors comprising of F10[N-O], Inflammat-50, Psychotic-80, H-047, BELe1, B10[C-O] and MAXDP. Such significant descriptors were used for QSAR model construction and results indicated that model 4 afforded the best statistical performance. Good predictive performance were achieved as verified from the internal (comprising the training and the leave-one-out cross-validation (LOO-CV) sets) and external sets affording the following statistical parameters: R (2) Tr = 0.9576 and RMSETr = 0.0958 for the training set; Q (2) CV = 0.9239 and RMSECV = 0.1304 for the LOO-CV set as well as Q (2) Ext = 0.7268 and RMSEExt = 0.2927 for the external set. Significant descriptors showed correlation with functional substituents, particularly, R1 in governing high potency as aromatase inhibitor. Molecular docking calculations suggest that key residues interacting with the coumarins were predominantly lipophilic or non-polar while a few were polar and positively-charged. Findings illuminated herein serve as the impetus that can be used to rationally guide the design of new aromatase inhibitors.

  14. Morphological docking of secretory vesicles

    PubMed Central

    2010-01-01

    Calcium-dependent secretion of neurotransmitters and hormones is essential for brain function and neuroendocrine-signaling. Prior to exocytosis, neurotransmitter-containing vesicles dock to the target membrane. In electron micrographs of neurons and neuroendocrine cells, like chromaffin cells many synaptic vesicles (SVs) and large dense-core vesicles (LDCVs) are docked. For many years the molecular identity of the morphologically docked state was unknown. Recently, we resolved the minimal docking machinery in adrenal medullary chromaffin cells using embryonic mouse model systems together with electron-microscopic analyses and also found that docking is controlled by the sub-membrane filamentous (F-)actin. Currently it is unclear if the same docking machinery operates in synapses. Here, I will review our docking assay that led to the identification of the LDCV docking machinery in chromaffin cells and also discuss whether identical docking proteins are required for SV docking in synapses. PMID:20577884

  15. Finding a Potential Dipeptidyl Peptidase-4 (DPP-4) Inhibitor for Type-2 Diabetes Treatment Based on Molecular Docking, Pharmacophore Generation, and Molecular Dynamics Simulation

    PubMed Central

    Meduru, Harika; Wang, Yeng-Tseng; Tsai, Jeffrey J. P.; Chen, Yu-Ching

    2016-01-01

    Dipeptidyl peptidase-4 (DPP-4) is the vital enzyme that is responsible for inactivating intestinal peptides glucagon like peptide-1 (GLP-1) and Gastric inhibitory polypeptide (GIP), which stimulates a decline in blood glucose levels. The aim of this study was to explore the inhibition activity of small molecule inhibitors to DPP-4 following a computational strategy based on docking studies and molecular dynamics simulations. The thorough docking protocol we applied allowed us to derive good correlation parameters between the predicted binding affinities (pKi) of the DPP-4 inhibitors and the experimental activity values (pIC50). Based on molecular docking receptor-ligand interactions, pharmacophore generation was carried out in order to identify the binding modes of structurally diverse compounds in the receptor active site. Consideration of the permanence and flexibility of DPP-4 inhibitor complexes by means of molecular dynamics (MD) simulation specified that the inhibitors maintained the binding mode observed in the docking study. The present study helps generate new information for further structural optimization and can influence the development of new DPP-4 inhibitors discoveries in the treatment of type-2 diabetes. PMID:27304951

  16. wFReDoW: A Cloud-Based Web Environment to Handle Molecular Docking Simulations of a Fully Flexible Receptor Model

    PubMed Central

    De Paris, Renata; Frantz, Fábio A.; Norberto de Souza, Osmar; Ruiz, Duncan D. A.

    2013-01-01

    Molecular docking simulations of fully flexible protein receptor (FFR) models are coming of age. In our studies, an FFR model is represented by a series of different conformations derived from a molecular dynamic simulation trajectory of the receptor. For each conformation in the FFR model, a docking simulation is executed and analyzed. An important challenge is to perform virtual screening of millions of ligands using an FFR model in a sequential mode since it can become computationally very demanding. In this paper, we propose a cloud-based web environment, called web Flexible Receptor Docking Workflow (wFReDoW), which reduces the CPU time in the molecular docking simulations of FFR models to small molecules. It is based on the new workflow data pattern called self-adaptive multiple instances (P-SaMIs) and on a middleware built on Amazon EC2 instances. P-SaMI reduces the number of molecular docking simulations while the middleware speeds up the docking experiments using a High Performance Computing (HPC) environment on the cloud. The experimental results show a reduction in the total elapsed time of docking experiments and the quality of the new reduced receptor models produced by discarding the nonpromising conformations from an FFR model ruled by the P-SaMI data pattern. PMID:23691504

  17. Analysis of cyclosporin A and a set of analogs as inhibitors of a T. cruzi cyclophilin by docking and molecular dynamics.

    PubMed

    Carraro, Roberto; Iribarne, Federico; Paulino, Margot

    2016-01-01

    Cyclophilins (CyPs) are enzymes involved in protein folding. In Trypanosoma cruzi (T. cruzi), the most abundantly expressed CyP is the isoform TcCyP19. It has been shown that TcCyP19 is inhibited by the immunosuppressive drug cyclosporin A (CsA) and analogs, which also proved to have potent trypanosomicidal activity in vitro. In this work, we continue and expand a previous study on the molecular interactions of CsA, and a set of analogs modeled in complexes with TcCyP19. The modeled complexes were used to evaluate binding free energies by molecular dynamics (MD), applying the Linear Interaction Energy (LIE) method. In addition, putative binding sites were identified by molecular docking. In our analysis, the binding free energy calculations did not correlate with experimental data. The heterogeneity of the non-bonded energies and the variation in the pattern of hydrogen bonds suggest that the systems may not be suitable for the application of the LIE method. Further, the docking calculations identified two other putative binding sites with comparable scoring energies to the active site, a fact that may also explain the lack of correlation found. Kinetic experiments are needed to confirm or reject the multiple binding sites hypothesis. In the meantime, MD simulations at the alternative sites, employing other methods to compute binding free energies, might be successful at finding good correlations with the experimental data.

  18. In silico study on β-aminoketone derivatives as thyroid hormone receptor inhibitors: a combined 3D-QSAR and molecular docking study.

    PubMed

    Wang, Fang-Fang; Yang, Wei; Shi, Yong-Hui; Le, Guo-Wei

    2016-12-01

    In order to explore the structure-activity correlation of a series of β-aminoketone analogs as inhibitors of thyroid hormone receptor (TR), a set of three-dimensional quantitative structure-activity relationship (3D-QSAR) models based on comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA), for the first time, were developed in the present work. The best CoMFA model with steric and electrostatic fields exhibited [Formula: see text], [Formula: see text] for TRβ, and [Formula: see text], [Formula: see text] for TRα. 3D contour maps produced from the optimal models were further analyzed individually, which provide the areas in space where interactive fields would affect the inhibitory activity. In addition, the binding modes of inhibitors at the active site of TRs were examined using molecular docking, the results indicated that this series of inhibitors fit into the active site of TRs by forming hydrogen bonding and electrostatic interactions. The docking studies also revealed that Leu305, Val458 for TRβ, and Asp407 for TRα are showing hydrogen bonds with the most active inhibitors. In any case, the 3D-QSAR models combined with the binding information will serve as a useful approach to explore the chemical space for improving the activity of TRβ and TRα inhibitors.

  19. Molecular Docking Studies of Flavonoids Derivatives on the Flavonoid 3- O-Glucosyltransferase.

    PubMed

    Harsa, Alexandra M; Harsa, Teodora E; Diudea, Mircea V; Janezic, Dusanka

    2015-01-01

    A study of 30 flavonoid derivatives, taken from PubChem database and docked on flavonoid 3-O-glucosyltransferase 3HBF, next submitted to a QSAR study, performed within a hypermolecule frame, to model their LD50 values, is reported. The initial set of molecules was split into a training set and the test set (taken from the best scored molecules in the docking test); the predicted LD50 values, computed on similarity clusters, built up for each of the molecules of the test set, surpassed in accuracy the best model. The binding energies to 3HBF protein, provided by the docking step, are not related to the LD50 of these flavonoids, more protein targets are to be investigated in this respect. However, the docking step was useful in choosing the test set of molecules.

  20. Molecular modeling studies on series of Btk inhibitors using docking, structure-based 3D-QSAR and molecular dynamics simulation: a combined approach.

    PubMed

    Balasubramanian, Pavithra K; Balupuri, Anand; Cho, Seung Joo

    2016-03-01

    Bruton tyrosine kinase (Btk) is a non-receptor tyrosine kinase. It is a crucial component in BCR pathway and expressed only in hematopoietic cells except T cells and Natural killer cells. BTK is a promising target because of its involvement in signaling pathways and B cell diseases such as autoimmune disorders and lymphoma. In this work, a combined molecular modeling study of molecular docking, 3D-QSAR and molecular dynamic (MD) simulation were performed on a series of 2,5-diaminopyrimidine compounds as inhibitors targeting Btk kinase to understand the interaction and key residues involved in the inhibition. A structure based CoMFA (q (2) = 0.675, NOC = 5, r (2) = 0.961) and COMSIA (q (2) = 0.704, NOC = 6, r (2) = 0.962) models were developed from the conformation obtained by docking. The developed models were subjected to various validation techniques such as leave-five-out, external test set, bootstrapping, progressive sampling and rm (2) metrics and found to have a good predictive ability in both internal and external validation. Our docking results showed the important residues that interacts in the active site residues in inhibition of Btk kinase. Furthermore, molecular dynamics simulation was employed to study the stability of the docked conformation and to investigate the binding interactions in detail. The MD simulation analyses identified several important hydrogen bonds with Btk, including the gatekeeper residue Thr474 and Met477 at the hinge region. Hydrogen bond with active site residues Leu408 and Arg525 were also recognized. A good correlation between the MD results, docking studies and the contour map analysis are observed. This indicates that the developed models are reliable. Our results from this study can provide insights in the designing and development of more potent Btk kinase inhibitors.

  1. Flexibases: A way to enhance the use of molecular docking methods

    NASA Astrophysics Data System (ADS)

    Kearsley, Simon K.; Underwood, Dennis J.; Sheridan, Robert P.; Miller, Michael D.

    1994-10-01

    Specially expanded databases containing three-dimensional structures are created to enhance the utility of docking methods to find new leads, i.e., active compounds of pharmacological interest. The expansion is based on the automatic generation of a set of maximally dissimilar conformations. The ligand receptor system of methotrexate and dihydrofolate reductase is used to demonstrate the feasibility of creating flexibases and their utility in docking studies.

  2. Lipoxygenase directed anti-inflammatory and anti-cancerous secondary metabolites: ADMET-based screening, molecular docking and dynamics simulation.

    PubMed

    Singh, Swati; Awasthi, Manika; Pandey, Veda P; Dwivedi, Upendra N

    2017-02-01

    Lipoxygenases (LOXs), key enzymes involved in the biosynthesis of leukotrienes, are well known to participate in the inflammatory and immune responses. With the recent reports of involvement of 5-LOX (one of the isozymes of LOX in human) in cancer, there is a need to find out selective inhibitors of 5-LOX for their therapeutic application. In the present study, plant-derived 300 anti-inflammatory and anti-cancerous secondary metabolites (100 each of alkaloids, flavonoids and terpenoids) have been screened for their pharmacokinetic properties and subsequently docked for identification of potent inhibitors of 5-LOX. Pharmacokinetic analyses revealed that only 18 alkaloids, 26 flavonoids, and 9 terpenoids were found to fulfill all the absorption, distribution, metabolism, excretion, and toxicity descriptors as well as those of Lipinski's Rule of Five. Docking analyses of pharmacokinetically screened metabolites and their comparison with a known inhibitor (drug), namely zileuton revealed that only three alkaloids, six flavonoids and three terpenoids were found to dock successfully with 5-LOX with the flavonoid, velutin being the most potent inhibitor among all. The results of the docking analyses were further validated by performing molecular dynamics simulation and binding energy calculations for the complexes of 5-LOX with velutin, galangin, chrysin (in order of LibDock scores), and zileuton. The data revealed stabilization of all the complexes within 15 ns of simulation with velutin complex exhibiting least root-mean-square deviation value (.285 ± .007 nm) as well as least binding energy (ΔGbind = -203.169 kJ/mol) as compared to others during the stabilization phase of simulation.

  3. Molecular recognition of malachite green by hemoglobin and their specific interactions: insights from in silico docking and molecular spectroscopy.

    PubMed

    Peng, Wei; Ding, Fei; Peng, Yu-Kui; Sun, Ying

    2014-01-01

    Malachite green is an organic compound that can be widely used as a dyestuff for various materials; it has also emerged as a controversial agent in aquaculture. Since malachite green is proven to be carcinogenic and mutagenic, it may become a hazard to public health. For this reason, it is urgently required to analyze this controversial dye in more detail. In our current research, the interaction between malachite green and hemoglobin under physiological conditions was investigated by the methods of molecular modeling, fluorescence spectroscopy, circular dichroism (CD) as well as hydrophobic ANS displacement experiments. From the molecular docking, the central cavity of hemoglobin was assigned to possess high-affinity for malachite green, this result was corroborated by time-resolved fluorescence and hydrophobic ANS probe results. The recognition mechanism was found to be of static type, or rather the hemoglobin-malachite green complex formation occurred via noncovalent interactions such as π-π interactions, hydrogen bonds and hydrophobic interactions with an association constant of 10(4) M(-1). Moreover, the results also show that the spatial structure of the biopolymer was changed in the presence of malachite green with a decrease of the α-helix and increase of the β-sheet, turn and random coil suggesting protein damage, as derived from far-UV CD and three-dimensional fluorescence. Results of this work will help to further comprehend the molecular recognition of malachite green by the receptor protein and the possible toxicological profiles of other compounds, which are the metabolites and ramifications of malachite green.

  4. SAMPL4 & DOCK3.7: Lessons for automated docking procedures

    PubMed Central

    Coleman, Ryan G.; Sterling, Teague; Weiss, Dahlia R.

    2014-01-01

    The SAMPL4 challenges were used to test current automated methods for solvation energy, virtual screening, pose and affinity prediction of the molecular docking pipeline DOCK 3.7. Additionally, first-order models of binding affinity were proposed as milestones for any method predicting binding affinity. Several important discoveries about the molecular docking software were made during the challenge: 1) Solvation energies of ligands were five-fold worse than any other method used in SAMPL4, including methods that were similarly fast, 2) HIV Integrase is a challenging target, but automated docking on the correct allosteric site performed well in terms of virtual screening and pose prediction (compared to other methods) but affinity prediction, as expected, was very poor, 3) Molecular docking grid sizes can be very important, serious errors were discovered with default settings that have been adjusted for all future work. Overall, lessons from SAMPL4 suggest many changes to molecular docking tools, not just DOCK 3.7, that could improve the state of the art. Future difficulties and projects will be discussed. PMID:24515818

  5. Structural, spectroscopic and molecular docking studies on 2-amino-3-chloro-5-trifluoromethyl pyridine: A potential bioactive agent

    NASA Astrophysics Data System (ADS)

    Mohamed Asath, R.; Premkumar, R.; Mathavan, T.; Milton Franklin Benial, A.

    2017-03-01

    The most stable, optimized structure of the 2-amino-3-chloro-5-trifluoromethyl pyridine (ACTP) molecule was predicted by the density functional theory calculations using the B3LYP method with cc-pVQZ basis set. Antitumor activity of the ACTP molecule was evaluated by molecular docking analysis. The structural parameters and vibrational wavenumbers were calculated for the optimized molecular structure. The experimental and theoretical vibrational wavenumbers were assigned and compared. Ultraviolet-visible spectrum was simulated and validated experimentally. The molecular electrostatic potential surface was simulated. Frontier molecular orbitals and related molecular properties were computed and further density of states spectrum was simulated. The natural bond orbital analysis was also performed to confirm the bioactivity of the ACTP molecule. The molecular docking analysis reveals the better inhibitory nature of the ACTP molecule against the colony-stimulating factor 1 (CSF1) gene which causes tenosynovial giant-cell tumor. Hence, the ACTP molecule can act as a potential inhibitor against tenosynovial giant-cell tumor.

  6. Structural, spectroscopic and molecular docking studies on 2-amino-3-chloro-5-trifluoromethyl pyridine: A potential bioactive agent.

    PubMed

    Mohamed Asath, R; Premkumar, R; Mathavan, T; Milton Franklin Benial, A

    2017-03-15

    The most stable, optimized structure of the 2-amino-3-chloro-5-trifluoromethyl pyridine (ACTP) molecule was predicted by the density functional theory calculations using the B3LYP method with cc-pVQZ basis set. Antitumor activity of the ACTP molecule was evaluated by molecular docking analysis. The structural parameters and vibrational wavenumbers were calculated for the optimized molecular structure. The experimental and theoretical vibrational wavenumbers were assigned and compared. Ultraviolet-visible spectrum was simulated and validated experimentally. The molecular electrostatic potential surface was simulated. Frontier molecular orbitals and related molecular properties were computed and further density of states spectrum was simulated. The natural bond orbital analysis was also performed to confirm the bioactivity of the ACTP molecule. The molecular docking analysis reveals the better inhibitory nature of the ACTP molecule against the colony-stimulating factor 1 (CSF1) gene which causes tenosynovial giant-cell tumor. Hence, the ACTP molecule can act as a potential inhibitor against tenosynovial giant-cell tumor.

  7. Combining Molecular Docking and Molecular Dynamics to Predict the Binding Modes of Flavonoid Derivatives with the Neuraminidase of the 2009 H1N1 Influenza A Virus

    PubMed Central

    Lu, Shih-Jen; Chong, Fok-Ching

    2012-01-01

    Control of flavonoid derivatives inhibitors release through the inhibition of neuraminidase has been identified as a potential target for the treatment of H1N1 influenza disease. We have employed molecular dynamics simulation techniques to optimize the 2009 H1N1 influenza neuraminidase X-ray crystal structure. Molecular docking of the compounds revealed the possible binding mode. Our molecular dynamics simulations combined with the solvated interaction energies technique was applied to predict the docking models of the inhibitors in the binding pocket of the H1N1 influenza neuraminidase. In the simulations, the correlation of the predicted and experimental binding free energies of all 20 flavonoid derivatives inhibitors is satisfactory, as indicated by R2 = 0.75. PMID:22605992

  8. Prediction of anticancer property of bowsellic acid derivatives by quantitative structure activity relationship analysis and molecular docking study

    PubMed Central

    Satpathy, Raghunath; Guru, R. K.; Behera, R.; Nayak, B.

    2015-01-01

    Context: Boswellic acid consists of a series of pentacyclic triterpene molecules that are produced by the plant Boswellia serrata. The potential applications of Bowsellic acid for treatment of cancer have been focused here. Aims: To predict the property of the bowsellic acid derivatives as anticancer compounds by various computational approaches. Materials and Methods: In this work, all total 65 derivatives of bowsellic acids from the PubChem database were considered for the study. After energy minimization of the ligands various types of molecular descriptors were computed and corresponding two-dimensional quantitative structure activity relationship (QSAR) models were obtained by taking Andrews coefficient as the dependent variable. Statistical Analysis Used: Different types of comparative analysis were used for QSAR study are multiple linear regression, partial least squares, support vector machines and artificial neural network. Results: From the study geometrical descriptors shows the highest correlation coefficient, which indicates the binding factor of the compound. To evaluate the anticancer property molecular docking study of six selected ligands based on Andrews affinity were performed with nuclear factor-kappa protein kinase (Protein Data Bank ID 4G3D), which is an established therapeutic target for cancers. Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. Conclusions: Along with QSAR study and docking result, it was predicted that bowsellic acid can also be treated as a potential anticancer compound. PMID:25709332

  9. Screening alpha-glucosidase and alpha-amylase inhibitors from natural compounds by molecular docking in silico.

    PubMed

    Jhong, Chien-Hung; Riyaphan, Jirawat; Lin, Shih-Hung; Chia, Yi-Chen; Weng, Ching-Feng

    2015-01-01

    The alpha-glucosidase inhibitor is a common oral anti-diabetic drug used for controlling carbohydrates normally converted into simple sugars and absorbed by the intestines. However, some adverse clinical effects have been observed. The present study seeks an alternative drug that can regulate the hyperglycemia by down-regulating alpha-glucosidase and alpha-amylase activity by molecular docking approach to screen the hyperglycemia antagonist against alpha-glucosidase and alpha-amylase activities from the 47 natural compounds. The docking data showed that Curcumin, 16-hydroxy-cleroda-3,13-dine-16,15-olide (16-H), Docosanol, Tetracosanol, Antroquinonol, Berberine, Catechin, Quercetin, Actinodaphnine, and Rutin from 47 natural compounds had binding ability towards alpha-amylase and alpha-glucosidase as well. Curcumin had a better biding ability of alpha-amylase than the other natural compounds. Analyzed alpha-glucosidase activity reveals natural compound inhibitors (below 0.5 mM) are Curcumin, Actinodaphnine, 16-H, Quercetin, Berberine, and Catechin when compared to the commercial drug Acarbose (3 mM). A natural compound with alpha-amylase inhibitors (below 0.5 mM) includes Curcumin, Berberine, Docosanol, 16-H, Actinodaphnine/Tetracosanol, Catechin, and Quercetin when compared to Acarbose (1 mM). When taken together, the implication is that molecular docking is a fast and effective way to screen alpha-glucosidase and alpha-amylase inhibitors as lead compounds of natural sources isolated from medicinal plants.

  10. Peptide binding to HLA-DP proteins at pH 5.0 and pH 7.0: a quantitative molecular docking study

    PubMed Central

    2012-01-01

    Background HLA-DPs are class II MHC proteins mediating immune responses to many diseases. Peptides bind MHC class II proteins in the acidic environment within endosomes. Acidic pH markedly elevates association rate constants but dissociation rates are almost unchanged in the pH range 5.0 – 7.0. This pH-driven effect can be explained by the protonation/deprotonation states of Histidine, whose imidazole has a pKa of 6.0. At pH 5.0, imidazole ring is protonated, making Histidine positively charged and very hydrophilic, while at pH 7.0 imidazole is unprotonated, making Histidine less hydrophilic. We develop here a method to predict peptide binding to the four most frequent HLA-DP proteins: DP1, DP41, DP42 and DP5, using a molecular docking protocol. Dockings to virtual combinatorial peptide libraries were performed at pH 5.0 and pH 7.0. Results The X-ray structure of the peptide – HLA-DP2 protein complex was used as a starting template to model by homology the structure of the four DP proteins. The resulting models were used to produce virtual combinatorial peptide libraries constructed using the single amino acid substitution (SAAS) principle. Peptides were docked into the DP binding site using AutoDock at pH 5.0 and pH 7.0. The resulting scores were normalized and used to generate Docking Score-based Quantitative Matrices (DS-QMs). The predictive ability of these QMs was tested using an external test set of 484 known DP binders. They were also compared to existing servers for DP binding prediction. The models derived at pH 5.0 predict better than those derived at pH 7.0 and showed significantly improved predictions for three of the four DP proteins, when compared to the existing servers. They are able to recognize 50% of the known binders in the top 5% of predicted peptides. Conclusions The higher predictive ability of DS-QMs derived at pH 5.0 may be rationalised by the additional hydrogen bond formed between the backbone carbonyl oxygen belonging to the peptide

  11. Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking

    PubMed Central

    Shoombuatong, Watshara; Malik, Aijaz Ahmad; Prachayasittikul, Virapong; Wikberg, Jarl E.S.

    2016-01-01

    {mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${Q}_{\\mathrm{CV }}^{2}$\\end{document}QCV2 and \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{upgreek} \\usepackage{mathrsfs} \\setlength{\\oddsidemargin}{-69pt} \\begin{document} }{}${Q}_{\\mathrm{Ext}}^{2}$\\end{document}QExt2 values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover, Kennard–Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals interaction. Molecular docking revealed that compounds 13, 5 and 28 exhibited the lowest binding energies of −12.2, −12.0 and −12.0 kcal/mol, respectively, against human AChE, which is modulated by hydrogen bonding, π–π stacking and hydrophobic interaction inside the binding pocket. These information may be used as guidelines for the design of novel and robust AChE inhibitors. PMID:27602288

  12. Design, synthesis and molecular docking of amide and urea derivatives as Escherichia coli PDHc-E1 inhibitors.

    PubMed

    He, Jun-Bo; Ren, Yan-Liang; Sun, Qiu-Shuang; You, Ge-Yun; Zhang, Li; Zou, Peng; Feng, Ling-Ling; Wan, Jian; He, Hong-Wu

    2014-06-15

    By targeting the ThDP binding site of Escherichia coli PDHc-E1, two new 'open-chain' classes of E. coli PDHc-E1 inhibitors, amide and urea derivatives, were designed, synthesized, and evaluated. The amide derivatives of compound 6d, with 4-NO2 in the benzene ring, showed the most potent inhibition of E. coli PDHc-E1. The urea derivatives displayed more potent inhibitory activity than the corresponding amide derivatives with the same substituent. Molecular docking studies confirmed that the urea derivatives have more potency due to the two hydrogen bonds formed by two NH of urea with Glu522. The docking results also indicate it might help us to design more efficient PDHc-E1 inhibitors that could interact with Glu522.

  13. Interaction of ganoderic acid on HIV related target: molecular docking studies

    PubMed Central

    Akbar, Rahmad; Yam, Wai Keat

    2011-01-01

    Finding the ultimate HIV cure remain a challenging tasks for decades. Various active compounds have been tested against various components of the virus in the effort to halt the virus development in infected host. The idea of finding cure from known pharmacologically active natural occurring compounds is intriguing and practical. Ganoderma lucidum (Ling-Zhi or Reishi) is one of the most productive and pharmacologically active compounds found in Asian countries. It has been used traditionally for many years throughout different cultures. More than a decade ago, el-Mekkawy and co-workers (1998) have tested several active compounds found in this plant. They have successfully identified several active compounds with reasonable inhibitory activity against HIV protease however; no further studies were done on these compounds. This study aimed to elucidate interactions for one of the active compounds of Ganoderma lucidum namely ganoderic acid with HIV-1 protease using molecular docking simulation. This study revealed four hydrogen bonds formed between model34 of ganoderic acid B and 1HVR. Hydrogen bonds in 1HVR-Model34 complex were formed through ILE50, ILE50', ASP29 and ASP30 residues. Interestingly similar interactions were also observed in the native ligand in 1HVR. Furthermore, interactions involving ILE50 and ILE50' residues have been previously identified to play central roles in HIV-1 protease-ligand interactions.These observed interactions not only suggested HIV-1 protease in general is a suitable target for ganoderic acid B, they also indicated a huge potential for HIV drug discovery based on this compound. PMID:22347784

  14. Chiral lactic hydrazone derivatives as potential bioactive antibacterial agents: Synthesis, spectroscopic, structural and molecular docking studies

    NASA Astrophysics Data System (ADS)

    Noshiranzadeh, Nader; Heidari, Azam; Haghi, Fakhri; Bikas, Rahman; Lis, Tadeusz

    2017-01-01

    A series of novel chiral lactic-hydrazone derivatives were synthesized by condensation of (S)-lactic acid hydrazide with salicylaldehyde derivatives and characterized by elemental analysis and spectroscopic studies (FT-IR, 1H NMR and 13C NMR spectroscopy). The structure of one compound was determined by single crystal X-ray analysis. Antibacterial activity of the synthesized compounds was studied against Staphylococcus aureus, Streptococcus pneumonia, Escherichia coli and Pseudomonas aeruginosa as bacterial cultures by broth microdilution method. All of the synthesized compounds showed good antibacterial activity with MIC range of 64-512 μg/mL. Compounds (S,E)-2-hydroxy-N-(2-hydroxy-5-nitrobenzylidene)propanehydrazide (5) and (S,E)-2-hydroxy-N-((3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl)propanehydrazide (7) were the most effective antibacterial derivatives against S. aureus and E. coli respectively with a MIC value of 64 μg/mL. Bacterial biofilm formation assay showed that these compounds significantly inhibited biofilm formation of P. aeruginosa. Also, in silico molecular docking studies were performed to show lipoteichoic acid synthase (LtaS) inhibitory effect of lactic hydrazone derivatives. The association between electronic and structural effects of some substituents on the benzylidene moiety and the biological activity of these chiral compounds were studied. Structural studies show that compound with higher hydrogen bonding interactions show higher antibacterial activity. The results show chiral hydrazone derivatives based on lactic acid hydrazide could be used as potential lead compounds for developing novel antibacterial agents.

  15. Vibrational, spectroscopic, molecular docking and density functional theory studies on N-(5-aminopyridin-2-yl)acetamide

    NASA Astrophysics Data System (ADS)

    Asath, R. Mohamed; Rekha, T. N.; Premkumar, S.; Mathavan, T.; Benial, A. Milton Franklin

    2016-12-01

    Conformational analysis was carried out for N-(5-aminopyridin-2-yl)acetamide (APA) molecule. The most stable, optimized structure was predicted by the density functional theory calculations using the B3LYP functional with cc-pVQZ basis set. The optimized structural parameters and vibrational frequencies were calculated. The experimental and theoretical vibrational frequencies were assigned and compared. Ultraviolet-visible spectrum was simulated and validated experimentally. The molecular electrostatic potential surface was simulated. Frontier molecular orbitals and related molecular properties were computed, which reveals that the higher molecular reactivity and stability of the APA molecule and further density of states spectrum was simulated. The natural bond orbital analysis was also performed to confirm the bioactivity of the APA molecule. Antidiabetic activity was studied based on the molecular docking analysis and the APA molecule was identified that it can act as a good inhibitor against diabetic nephropathy.

  16. Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase

    NASA Astrophysics Data System (ADS)

    Birch, Louise; Murray, Christopher W.; Hartshorn, Michael J.; Tickle, Ian J.; Verdonk, Marcel L.

    2002-12-01

    Many proteins undergo small side chain or even backbone movements on binding of different ligands into the same protein structure. This is known as induced fit and is potentially problematic for virtual screening of databases against protein targets. In this report we investigate the limits of the rigid protein approximation used by the docking program, GOLD, through cross-docking using protein structures of influenza neuraminidase. Neuraminidase is known to exhibit small but significant induced fit effects on ligand binding. Some neuraminidase crystal structures caused concern due to the bound ligand conformation and GOLD performed poorly on these complexes. A `clean' set, which contained unique, unambiguous complexes, was defined. For this set, the lowest energy structure was correctly docked (i.e. RMSD < 1.5 Å away from the crystal reference structure) in 84% of proteins, and the most promiscuous protein (1mwe) was able to dock all 15 ligands accurately including those that normally required an induced fit movement. This is considerably better than the 70% success rate seen with GOLD against general validation sets. Inclusion of specific water molecules involved in water-mediated hydrogen bonds did not significantly improve the docking performance for ligands that formed water-mediated contacts but it did prevent docking of ligands that displaced these waters. Our data supports the use of a single protein structure for virtual screening with GOLD in some applications involving induced fit effects, although care must be taken to identify the protein structure that performs best against a wide variety of ligands. The performance of GOLD was significantly better than the GOLD implementation of ChemScore and the reasons for this are discussed. Overall, GOLD has shown itself to be an extremely good, robust docking program for this system.

  17. Molecular docking and QSAR analyses for understanding the antimalarial activity of some 7-substituted-4-aminoquinoline derivatives.

    PubMed

    Shibi, I G; Aswathy, L; Jisha, R S; Masand, V H; Divyachandran, A; Gajbhiye, J M

    2015-09-18

    The quinoline moiety is one of the widely studied scaffolds for generating derivatives with various pharmacophoric groups due to its potential antimalarial activities. In the present study, a series of 7-substituted-4-aminoquinoline derivatives were selected to understand their antimalarial properties computationally by molecular modeling techniques including 2D QSAR, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and molecular docking. The 2D-QSAR model built with four descriptors selected by genetic algorithm technique and CoMFA model showed satisfactory statistical results (Q(2)=0.540, R(2)ncv=0.881, F value=157.09). A reliable CoMSIA model out of the fourteen different combinations has a Q(2) value of 0.638. The molecular docking studies of the compounds for 1CET as the protein target revealed that ten compounds showed maximum interactions with the binding site of the protein. The present study highlights the unique binding signatures of the ligands within the active site groove of the target and it explains the subtle differences in their EC50 values and their mechanism of inhibition.

  18. Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR, molecular docking, and dynamics simulation techniques.

    PubMed

    Wang, Jing Li; Cheng, Li Ping; Wang, Tian Chi; Deng, Wei; Wu, Fan Hong

    2017-03-01

    To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q(2)) and non-cross-validated correlation coefficient (r(2)) of the best CoMFA model are 0.715 and 0.992, respectively. The q(2) and r(2) values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives. Some new JAK3 kinase inhibitors were designed. Some of them have better inhibitory activity than the most potent Tofacitinib (CP-690550). Molecular docking was used to identify some key amino acid residues at the active site of JAK3 protein. 10ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. The calculation of the binding free energies by MMPBSA method gives a good correlation with the predicted biological activity. To our knowledge, this is the first report on MD simulations and free energy calculations for this series of compounds. The combination results of this study will be valuable for the development of potent and novel JAK3 kinase inhibitors.

  19. Interaction of the minocycline with extracelluar protein and intracellular protein by multi-spectral techniques and molecular docking

    NASA Astrophysics Data System (ADS)

    Fang, Qing; Wang, Yirun; Hu, Taoying; Liu, Ying

    2017-02-01

    The interaction of minocyeline (MNC) with extracelluar protein (lysozyme, LYSO) or intracellular protein (bovine hemoglobin, BHb) was investigated using multi-spectral techniques and molecular docking in vitro. Fluorescence studies suggested that MNC quenched LYSO/BHb fluorescence in a static mode with binding constants of 2.01 and 0.26 × 104 L•mol-1 at 298 K, respectively. The LYZO-MNC system was more easily influenced by temperature (298 and 310 K) than the BHb-MNC system. The thermodynamic parameters demonstrated that hydrogen bonds and van der Waals forces played the major role in the binding process. Based on the Förster theory of nonradiative energy transfer, the binding distances between MNC and the inner tryptophan residues of LYSO and BHb were calculated to be 4.34 and 3.49 nm, respectively. Furthermore, circular dichroism spectra (CD), Fourier transforms infrared (FTIR), UV-vis, and three-dimensional fluorescence spectra results indicated the secondary structures of LYSO and BHb were partially destroyed by MNC with the α-helix percentage of LYZO-MNC increased (17.8-28.6%) while that of BHb-MNC was decreased (41.6-39.6%). UV-vis spectral results showed these binding interactions could cause conformational and some micro-environmental changes of LYSO and BHb. In accordance with the results of molecular docking, In LYZO-MNC system, MNC was mainly bound in the active site hinge region where Trp-62 and Trp-63 are located, and in MNC-BHb system, MNC was close to the subunit α 1 of BHb, molecular docking analysis supported the thermodynamic results well. The work contributes to clarify the mechanism of MNC with two proteins at molecular level.

  20. Open Syntaxin Docks Synaptic Vesicles

    PubMed Central

    Olsen, Shawn; Jorgensen, Erik M

    2007-01-01

    Synaptic vesicles dock to the plasma membrane at synapses to facilitate rapid exocytosis. Docking was originally proposed to require the soluble N-ethylmaleimide–sensitive fusion attachment protein receptor (SNARE) proteins; however, perturbation studies suggested that docking was independent of the SNARE proteins. We now find that the SNARE protein syntaxin is required for docking of all vesicles at synapses in the nematode Caenorhabditis elegans. The active zone protein UNC-13, which interacts with syntaxin, is also required for docking in the active zone. The docking defects in unc-13 mutants can be fully rescued by overexpressing a constitutively open form of syntaxin, but not by wild-type syntaxin. These experiments support a model for docking in which UNC-13 converts syntaxin from the closed to the open state, and open syntaxin acts directly in docking vesicles to the plasma membrane. These data provide a molecular basis for synaptic vesicle docking. PMID:17645391

  1. Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain: Functional and molecular docking analyses.

    PubMed

    Kadioglu, Onat; Saeed, Mohamed E M; Valoti, Massimo; Frosini, Maria; Sgaragli, Giampietro; Efferth, Thomas

    2016-03-15

    Rhodamine 123 (R123) transport substrate sensitizes P-glycoprotein (P-gp) to inhibition by compound 2c (cis-cis) N,N-bis(cyclohexanolamine)aryl ester isomer in a concentration-dependent manner in human MDR1-gene transfected mouse T-lymphoma L5178 cells as shown previously. By contrast, epirubicin (EPI) concentration changes left unaltered 2c IC50 values of EPI efflux. To clarify this discrepancy, defined molecular docking (DMD) analyses of 12 N,N-bis(cyclohexanolamine)aryl esters, the highly flexible aryl ester analog 4, and several P-gp substrate/non-substrate inhibitors were performed on human P-gp drug- or nucleotide-binding domains (DBD or NBD). DMD measurements yielded lowest binding energy (LBE, kcal/mol) values (mean ± SD) ranging from -11.8 ± 0.54 (valspodar) to -3.98 ± 0.01 (4). Lys234, Ser952 and Tyr953 residues formed H-bonds with most of the compounds. Only 2c docked also at ATP binding site (LBE value of -6.9 ± 0.30 kcal/mol). Inhibition of P-gp-mediated R123 efflux by 12 N,N-bis(cyclohexanolamine)aryl esters and 4 significantly correlated with LBE values. DMD analysis of EPI, (3)H-1EPI, (3)H-2EPI, (14)C-1EPI, (14)C-2EPI, R123 and 2c before and after previous docking of each of them indicated that pre-docking of either 2c or EPI significantly reduced LBE of both EPI and R123, and that of both (3)H-2EPI and (14)C-2EPI, respectively. Since the clusters of DBD amino acid residues interacting with EPI were different, if EPI docked alone or after pre-docking of EPI or 2c, the existence of alternative secondary binding site for EPI on P-gp is credible. In conclusion, 2c may allocate the drug-binding pocket and reduce strong binding of EPI and R123 in agreement with P-gp inhibition experiments, where 2c reduced efflux of EPI and R123.

  2. Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

    PubMed Central

    Miceli, Leonardo A.; Teixeira, Valéria L.; Castro, Helena C.; Rodrigues, Carlos R.; Mello, Juliana F. R.; Albuquerque, Magaly G.; Cabral, Lucio M.; de Brito, Monique A.; de Souza, Alessandra M. T.

    2013-01-01

    AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (ELUMO–EHOMO), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity. PMID:24172210

  3. 3D Structure Generation, Molecular Dynamics and Docking Studies of IRHOM2 Protein Involved in Cancer & Rheumatoid Arthritis.

    PubMed

    Raj, Utkarsh; Kumar, Himansu; Varadwaj, Pritish Kumar

    2015-01-01

    A short-lived membrane protein IRHOM2 pedals a cascade of events by regulating Epidermal Growth Factor Receptor (EGFR) signalling in parallel with metalloproteases which results their involvement in cancer as well as in rheumatoid arthritis. Therefore, IRHOM2 is a potential therapeutic drug target for these diseases, but its 3D-structure has not been reported yet. In this study, the three-dimensional structure of the IRHOM2 protein was generated using I-TASSER (Iterative Threading Assembly Refinement) server. The modeled structure of IRHOM2 receptor was validated using various Structural Analysis and Verification Server (SAVES) in which 99.7% of amino acid residues are present in the favoured regions of the Ramachandran Plot. Further, the refined modeled structure was subjected to molecular dynamics simulation & docking analysis. Virtual screening studies were carried out using Glide with various selective libraries containing 24552 compounds and the analysis indicated extensive hydrogen bonding network and hydrophobic interactions which play a significant role in its binding. Docking results were analyzed for high ranking compounds using a consensus based docking score to calculate the binding affinity as a measure of protein-ligand interactions. The top ranking molecule against IRHOM2 active site has a glide g-score of -12.565 kcal/mol and glide e-model score of -74.967 with 3 hydrogen bonds and 11 hydrophobic contacts. This compound may act as probable inhibitor against these chronic diseases but further in vitro studies are required.

  4. Computational approaches for protein function prediction: a combined strategy from multiple sequence alignment to molecular docking-based virtual screening.

    PubMed

    Pierri, Ciro Leonardo; Parisi, Giovanni; Porcelli, Vito

    2010-09-01

    The functional characterization of proteins represents a daily challenge for biochemical, medical and computational sciences. Although finally proved on the bench, the function of a protein can be successfully predicted by computational approaches that drive the further experimental assays. Current methods for comparative modeling allow the construction of accurate 3D models for proteins of unknown structure, provided that a crystal structure of a homologous protein is available. Binding regions can be proposed by using binding site predictors, data inferred from homologous crystal structures, and data provided from a careful interpretation of the multiple sequence alignment of the investigated protein and its homologs. Once the location of a binding site has been proposed, chemical ligands that have a high likelihood of binding can be identified by using ligand docking and structure-based virtual screening of chemical libraries. Most docking algorithms allow building a list sorted by energy of the lowest energy docking configuration for each ligand of the library. In this review the state-of-the-art of computational approaches in 3D protein comparative modeling and in the study of protein-ligand interactions is provided. Furthermore a possible combined/concerted multistep strategy for protein function prediction, based on multiple sequence alignment, comparative modeling, binding region prediction, and structure-based virtual screening of chemical libraries, is described by using suitable examples. As practical examples, Abl-kinase molecular modeling studies, HPV-E6 protein multiple sequence alignment analysis, and some other model docking-based characterization reports are briefly described to highlight the importance of computational approaches in protein function prediction.

  5. Comparative molecular field analysis and molecular docking studies on novel aryl chalcone derivatives against an important drug target cysteine protease in Plasmodium falciparum.

    PubMed

    Thillainayagam, Mahalakshmi; Anbarasu, Anand; Ramaiah, Sudha

    2016-08-21

    The computational studies namely molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are executed on series of 52 novel aryl chalcones derivatives using Plasmodium falciparum cysteine proteases (falcipain - 2) as vital target. In the present study, the correlation between different molecular field effects namely steric and electrostatic interactions and chemical structures to the inhibitory activities of novel aryl chalcone derivatives is inferred to perceive the major structural prerequisites for the rational design and development of potent and novel lead anti-malarial compound. The apparent binding conformations of all the compounds at the active site of falcipain - 2 and the hydrogen-bond interactions which could be used to modify the inhibitory activities are identified by using Surflex-dock study. Statistically significant CoMFA model has been developed with the cross-validated correlation coefficient (q(2)) of 0.912 and the non-cross-validated correlation coefficient (r(2)) of 0.901. Standard error of estimation (SEE) of 0.210, with the optimum number of components is ten. The predictability of the derived model is examined with a test set consists of sixteen compounds and the predicted r(2) value is found to be 0.924. The docking and QSAR study results confer crucial suggestions for the optimization of novel 1,3-diphenyl-2-propen-1-one derivatives and synthesis of effective anti- malarial compounds.

  6. Activity of the dietary flavonoid, apigenin, against multidrug-resistant tumor cells as determined by pharmacogenomics and molecular docking.

    PubMed

    Saeed, Mohamed; Kadioglu, Onat; Khalid, Hassan; Sugimoto, Yoshikazu; Efferth, Thomas

    2015-01-01

    Apigenin is a common dietary flavonoid with considerable cytotoxic activity in vitro and in vivo. Despite many mechanistic studies, less is known about resistance factors hampering apigenin's activity. We investigated the ATP-binding cassette (ABC) transporters BCRP/ABCG2, P-glycoprotein/ABCB1 and its close relative ABCB5. Multidrug-resistant cells overexpressing these ABC transporters were not cross-resistant toward apigenin. Moreover, apigenin inhibited not only P-glycoprotein but also BCRP by increasing cellular uptake of doxorubicin and synergistic inhibition of cell viability in combination with doxorubicin or docetaxel in multidrug-resistant cells. To perform in silico molecular docking studies, we first generated homology models for human P-glycoprotein and ABCB5 based on the crystal structure of murine P-glycoprotein. Their nucleotide binding domains (NDBs) revealed the highest degrees of sequence homologies (89%-100%), indicating that ATP binding and cleavage is of crucial importance for ABC transporters. Molecular docking of apigenin bound to the NDBs of P-glycoprotein and ABCB5 in molecular docking studies. Hence, apigenin may compete with ATP for NDB-binding leading to energy depletion to fuel the transport of ABC transporter substrates. Furthermore, we performed COMPARE and hierarchical cluster analyses of transcriptome-wide mRNA expression profiles of the National Cancer Institute tumor cell line panel. Microarray-based mRNA expressions of genes of diverse biological functions (signal transduction, transcriptional regulation, ubiquitination, autophagy, metabolic activity, xenobiotic detoxification and microtubule formation) significantly predicted responsiveness of tumor cells to apigenin. In conclusion, apigenin's activity is not hampered by classical mechanisms of multidrug resistance and the inhibition of ABC transporters by apigenin indicates that apigenin may overcome multidrug resistance in otherwise refractory tumors.

  7. Kinetic, structural and molecular docking studies on the inhibition of tyrosinase induced by arabinose.

    PubMed

    Hu, Wei-Jiang; Yan, Li; Park, Daeui; Jeong, Hyoung Oh; Chung, Hae Young; Yang, Jun-Mo; Ye, Zhuo Ming; Qian, Guo-Ying

    2012-04-01

    Tyrosinase plays a central role in biological pigment formation, and hence knowledge of tyrosinase catalytic mechanisms and regulation may have medical, cosmetic, and agricultural applications. We found in this study that arabinose significantly inhibited tyrosinase, and this was accompanied by conformational changes in enzyme structure. Kinetic analysis showed that arabinose-mediated inactivation followed first-order kinetics, and single and multiple classes of rate constants were measured. Arabinose displayed a mixed-type inhibitory mechanism with K(i)=0.22±0.07 mM. Measurements of intrinsic and ANS-binding fluorescence showed that arabinose induced tyrosinase to unfold and expose inner hydrophobic regions. We simulated the docking between tyrosinase and arabinose (binding energies were -26.28 kcal/mol for Dock6.3 and -2.02 kcal/mol for AutoDock4.2) and results suggested that arabinose interacts mostly with His61, Asn260, and Met280. The present strategy of predicting tyrosinase inhibition by simulation of docking by hydroxyl groups may prove useful in screening for potential tyrosinase inhibitors, as shown here for arabinose.

  8. Biophysical study on the interaction between eperisone hydrochloride and human serum albumin using spectroscopic, calorimetric, and molecular docking analysis.

    PubMed

    Rabbani, Gulam; Baig, Mohammad Hassan; Lee, Eun Ju; Cho, Won Kyung; Ma, Jin Yeul; Choi, Inho

    2017-04-05

    Eperisone hydrochloride (EH) is a widely used as a muscle relaxant for patients with muscular contracture, low back pain, or spasticity. Human serum albumin (HSA), a highly soluble negatively charged, endogenous and abundant plasma protein ascribed with the ligand binding and transport properties. The current study was undertaken to explore the interaction between EH and the serum transport protein, HSA. Study of the interaction between HSA and EH was carried by UV-vis, fluorescence quenching, circular dichroism (CD) spectroscopy, FRET, and ITC. Tryptophan fluorescence intensity of HSA was strongly quenched by EH. The binding constants (Kb) were obtained by fluorescence quenching and results shows that the EH-HSA interaction revealed a static mode of quenching, with binding constant Kb ~104 reflecting high affinity of EH for HSA. The negative ΔGº value for binding indicated that HSA-EH interaction is a spontaneous process. Thermodynamic analysis shows HSA-EH complex formation occurs primarily due to hydrophobic interactions and hydrogen bonds were facilitate the binding of EH. EH binding induces α-helix of HSA as obtained by far-UV CD and FTIR spectroscopy. In addition, the distance between EH (acceptor) and Trp residue of HSA (donor) was calculated 2.18 nm using Förster's resonance energy transfer theory. Furthermore, molecular docking results revealed EH binds with HSA, and binding site is positioned in Sudlow Site I of HSA (subdomain IIA). This work provides a useful experimental strategy for studying the interaction of myorelaxant with HSA, helping to understand the activity and mechanism of drug binding.

  9. Synthesis, molecular docking and biological evaluation of 1,3,4-oxadiazole derivatives as potential immunosuppressive agents.

    PubMed

    Yan, Ru; Zhang, Zhi-Ming; Fang, Xian-Ying; Hu, Yang; Zhu, Hai-Liang

    2012-02-15

    A series of novel 1,3,4-oxadiazole derivatives (5a-5s) have been designed, synthesized and evaluated for their immunosuppressive activity. Most of these synthesized compounds were proved to have potent immunosuppressive activity and low toxicity. Among them, compounds (5m-5r) showed the most potent biological activity against lymph node cells. The results of flow cytometry (FCM) and western blotting demonstrated that compound 5q induce cell apoptosis by the inhibition of PI3K/AKT pathway. Molecular docking was performed to position compound 5q into PI3Kγ binding site in order to explore the potential target.

  10. Synthesis, α-glucosidase inhibitory and molecular docking studies of prenylated and geranylated flavones, isoflavones and chalcones.

    PubMed

    Sun, Hua; Li, Yashan; Zhang, Xiaoting; Lei, Yanan; Ding, Weina; Zhao, Xue; Wang, Haomeng; Song, Xiaotong; Yao, Qingwei; Zhang, Yongmin; Ma, Ying; Wang, Runling; Zhu, Tao; Yu, Peng

    2015-10-15

    Three series of prenylated and/or geranylated flavonoids were synthesized and evaluated for their α-glucosidase inhibitory activity. The 3',5'-digeranylated chalcone (16) was identified as a new α-glucosidase inhibitor whose activity (IC50=0.90 μM) was 50-fold more than that of acarbose (IC50=51.32 μM). Molecular docking studies revealed the existence of strong hydrophobic interaction and H-bonding between compound 16 and α-glucosidase's active site. The inhibitory mode analysis showed that 16 exhibited a competitive inhibitory mode.

  11. Computational simulation of the effect of quantum chemical parameters on the molecular docking of HMG-CoA reductase drugs

    NASA Astrophysics Data System (ADS)

    Atlam, Faten M.; Awad, Mohamed K.; El-Bastawissy, Eman A.

    2014-10-01

    Density functional theory (B3LYP-6-31G(d)) was performed to study the effect of molecular and electronic structures, of 2-cyclopropyl-4-thiophenyl-quinoline mevalonolactones as potential hypocholesterolemic inhibitors, on their biological activities and discuss the correlation between the inhibition efficiency and quantum chemical parameters. Molecular docking was performed to investigate the mode of interactions between the investigated inhibitors and the active sites of the target Hydroxymethylglutaryl-Coenzyme A(HMG-CoA) reductase. The results could suggest further structural modifications to discover more potent and selective HMG-CoA reductase inhibitors. The catalytic active sites of HMGR have a positive electrostatic potential which is complemented with a negative electrostatic potential of the investigated drugs to form a stabilized complex. The presence of lipophobic groups, such as quinoline nucleus, cyclopropyl and substituted thiophenyl groups as well as a lactone moiety, is important for binding to the active sites. A good correlation between the experimental and theoretical data confirms that the quantum chemical methods and molecular docking studies are successful tools for enriching screening experiments aimed at the discovery of novel bioactive compounds.

  12. Design, synthesis, crystal structure, insecticidal activity, molecular docking, and QSAR studies of novel N3-substituted imidacloprid derivatives.

    PubMed

    Wang, Mei-Juan; Zhao, Xiao-Bo; Wu, Dan; Liu, Ying-Qian; Zhang, Yan; Nan, Xiang; Liu, Huanxiang; Yu, Hai-Tao; Hu, Guan-Fang; Yan, Li-Ting

    2014-06-18

    Three novel series of N3-substituted imidacloprid derivatives were designed and synthesized, and their structures were identified on the basis of satisfactory analytical and spectral ((1)H NMR, (13)C NMR, MS, elemental analysis, and X-ray) data. Preliminary bioassays indicated that all of the derivatives exhibited significant insecticidal activities against Aphis craccivora, with LC50 values ranging from 0.00895 to 0.49947 mmol/L, and the insecticidal activities of some of them were comparable to those of the control imidacloprid. Some key structural features related to their insecticidal activities were identified, and the binding modes between target compounds and nAChR model were also further explored by molecular docking. By comparing the interaction features of imidacloprid and compound 26 with highest insecticidal activity, the origin of the high insecticidal activity of compound 26 was identified. On the basis of the conformations generated by molecular docking, a satisfactory 2D-QSAR model with six selected descriptors was built using genetic algorithm-multiple linear regression (GA-MLR) method. The analysis of the built model showed the molecular size, shape, and the ability to form hydrogen bond were important for insecticidal potency. The information obtained in the study will be very helpful for the design of new derivatives with high insecticidal activities.

  13. Molecular docking and 3D-QSAR studies on the glucocorticoid receptor antagonistic activity of hydroxylated polychlorinated biphenyls.

    PubMed

    Liu, S; Luo, Y; Fu, J; Zhou, J; Kyzas, G Z

    2016-01-01

    The glucocorticoid receptor (GR) antagonistic activities of hydroxylated polychlorinated biphenyls (HO-PCBs) were recently characterised. To further explore the interactions between HO-PCBs and the GR, and to elucidate structural characteristics that influence the GR antagonistic activity of HO-PCBs, molecular docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed. Comparative molecular similarity indices analysis (CoMSIA) was performed using both ligand- and receptor-based alignment schemes. Results generated from the receptor-based model were found to be more satisfactory, with q(2) of 0.632 and r(2) of 0.931 compared with those from the ligand-based model. Some internal validation strategies (e.g. cross-validation analysis, bootstrapping analysis and Y-randomisation) and an external validation method were used respectively to further assess the stability and predictive ability of the derived model. Graphical interpretation of the model provided some insights into the structural features that affected the GR antagonistic activity of HO-PCBs. Molecular docking studies revealed that some key residues were critical for ligand-receptor interactions by forming hydrogen bonds (Glu540) and hydrophobic interactions with ligands (Ile539, Val543 and Trp577). Although CoMSIA sometimes depends on the alignment of the molecules, the information provided is beneficial for predicting the GR antagonistic activities of HO-PCB homologues and is helpful for understanding the binding mechanisms of HO-PCBs to GR.

  14. Investigating the Inhibitory Effect of Wortmannin in the Hotspot Mutation at Codon 1047 of PIK3CA Kinase Domain: A Molecular Docking and Molecular Dynamics Approach.

    PubMed

    Kumar, D Thirumal; Doss, C George Priya

    2016-01-01

    Oncogenic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) are the most frequently reported in association with various forms of cancer. Several studies have reported the significance of hotspot mutations in a catalytic subunit of PIK3CA in association with breast cancer. Mutations are frequently observed in the highly conserved region of the kinase domain (797-1068 amino acids) of PIK3CA are activating or gain-of-function mutations. Mutation in codon 1047 occurs in the C-terminal region of the kinase domain with histidine (H) replaced by arginine (R), lysine (L), and tyrosine (Y). Pathogenicity and protein stability predictors PhD-SNP, Align GVGD, HANSA, iStable, and MUpro classified H1047R as highly deleterious when compared to H1047L and H1047Y. To explore the inhibitory activity of Wortmannin toward PIK3CA, the three-dimensional structure of the mutant protein was determined using homology modeling followed by molecular docking and molecular dynamics analysis. Docking studies were performed for the three mutants and native with Wortmannin to measure the differences in their binding pattern. Comparative docking study revealed that H1047R-Wortmannin complex has a higher number of hydrogen bonds as well as the best binding affinity next to the native protein. Furthermore, 100 ns molecular dynamics simulation was initiated with the docked complexes to understand the various changes induced by the mutation. Though Wortmannin was found to nullify the effect of H1047R over the protein, further studies are required for designing a better compound. As SNPs are major genetic variations observed in disease condition, personalized medicine would provide enhanced drug therapy.

  15. Molecular docking and 3D-quantitative structure activity relationship analyses of peptidyl vinyl sulfones: Plasmodium Falciparum cysteine proteases inhibitors

    NASA Astrophysics Data System (ADS)

    Teixeira, Cátia; Gomes, José R. B.; Couesnon, Thierry; Gomes, Paula

    2011-08-01

    Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (39 molecules) of peptidyl vinyl sulfone derivatives as potential Plasmodium Falciparum cysteine proteases inhibitors. Two different methods of alignment were employed: (i) a receptor-docked alignment derived from the structure-based docking algorithm GOLD and (ii) a ligand-based alignment using the structure of one of the ligands derived from a crystal structure from the PDB databank. The best predictions were obtained for the receptor-docked alignment with a CoMFA standard model ( q 2 = 0.696 and r 2 = 0.980) and with CoMSIA combined electrostatic, and hydrophobic fields ( q 2 = 0.711 and r 2 = 0.992). Both models were validated by a test set of nine compounds and gave satisfactory predictive r 2 pred values of 0.76 and 0.74, respectively. CoMFA and CoMSIA contour maps were used to identify critical regions where any change in the steric, electrostatic, and hydrophobic fields may affect the inhibitory activity, and to highlight the key structural features required for biological activity. Moreover, the results obtained from 3D-QSAR analyses were superimposed on the Plasmodium Falciparum cysteine proteases active site and the main interactions were studied. The present work provides extremely useful guidelines for future structural modifications of this class of compounds towards the development of superior antimalarials.

  16. Potential charge transfer probe induced conformational changes of model plasma protein human serum albumin: Spectroscopic, molecular docking, and molecular dynamics simulation study.

    PubMed

    Jana, Sankar; Dalapati, Sasanka; Ghosh, Shalini; Guchhait, Nikhil

    2012-10-01

    The nature of binding of specially designed charge transfer (CT) fluorophore at the hydrophobic protein interior of human serum albumin (HSA) has been explored by massive blue-shift (82 nm) of the polarity sensitive probe emission accompanying increase in emission intensity, fluorescence anisotropy, red edge excitation shift, and average fluorescence lifetimes. Thermal unfolding of the intramolecular CT probe bound HSA produces almost opposite spectral changes. The spectral responses of the molecule reveal that it can be used as an extrinsic fluorescent reporter for similar biological systems. Circular dichrosim spectra, molecular docking, and molecular dynamics simulation studies scrutinize this binding process and stability of the protein probe complex more closely.

  17. Identification of 1H-indene-(1,3,5,6)-tetrol derivatives as potent pancreatic lipase inhibitors using molecular docking and molecular dynamics approach.

    PubMed

    Kalathiya, Umesh; Padariya, M; Baginski, M

    2016-11-01

    Pancreatic lipase is a potential therapeutic target to treat diet-induced obesity in humans, as obesity-related diseases continue to be a global problem. Despite intensive research on finding potential inhibitors, very few compounds have been introduced to clinical studies. In this work, new chemical scaffold 1H-indene-(1,3,5,6)-tetrol was proposed using knowledge-based approach, and 36 inhibitors were derived by modifying its functional groups at different positions in scaffold. To explore binding affinity and interactions of ligands with protein, CDOCKER and AutoDock programs were used for molecular docking studies. Analyzing results of rigid and flexible docking algorithms, inhibitors C_12, C_24, and C_36 were selected based on different properties and high predicted binding affinities for further analysis. These three inhibitors have different moieties placed at different functional groups in scaffold, and to characterize structural rationales for inhibitory activities of compounds, molecular dynamics simulations were performed (500 nSec). It has been shown through simulations that two structural fragments (indene and indole) in inhibitor can be treated as isosteric structures and their position at binding cleft can be replaced by each other. Taking into account these information, two lines of inhibitors can further be developed, each line based on a different core scaffold, that is, indene/indole.

  18. Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

    PubMed

    Ramírez, David; Caballero, Julio

    2016-04-20

    Molecular docking is a computational chemistry method which has become essential for the rational drug design process. In this context, it has had great impact as a successful tool for the study of ligand-receptor interaction modes, and for the exploration of large chemical datasets through virtual screening experiments. Despite their unquestionable merits, docking methods are not reliable for predicting binding energies due to the simple scoring functions they use. However, comparisons between two or three complexes using the predicted binding energies as a criterion are commonly found in the literature. In the present work we tested how wise is it to trust the docking energies when two complexes between a target protein and enantiomer pairs are compared. For this purpose, a ligand library composed by 141 enantiomeric pairs was used, including compounds with biological activities reported against seven protein targets. Docking results using the software Glide (considering extra precision (XP), standard precision (SP), and high-throughput virtual screening (HTVS) modes) and AutoDock Vina were compared with the reported biological activities using a classification scheme. Our test failed for all modes and targets, demonstrating that an accurate prediction when binding energies of enantiomers are compared using docking may be due to chance. We also compared pairs of compounds with different molecular weights and found the same results.

  19. Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target?

    PubMed Central

    Ramírez, David; Caballero, Julio

    2016-01-01

    Molecular docking is a computational chemistry method which has become essential for the rational drug design process. In this context, it has had great impact as a successful tool for the study of ligand–receptor interaction modes, and for the exploration of large chemical datasets through virtual screening experiments. Despite their unquestionable merits, docking methods are not reliable for predicting binding energies due to the simple scoring functions they use. However, comparisons between two or three complexes using the predicted binding energies as a criterion are commonly found in the literature. In the present work we tested how wise is it to trust the docking energies when two complexes between a target protein and enantiomer pairs are compared. For this purpose, a ligand library composed by 141 enantiomeric pairs was used, including compounds with biological activities reported against seven protein targets. Docking results using the software Glide (considering extra precision (XP), standard precision (SP), and high-throughput virtual screening (HTVS) modes) and AutoDock Vina were compared with the reported biological activities using a classification scheme. Our test failed for all modes and targets, demonstrating that an accurate prediction when binding energies of enantiomers are compared using docking may be due to chance. We also compared pairs of compounds with different molecular weights and found the same results. PMID:27104528

  20. Molecular docking studies of 1-(substituted phenyl)-3-(naphtha [1, 2-d] thiazol-2-yl) urea/thiourea derivatives with human adenosine A(2A) receptor.

    PubMed

    Azam, Faizul; Prasad, Medapati Vijaya Vara; Thangavel, Neelaveni; Ali, Hamed Ismail

    2011-01-01

    Computational assessment of the binding interactions of drugs is an important component of computer-aided drug design paradigms. In this perspective, a set of 30 1-(substituted phenyl)-3-(naphtha[1, 2-d] thiazol-2-yl) urea/thiourea derivatives showing antiparkinsonian activity were docked into inhibitor binding cavity of human adenosine A(2A) receptor (AA2AR) to understand their mode of binding interactions in silico. Lamarckian genetic algorithm methodology was employed for docking simulations using AutoDock 4.2 program. The results signify that the molecular docking approach is reliable and produces a good correlation coefficient (r(2) = 0.483) between docking score and antiparkinsonian activity (in terms of % reduction in catalepsy score). Potent antiparkinsonian agents carried methoxy group in the phenyl ring, exhibited both hydrophilic and lipophilic interactions with lower energy of binding at the AA(2A)R. These molecular docking analyses should, in our view, contribute for further development of selective AA(2A)R antagonists for the treatment of Parkinson's disease.

  1. Estimation of Inhibitory Effect against Tyrosinase Activity through Homology Modeling and Molecular Docking

    PubMed Central

    Nokinsee, Daungkamon; Shank, Lalida; Lee, Vannajan Sanghiran; Nimmanpipug, Piyarat

    2015-01-01

    Tyrosinase is a key enzyme in melanogenesis. Generally, mushroom tyrosinase from A. bisporus had been used as a model in skin-whitening agent tests employed in the cosmetic industry. The recently obtained crystal structure of bacterial tyrosinase from B. megaterium has high similarity (33.5%) to the human enzyme and thus it was used as a template for constructing of the human model. Binding of tyrosinase to a series of its inhibitors was simulated by automated docking calculations. Docking and MD simulation results suggested that N81, N260, H263, and M280 are involved in the binding of inhibitors to mushroom tyrosinase. E195 and H208 are important residues in bacterial tyrosinase, while E230, S245, N249, H252, V262, and S265 bind to inhibitors and are important in forming pi interaction in human tyrosinase. PMID:26788364

  2. Synthesis, evaluation and molecular docking studies of amino acid derived N-glycoconjugates as antibacterial agents.

    PubMed

    Baig, Noorullah; Singh, Rajnish Prakash; Chander, Subhash; Jha, Prabhat Nath; Murugesan, Sankaranarayanan; Sah, Ajay K

    2015-12-01

    Six amino acid derived N-glycoconjugates of d-glucose were synthesized, characterized and tested for antibacterial activity against G(+)ve (Bacillus cereus) as well as G(-)ve (Escherichia coli and Klebsiella pneumoniae) bacterial strains. All the tested compounds exhibited moderate to good antibacterial activity against these bacterial strains. The results were compared with the antibacterial activity of standard drug Chloramphenicol, where results of A5 (Tryptophan derived glycoconjugates) against E. coli and A4 (Isoleucine derived glycoconjugates) against K. pneumoniae bacterial strains are comparable with the standard drug molecule. In silico docking studies were also performed in order to understand the mode of action and binding interactions of these molecules. The docking studies revealed that, occupation of compound A5 at the ATP binding site of subunit GyrB (DNA gyrase, PDB ID: 3TTZ) via hydrophobic and hydrogen bonding interactions may be the reason for its significant in vitro antibacterial activity.

  3. Molecular docking study, synthesis and biological evaluation of Schiff bases as Hsp90 inhibitors.

    PubMed

    Dutta Gupta, Sayan; Snigdha, D; Mazaira, Gisela I; Galigniana, Mario D; Subrahmanyam, C V S; Gowrishankar, N L; Raghavendra, N M

    2014-04-01

    Heat shock protein 90 (Hsp90) is an emerging attractive target for the discovery of novel cancer therapeutic agents. Docking methods are powerful in silico tools for lead generation and optimization. In our mission to rationally develop novel effective small molecules against Hsp90, we predicted the potency of our designed compounds by Sybyl surflex Geom X docking method. The results of the above studies revealed that Schiff bases derived from 2,4-dihydroxy benzaldehyde/5-chloro-2,4-dihydroxy benzaldehyde demonstrated effective binding with the protein. Subsequently, a few of them were synthesized (1-10) and characterized by IR, (1)HNMR and mass spectral analysis. The synthesized molecules were evaluated for their potential to suppress Hsp90 ATPase activity by Malachite green assay. The anticancer studies were performed by 3-(4,5-dimethythiazol- 2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay method. The software generated results was in satisfactory agreement with the evaluated biological activity.

  4. Cytotoxic activity and molecular docking of a novel biflavonoid isolated from Jacaranda acutifolia (Bignoniaceae).

    PubMed

    Mostafa, Nada M; Ashour, Mohamed L; Eldahshan, Omayma A; Singab, Abdel Nasser B

    2016-09-01

    A novel biflavonoid [kaempferol (6→8″) apigenin] was isolated from the leaves of Jacaranda acutifolia. The structure was elucidated based on chemical evidence, 1D and 2D spectroscopic analyses as well as spectrometric techniques. The compound showed promising cytotoxic activity against breast cancer cell line MCF-7. The anticancer activity was explained via virtual docking of the isolated compound to the main sites in the human cyclin-dependent kinase2 (CDK2) crystal structure.

  5. Comparative Molecular docking analysis of DNA Gyrase subunit A in Pseudomonas aeruginosaPAO1.

    PubMed

    Gupta, Aman; Sharma, Vanashika; Tewari, Ashish Kumar; Surenderkumar, Vipul; Wadhwa, Gulshan; Mathur, Ashwani; Sharma, Sanjeev Kumar; Jain, Chakresh Kumar

    2013-01-01

    Pseudomonas aeruginosa is an opportunistic bacterium known for causing chronic infections in cystic fibrosis and chronic obstructive pulmonary disease (COPD) patients. Recently, several drug targets in Pseudomonas aeruginosa PAO1 have been reported using network biology approaches on the basis of essentiality and topology and further ranked on network measures viz. degree and centrality. Till date no drug/ligand molecule has been reported against this targets.In our work we have identified the ligand /drug molecules, through Orthologous gene mapping against Bacillus subtilis subsp. subtilis str. 168 and performed modelling and docking analysis. From the predicted drug targets in PA PAO1, we selected those drug targets which show statistically significant orthology with a model organism and whose orthologs are present in all the selected drug targets of PA PAO1.Modeling of their structure has been done using I-Tasser web server. Orthologous gene mapping has been performed using Cluster of Orthologs (COGs) and based on orthology; drugs available for Bacillus sp. have been docked with PA PAO1 protein drug targets using MoleGro virtual docker version 4.0.2.Orthologous gene for PA3168 gyrA is BS gyrAfound in Bacillus subtilis subsp. subtilis str. 168. The drugs cited for Bacillus sp. have been docked with PA genes and energy analyses have been made. Based on Orthologous gene mapping andin-silico studies, Nalidixic acid is reported as an effective drug against PA3168 gyrA for the treatment of CF and COPD.

  6. Epitope mapping of metuximab on CD147 using phage display and molecular docking.

    PubMed

    He, Bifang; Mao, Canquan; Ru, Beibei; Han, Hesong; Zhou, Peng; Huang, Jian

    2013-01-01

    Metuximab is the generic name of Licartin, a new drug for radioimmunotherapy of hepatocellular carcinoma. Although it is known to be a mouse monoclonal antibody against CD147, the complete epitope mediating the binding of metuximab to CD147 remains unknown. We panned the Ph.D.-12 phage display peptide library against metuximab and got six mimotopes. The following bioinformatics analysis based on mimotopes suggested that metuximab recognizes a conformational epitope composed of more than 20 residues. The residues of its epitope may include T28, V30, K36, L38, K57, F74, D77, S78, D79, D80, Q81, G83, S86, N98, Q100, L101, H102, G103, P104, V131, P132, and K191. The homology modeling of metuximab and the docking of CD147 to metuximab were also performed. Based on the top one docking model, the epitope was predicted to contain 28 residues: AGTVFTTV (23-30), I37, D45, E84, V88, EPMGTANIQLH (92-102), VPP (131-133), Q164, and K191. Almost half of the residues predicted on the basis of mimotope analysis also appear in the docking result, indicating that both results are reliable. As the predicted epitopes of metuximab largely overlap with interfaces of CD147-CD147 interactions, a structural mechanism of metuximab is proposed as blocking the formation of CD147 dimer.

  7. Molecular docking and QSAR of aplyronine A and analogues: potent inhibitors of actin

    NASA Astrophysics Data System (ADS)

    Hussain, Abrar; Melville, James L.; Hirst, Jonathan D.

    2010-01-01

    Actin-binding natural products have been identified as a potential basis for the design of cancer therapeutic agents. We report flexible docking and QSAR studies on aplyronine A analogues. Our findings show the macrolide `tail' to be fundamental for the depolymerisation effect of actin-binding macrolides and that it is the tail which forms the initial interaction with the actin rather than the macrocycle, as previously believed. Docking energy scores for the compounds were highly correlated with actin depolymerisation activity. The 3D-QSAR models were predictive, with the best model giving a q 2 value of 0.85 and a r 2 of 0.94. Results from the docking simulations and the interpretation from QSAR "coeff*stdev" contour maps provide insight into the binding mechanism of each analogue and highlight key features that influence depolymerisation activity. The results herein may aid the design of a putative set of analogues that can help produce efficacious and tolerable anti-tumour agents. Finally, using the best QSAR model, we have also made genuine predictions for an independent set of recently reported aplyronine analogues.

  8. In-vitro analysis of selective nutraceuticals binding to human transcription factors through computer aided molecular docking predictions

    PubMed Central

    Teimouri, Mohammad; Junaid, Muhammad; Saleem, Shoaib; Khan, Abbas; Ali, Arif

    2016-01-01

    The contest of cancer couldn’t be completed without novel drug with novel modes of action, improved efficacy and acceptable pharmacokinetic properties. Transcription factors are attractive targets to develop anti-cancerous drugs. 6-Gingerol, Anethol analogues, Capsaicinoids, Curcumin, Dibenzoylmethane, Diosgenin, Eugenol, Gambogic acid, Thymoquinone, Ursolic acid, Xanthohumol, Zerumbone are the promising nutraceuticals that help in the prevention of cancer. These nutraceuticals showed promising activity in invitro tests. In this study In-silico tools were applied to confirm the activity of these nutraceuticals against the transcription factors including Nuclear Factor-Kappa B (NF-κB), AP-1, NRF2, PPAR-γ, β-catenin/Wnt and Sonic Hedgehog. This studied followed molecular docking based approach to verify the in-vitro activities of the said nutraceuticals against the cancer. Molecular Docking based approached provide a path towards the identification of novel ligands against these transcription factors. Based on the interaction of Cardamoninand capsaicin it was found to have an influencing role against the transcription factor like NF-κB andPPAR-γ. The interaction of Cardamoninwith NF- κBand capsaicinwith PPAR-γ provide a way toward structure-based virtual screening to identify novel ligands against the targets which could be very help full in successful chemotherapy of cancer. This study delivers structural features of nutraceuticals and its interactions against different transcription factors and gives a theoretical entry to use these compounds as a potential inhibitor against the transcription factors involved in cancer. PMID:28246465

  9. Binding studies of lophirone B with bovine serum albumin (BSA): Combination of spectroscopic and molecular docking techniques

    NASA Astrophysics Data System (ADS)

    Chaves, Otávio Augusto; da Silva, Veridiana A.; Sant'Anna, Carlos Maurício R.; Ferreira, Aurélio B. B.; Ribeiro, Tereza Auxiliadora N.; de Carvalho, Mário G.; Cesarin-Sobrinho, Dari; Netto-Ferreira, José Carlos

    2017-01-01

    The interaction between the transport protein bovine serum albumin (BSA) and the natural product lophirone B, was investigated by spectroscopic techniques combined with a computational method (molecular docking). From the KSV and kq values it was concluded that lophirone B quenches the fluorescence of BSA by dynamic and static mechanisms. The Ka values, of the order of 104 M-1, and the number of binding sites (n ≈ 1), indicate that the binding is moderate and there is just one main binding site in BSA for lophirone B. The negative ΔG° values are in accordance with the spontaneity of the process and the positive ΔH° and ΔS° values indicate that the binding is entropically driven; the main binding forces for the association BSA:lophirone B are probably lipophilic interactions. Circular dichroism (CD) studies show there is not a significant perturbation on the secondary structure of the albumin upon the binding process. In order to better understand the spectroscopic results, a computational method was applied: molecular docking suggests Trp-213 site, as the main binding site for the ligand. Lophirone B seems to be exposed to the aqueous media as well as accommodated inside the protein cavity, resulting in a moderate affinity for the albumin. The Arg-198, His-287, Lys-294 and Lys-439 residues are interacting via hydrogen bonding with lophirone B, whereas the interaction with Trp-213 residue occurs through a lipophilic interaction.

  10. Identification of the antiepileptic racetam binding site in the synaptic vesicle protein 2A by molecular dynamics and docking simulations.

    PubMed

    Correa-Basurto, José; Cuevas-Hernández, Roberto I; Phillips-Farfán, Bryan V; Martínez-Archundia, Marlet; Romo-Mancillas, Antonio; Ramírez-Salinas, Gema L; Pérez-González, Óscar A; Trujillo-Ferrara, José; Mendoza-Torreblanca, Julieta G

    2015-01-01

    Synaptic vesicle protein 2A (SV2A) is an integral membrane protein necessary for the proper function of the central nervous system and is associated to the physiopathology of epilepsy. SV2A is the molecular target of the anti-epileptic drug levetiracetam and its racetam analogs. The racetam binding site in SV2A and the non-covalent interactions between racetams and SV2A are currently unknown; therefore, an in silico study was performed to explore these issues. Since SV2A has not been structurally characterized with X-ray crystallography or nuclear magnetic resonance, a three-dimensional (3D) model was built. The model was refined by performing a molecular dynamics simulation (MDS) and the interactions of SV2A with the racetams were determined by docking studies. A reliable 3D model of SV2A was obtained; it reached structural equilibrium during the last 15 ns of the MDS (50 ns) with remaining structural motions in the N-terminus and long cytoplasmic loop. The docking studies revealed that hydrophobic interactions and hydrogen bonds participate importantly in ligand recognition within the binding site. Residues T456, S665, W666, D670 and L689 were important for racetam binding within the trans-membrane hydrophilic core of SV2A. Identifying the racetam binding site within SV2A should facilitate the synthesis of suitable radio-ligands to study treatment response and possibly epilepsy progression.

  11. Identification of the antiepileptic racetam binding site in the synaptic vesicle protein 2A by molecular dynamics and docking simulations

    PubMed Central

    Correa-Basurto, José; Cuevas-Hernández, Roberto I.; Phillips-Farfán, Bryan V.; Martínez-Archundia, Marlet; Romo-Mancillas, Antonio; Ramírez-Salinas, Gema L.; Pérez-González, Óscar A.; Trujillo-Ferrara, José; Mendoza-Torreblanca, Julieta G.

    2015-01-01

    Synaptic vesicle protein 2A (SV2A) is an integral membrane protein necessary for the proper function of the central nervous system and is associated to the physiopathology of epilepsy. SV2A is the molecular target of the anti-epileptic drug levetiracetam and its racetam analogs. The racetam binding site in SV2A and the non-covalent interactions between racetams and SV2A are currently unknown; therefore, an in silico study was performed to explore these issues. Since SV2A has not been structurally characterized with X-ray crystallography or nuclear magnetic resonance, a three-dimensional (3D) model was built. The model was refined by performing a molecular dynamics simulation (MDS) and the interactions of SV2A with the racetams were determined by docking studies. A reliable 3D model of SV2A was obtained; it reached structural equilibrium during the last 15 ns of the MDS (50 ns) with remaining structural motions in the N-terminus and long cytoplasmic loop. The docking studies revealed that hydrophobic interactions and hydrogen bonds participate importantly in ligand recognition within the binding site. Residues T456, S665, W666, D670 and L689 were important for racetam binding within the trans-membrane hydrophilic core of SV2A. Identifying the racetam binding site within SV2A should facilitate the synthesis of suitable radio-ligands to study treatment response and possibly epilepsy progression. PMID:25914622

  12. Inhibition of pro-/active MMP-2 by green tea catechins and prediction of their interaction by molecular docking studies.

    PubMed

    Chowdhury, Animesh; Nandy, Suman Kumar; Sarkar, Jaganmay; Chakraborti, Tapati; Chakraborti, Sajal

    2017-03-01

    Matrix metalloproteinases (MMPs) play a crucial role in developing different types of lung diseases, e.g., pulmonary arterial hypertension (PAH). Green tea polyphenolic catechins such as EGCG and ECG have been shown to ameliorate various types of diseases including PAH. Our present study revealed that among the four green tea catechins (EGCG, ECG, EC, and EGC), EGCG and ECG inhibit pro-/active MMP-2 activities in pulmonary artery smooth muscle cell (PASMC) culture supernatant. Based on the above, we investigated the interactions of pro-/active MMP-2 with the green tea catechins by computational methods. In silico analysis revealed a strong interaction of pro-/active MMP-2 with EGCG/ECG, and galloyl group has been observed to be responsible for this interaction. The in silico analysis corroborated our experimental observation that EGCG and ECG are active in preventing both the proMMP-2 and MMP-2 activities. Importantly, these two catechins appeared to be better inhibitors for proMMP-2 in comparison to MMP-2 as revealed by gelatin zymogram and also by molecular docking studies. In many type of cells, activation of proMMP-2 occurs via an increase in the level of MT1-MMP (MMP-14). We, therefore, determined the interactions of MT1-MMP with the green tea catechins by molecular docking analysis. The study revealed a strong interaction of MT1-MMP with EGCG/ECG, and galloyl group has been observed to be responsible for the interaction.

  13. Revealing interaction between sulfobutylether-β-cyclodextrin and reserpine by chemiluminescence and site-directed molecular docking.

    PubMed

    Xiong, Xunyu; Wu, Min; Zhao, Xinfeng; Song, Zhenghua

    2014-09-01

    The host-guest interaction between sulfobutylether-β-cyclodextrin (SBE-β-CD) and reserpine (RSP) is described using flow injection-chemiluminescence (FI-CL) and site-directed molecular docking methods. It was found that RSP could inhibit the CL intensity produced by a luminol/SBE-β-CD system. The decrease in CL intensity was logarithmic over an RSP concentration range of 0.03 to 700.0 nM, giving a regression equation of ∆I = 107.1lgCRES  + 186.1 with a detection limit of 10 pM (3σ). The CL assay was successfully applied in the determination of RSP in injection, saliva and urine samples with recoveries in the range 93.5-106.1%. Using the proposed CL model, the binding constant (KCD-R ) and the stoichiometric ratio of SBE-β-CD/RSP were calculated to be 7.4 × 10(6)  M(-1) and 1 : 1, respectively. Using molecular docking, it was confirmed that luminol binds to the small cavity of SBE-β-CD with a nonpolar interaction, while RSP targeted the larger cavity of SBE-β-CD and formed a 1 : 1 complex with hydrogen bonds. The proposed new CL method has the potential to become a powerful tool for revealing the host-guest interaction between CDs and drugs, as well as monitoring drugs with high sensitivity.

  14. Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents

    PubMed Central

    Ravula, Parameshwar; Vamaraju, Harinadha Babu; Paturi, Manichandrika; Chandra JN, Narendra Sharath; Kolli, Swetha

    2016-01-01

    A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity. PMID:27103897

  15. Study on the interaction of the epilepsy drug, zonisamide with human serum albumin (HSA) by spectroscopic and molecular docking techniques

    NASA Astrophysics Data System (ADS)

    Shahabadi, Nahid; Khorshidi, Aref; Moghadam, Neda Hossinpour

    2013-10-01

    In the present investigation, an attempt has been made to study the interaction of zonisamide (ZNS) with the transport protein, human serum albumin (HSA) employing UV-Vis, fluorometric, circular dichroism (CD) and molecular docking techniques. The results indicated that binding of ZNS to HSA caused strong fluorescence quenching of HSA through static quenching mechanism, hydrogen bonds and van der Waals contacts are the major forces in the stability of protein ZNS complex and the process of the binding of ZNS with HSA was driven by enthalpy (ΔH = -193.442 kJ mol-1). The results of CD and UV-Vis spectroscopy showed that the binding of this drug to HSA induced conformational changes in HSA. Furthermore, the study of molecular docking also indicated that zonisamide could strongly bind to the site I (subdomain IIA) of HSA mainly by hydrophobic interaction and there were hydrogen bond interactions between this drug and HSA, also known as the warfarin binding site.

  16. In silico designing breast cancer peptide vaccine for binding to MHC class I and II: A molecular docking study.

    PubMed

    Mahdavi, Manijeh; Moreau, Violaine

    2016-12-01

    Antigenic peptides or cancer peptide vaccines can be directly delivered to cancer patients to produce immunologic responses against cancer cells. Specifically, designed peptides can associate with Major Histocompatibility Complex (MHC) class I or II molecules on the cell surface of antigen presenting cells activating anti-tumor effector mechanisms by triggering helper T cell (Th) or cytotoxic T cells (CTL). In general, high binding to MHCs approximately correlates with in vivo immunogenicity. Consequently, a molecular docking technique was run on a library of novel discontinuous peptides predicted by PEPOP from Human epidermal growth factor receptor 2 (HER2 ECD) subdomain III. This technique is expected to improve the prediction accuracy in order to identify the best MHC class I and II binder peptides. Molecular docking analysis through GOLD identified the peptide 1412 as the best MHC binder peptide to both MHC class I and II molecules used in the study. The GOLD results predicted HLA-DR4, HLA-DP2 and TCR as the most often targeted receptors by the peptide 1412. These findings, based on bioinformatics analyses, can be exploited in further experimental analyses in vaccine design and cancer therapy to find possible proper approaches providing beneficial effects.

  17. Combined spectroscopies and molecular docking approach to characterizing the binding interaction between lisinopril and bovine serum albumin.

    PubMed

    Jiang, Min; Huang, Chuan-ren; Wang, Qi; Zhu, Ying-yao; Wang, Jing; Chen, Jun; Shi, Jie-hua

    2016-03-01

    To further understand the mode of action and pharmacokinetics of lisinopril, the binding interaction of lisinopril with bovine serum albumin (BSA) under imitated physiological conditions (pH 7.4) was investigated using fluorescence emission spectroscopy, synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD) and molecular docking methods. The results showed that the fluorescence quenching of BSA near 338 nm resulted from the formation of a lisinopril-BSA complex. The number of binding sites (n) for lisinopril binding on subdomain IIIA (site II) of BSA and the binding constant were ~ 1 and 2.04 × 10(4) M(-1), respectively, at 310 K. The binding of lisinopril to BSA induced a slight change in the conformation of BSA, which retained its α-helical structure. However, the binding of lisinopril with BSA was spontaneous and the main interaction forces involved were van der Waal's force and hydrogen bonding interaction as shown by the negative values of ΔG(0), ΔH(0) and ΔS(0) for the binding of lisinopril with BSA. It was concluded from the molecular docking results that the flexibility of lisinopril also played an important role in increasing the stability of the lisinopril-BSA complex.

  18. Insights into the structure and inhibition of Giardia intestinalis arginine deiminase: homology modeling, docking, and molecular dynamics studies.

    PubMed

    Trejo-Soto, Pedro Josué; Aguayo-Ortiz, Rodrigo; Yépez-Mulia, Lilián; Hernández-Campos, Alicia; Medina-Franco, José Luis; Castillo, Rafael

    2016-01-01

    Giardia intestinalis arginine deiminase (GiADI) is an important metabolic enzyme involved in the energy production and defense of this protozoan parasite. The lack of this enzyme in the human host makes GiADI an attractive target for drug design against G. intestinalis. One approach in the design of inhibitors of GiADI could be computer-assisted studies of its crystal structure, such as docking; however, the required crystallographic structure of the enzyme still remains unresolved. Because of its relevance, in this work, we present a three-dimensional structure of GiADI obtained from its amino acid sequence using the homology modeling approximation. Furthermore, we present an approximation of the most stable dimeric structure of GiADI identified through molecular dynamics simulation studies. An in silico analysis of druggability using the structure of GiADI was carried out in order to know if it is a good target for design and optimization of selective inhibitors. Potential GiADI inhibitors were identified by docking of a set of 3196 commercial and 19 in-house benzimidazole derivatives, and molecular dynamics simulation studies were used to evaluate the stability of the ligand-enzyme complexes.

  19. Design, synthesis, in silico toxicity prediction, molecular docking, and evaluation of novel pyrazole derivatives as potential antiproliferative agents.

    PubMed

    Ravula, Parameshwar; Vamaraju, Harinadha Babu; Paturi, Manichandrika; Chandra Jn, Narendra Sharath; Kolli, Swetha

    2016-01-01

    A new series of pyrazole derivatives were designed by docking into vascular endothelial growth factor receptor-2 (VEGFR-2) kinase active site. The designed compounds were synthesized and evaluated for in vitro antiproliferative activity against HT-29 colon and PC-3 prostate cancer cell lines, and angioinhibitory activity in chorioallantoic membrane (CAM) model. Based on the obtained antiproliferative activity results of in vitro and CAM assay, compounds 4b, 4c, 4f, 5b, 5c and 5f were selected, and tested for anticancer activity using in vivo ehrlich ascites carcinoma (EAC) bearing mice. Compound 5c showed the highest in vitro antiproliferative activity against HT-29 and PC-3 with IC50 values of 6.43 µM and 9.83 µM respectively and comparable to reference drug Doxorubicin. Results of in vivo anticancer activity revealed that compound 5c showed the highest percentage increase in life span ( %ILS), and mean survival time (MST) with 75.13 % and 32.4 ± 0.53 days respectively. Moreover, compound 5c demonstrated significant reduction of microvessel density (MVD) in CAM assay. In silico prediction of toxicities, and drug score profiles of designed compounds are promising. A correlation made between the results obtained by antiproliferative study and molecular docking studies suggest that the synthesized compounds may be beneficial as molecular scaffolds for antiproliferative activity.

  20. Investigation of the binding sites and orientation of caffeine on human serum albumin by surface-enhanced Raman scattering and molecular docking

    NASA Astrophysics Data System (ADS)

    Wang, Weinan; Zhang, Wei; Duan, Yaokai; Jiang, Yong; Zhang, Liangren; Zhao, Bing; Tu, Pengfei

    2013-11-01

    Fluorescence, normal Raman and surface-enhanced Raman scattering (SERS) were introduced to explore the absorptive geometry of caffeine on Human Serum Albumin (HSA) at physiological condition. The molecular docking was also employed to make a better understanding of the interaction between caffeine and HSA as well as to elucidate the detailed information of the major binding site. The results showed that caffeine could bind to HSA via the hydrophobic force of aromatic stacking and the main binding group on caffeine could be the pyrimidine ring. In addition, a consecutive set of changes in the orientation of caffeine molecule had been demonstrated during the process of caffeine binding to HSA, and the primary binding site was considered to be a hydrophobic cavity formed by Leu198, Lys199, Ser202, Phe211, Trp214, Val344, Ser454 and Leu481 in domain II.

  1. 3D-QSAR and molecular docking studies on derivatives of MK-0457, GSK1070916 and SNS-314 as inhibitors against Aurora B kinase.

    PubMed

    Zhang, Baidong; Li, Yan; Zhang, Huixiao; Ai, Chunzhi

    2010-11-02

    Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q(2) = 0.605, r(2) (pred) = 0.826), (q(2) = 0.52, r(2) (pred) = 0.798) and (q(2) = 0.582, r(2) (pred) = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.

  2. Molecular dynamics simulations and docking enable to explore the biophysical factors controlling the yields of engineered nanobodies.

    PubMed

    Soler, Miguel A; de Marco, Ario; Fortuna, Sara

    2016-10-10

    Nanobodies (VHHs) have proved to be valuable substitutes of conventional antibodies for molecular recognition. Their small size represents a precious advantage for rational mutagenesis based on modelling. Here we address the problem of predicting how Camelidae nanobody sequences can tolerate mutations by developing a simulation protocol based on all-atom molecular dynamics and whole-molecule docking. The method was tested on two sets of nanobodies characterized experimentally for their biophysical features. One set contained point mutations introduced to humanize a wild type sequence, in the second the CDRs were swapped between single-domain frameworks with Camelidae and human hallmarks. The method resulted in accurate scoring approaches to predict experimental yields and enabled to identify the structural modifications induced by mutations. This work is a promising tool for the in silico development of single-domain antibodies and opens the opportunity to customize single functional domains of larger macromolecules.

  3. Impact of the subtle differences in MMP-12 structure on Glide-based molecular docking for pose prediction of inhibitors

    NASA Astrophysics Data System (ADS)

    Zhang, Huan; Wang, Yajing; Xu, Feng

    2014-11-01

    Human MMP-12 is involved in many aspects of disease pathology. Substantial efforts have been made to develop MMP-12 inhibitors. However, the mechanism of some MMP-12 inhibitors is still unclear. Recently, the method of molecular modeling was used to explore the mechanism, but selecting the best candidate among the wealth of MMP-12 structures poses a challenge. In this study, we attempted to identify several criteria to predict the most appropriate MMP-12 PDB ID for enzyme-ligand interaction studies based on cross-docking by Glide. Furthermore, the parameters from PDB files such as R-free, resolution, B factor, and the molecular volume of the ligand in the complex can provide useful clues for choosing a suitable approximate initial model for pose prediction for MMP-12 inhibitors. This work might also provide a useful reference for other drug targets.

  4. Molecular dynamics simulations and docking enable to explore the biophysical factors controlling the yields of engineered nanobodies

    PubMed Central

    Soler, Miguel A.; de Marco, Ario; Fortuna, Sara

    2016-01-01

    Nanobodies (VHHs) have proved to be valuable substitutes of conventional antibodies for molecular recognition. Their small size represents a precious advantage for rational mutagenesis based on modelling. Here we address the problem of predicting how Camelidae nanobody sequences can tolerate mutations by developing a simulation protocol based on all-atom molecular dynamics and whole-molecule docking. The method was tested on two sets of nanobodies characterized experimentally for their biophysical features. One set contained point mutations introduced to humanize a wild type sequence, in the second the CDRs were swapped between single-domain frameworks with Camelidae and human hallmarks. The method resulted in accurate scoring approaches to predict experimental yields and enabled to identify the structural modifications induced by mutations. This work is a promising tool for the in silico development of single-domain antibodies and opens the opportunity to customize single functional domains of larger macromolecules. PMID:27721441

  5. Molecular dynamics simulations and docking enable to explore the biophysical factors controlling the yields of engineered nanobodies

    NASA Astrophysics Data System (ADS)

    Soler, Miguel A.; De Marco, Ario; Fortuna, Sara

    2016-10-01

    Nanobodies (VHHs) have proved to be valuable substitutes of conventional antibodies for molecular recognition. Their small size represents a precious advantage for rational mutagenesis based on modelling. Here we address the problem of predicting how Camelidae nanobody sequences can tolerate mutations by developing a simulation protocol based on all-atom molecular dynamics and whole-molecule docking. The method was tested on two sets of nanobodies characterized experimentally for their biophysical features. One set contained point mutations introduced to humanize a wild type sequence, in the second the CDRs were swapped between single-domain frameworks with Camelidae and human hallmarks. The method resulted in accurate scoring approaches to predict experimental yields and enabled to identify the structural modifications induced by mutations. This work is a promising tool for the in silico development of single-domain antibodies and opens the opportunity to customize single functional domains of larger macromolecules.

  6. Ole e 13 is the unique food allergen in olive: Structure-functional, substrates docking, and molecular allergenicity comparative analysis.

    PubMed

    Jimenez-Lopez, J C; Robles-Bolivar, P; Lopez-Valverde, F J; Lima-Cabello, E; Kotchoni, S O; Alché, J D

    2016-05-01

    Thaumatin-like proteins (TLPs) are enzymes with important functions in pathogens defense and in the response to biotic and abiotic stresses. Last identified olive allergen (Ole e 13) is a TLP, which may also importantly contribute to food allergy and cross-allergenicity to pollen allergen proteins. The goals of this study are the characterization of the structural-functionality of Ole e 13 with a focus in its catalytic mechanism, and its molecular allergenicity by extensive analysis using different molecular computer-aided approaches covering a) functional-regulatory motifs, b) comparative study of linear sequence, 2-D and 3D structural homology modeling, c) molecular docking with two different β-D-glucans, d) conservational and evolutionary analysis, e) catalytic mechanism modeling, and f) IgE-binding, B- and T-cell epitopes identification and comparison to other allergenic TLPs. Sequence comparison, structure-based features, and phylogenetic analysis identified Ole e 13 as a thaumatin-like protein. 3D structural characterization revealed a conserved overall folding among plants TLPs, with mayor differences in the acidic (catalytic) cleft. Molecular docking analysis using two β-(1,3)-glucans allowed to identify fundamental residues involved in the endo-1,3-β-glucanase activity, and defining E84 as one of the conserved residues of the TLPs responsible of the nucleophilic attack to initiate the enzymatic reaction and D107 as proton donor, thus proposing a catalytic mechanism for Ole e 13. Identification of IgE-binding, B- and T-cell epitopes may help designing strategies to improve diagnosis and immunotherapy to food allergy and cross-allergenic pollen TLPs.

  7. Study on Interaction between 5-Bromo-4-thio-2‧-deoxyuridine and human serum albumin by spectroscopy and molecular docking

    NASA Astrophysics Data System (ADS)

    Zhang, Xiaohui; Gao, Ruiqi; Li, Depeng; Yin, Hongyan; Zhang, Juling; Cao, Hongyu; Zheng, Xuefang

    2015-02-01

    The interaction between 5-Bromo-4-thio-2‧-deoxyuridine (4-SBrdU) and human serum albumin (HSA) was investigated by the methods of UV-vis absorbance, fluorescence and circular dichroism (CD) spectroscopy and molecular docking under simulative physiological conditions. The results showed that the quenching mechanism of HAS by 4-SBrdU was dynamic fluorescence quenching, hydrophobic interaction was the main intermolecular force based on thermodynamic data, the fluorescence experimental results were in agreement with results obtained by the molecular docking study.

  8. Molecular modeling and docking simulations of scorpion toxins and related analogs on human SKCa2 and SKCa3 channels.

    PubMed

    Andreotti, Nicolas; di Luccio, Eric; Sampieri, François; De Waard, Michel; Sabatier, Jean-Marc

    2005-07-01

    The small-conductance Ca2+-activated K+ (SKCa) channels modulate cytosolic Ca2+ concentration in excitable and non-excitable tissues by regulating the membrane potential and are responsible of slow action potential after hyperpolarization that inhibits cell firing. Among these, human SKCa2 and SKCa3 channels differ in the pore region by only two residues: Ala331 and Asn367 (human small-conductance calcium-activated potassium channel, hSKCa2) instead of Val485 and His521 (hSKCa3). To design highly selective blockers of hSKCa channels, a number of known hSKCa2 and/or hSKCa3-active peptides (i.e. scorpion toxins and analogs thereof) were analyzed for their interactions and selectivities toward these channels. Molecular models of hSKCa2 and hSKCa3 channels (S5-H5-S6 portion) were generated, and scorpion toxins/peptides of unsolved three-dimensional (3D) structures were modeled. Models of toxin-channel complexes were generated by the bimolecular complex generation with global evaluation, and ranking (BiGGER) docking software and selected by using a screening method of the docking solutions. A high degree of correlation was found to exist between docking energies and experimental Kd values of peptides that blocked hSKCa2 and/or hSKCa3 channels, suggesting it could be appropriate to predict Kd values of other bioactive peptides. The best scoring complexes were also used to identify key residues of both interacting partners, indicating that such an approach should help the design of more active and/or selective peptide blockers of targeted ion channels.

  9. In Silico Exploration of 1,7-Diazacarbazole Analogs as Checkpoint Kinase 1 Inhibitors by Using 3D QSAR, Molecular Docking Study, and Molecular Dynamics Simulations.

    PubMed

    Gao, Xiaodong; Han, Liping; Ren, Yujie

    2016-05-05

    Checkpoint kinase 1 (Chk1) is an important serine/threonine kinase with a self-protection function. The combination of Chk1 inhibitors and anti-cancer drugs can enhance the selectivity of tumor therapy. In this work, a set of 1,7-diazacarbazole analogs were identified as potent Chk1 inhibitors through a series of computer-aided drug design processes, including three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, and molecular dynamics simulations. The optimal QSAR models showed significant cross-validated correlation q² values (0.531, 0.726), fitted correlation r² coefficients (higher than 0.90), and standard error of prediction (less than 0.250). These results suggested that the developed models possess good predictive ability. Moreover, molecular docking and molecular dynamics simulations were applied to highlight the important interactions between the ligand and the Chk1 receptor protein. This study shows that hydrogen bonding and electrostatic forces are key interactions that confer bioactivity.

  10. Quantum.Ligand.Dock: protein–ligand docking with quantum entanglement refinement on a GPU system

    PubMed Central

    Kantardjiev, Alexander A.

    2012-01-01

    Quantum.Ligand.Dock (protein–ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein–ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments—the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein–ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pKa values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html. PMID:22669908

  11. Quantum.Ligand.Dock: protein-ligand docking with quantum entanglement refinement on a GPU system.

    PubMed

    Kantardjiev, Alexander A

    2012-07-01

    Quantum.Ligand.Dock (protein-ligand docking with graphic processing unit (GPU) quantum entanglement refinement on a GPU system) is an original modern method for in silico prediction of protein-ligand interactions via high-performance docking code. The main flavour of our approach is a combination of fast search with a special account for overlooked physical interactions. On the one hand, we take care of self-consistency and proton equilibria mutual effects of docking partners. On the other hand, Quantum.Ligand.Dock is the the only docking server offering such a subtle supplement to protein docking algorithms as quantum entanglement contributions. The motivation for development and proposition of the method to the community hinges upon two arguments-the fundamental importance of quantum entanglement contribution in molecular interaction and the realistic possibility to implement it by the availability of supercomputing power. The implementation of sophisticated quantum methods is made possible by parallelization at several bottlenecks on a GPU supercomputer. The high-performance implementation will be of use for large-scale virtual screening projects, structural bioinformatics, systems biology and fundamental research in understanding protein-ligand recognition. The design of the interface is focused on feasibility and ease of use. Protein and ligand molecule structures are supposed to be submitted as atomic coordinate files in PDB format. A customization section is offered for addition of user-specified charges, extra ionogenic groups with intrinsic pK(a) values or fixed ions. Final predicted complexes are ranked according to obtained scores and provided in PDB format as well as interactive visualization in a molecular viewer. Quantum.Ligand.Dock server can be accessed at http://87.116.85.141/LigandDock.html.

  12. Synthesis, biological evaluation, and molecular docking studies of xanthone sulfonamides as ACAT inhibitors.

    PubMed

    Li, Xiang; Zou, Yan; Zhao, Qingjie; Yang, Yan; Wu, Maocheng; Huang, Ting; Hu, Honggang; Wu, Qiuye

    2015-03-01

    Three series of xanthone sulfonamides were synthesized, and their inhibitory activities against acyl-CoA: cholesterol acyltransferase (ACAT) were evaluated. Results showed that most of the title compounds exhibited strong inhibitory activity against ACAT, of which compounds 1c, 1e, 1f, 2d, 2e, and 3d were proved to be more active than the positive control Sandoz 58-035. Computational docking experiments indicated that the interaction between inhibitors and ACAT contained the H-bond interaction, the hydrophobic interaction, and the narrow hydrophobic cleft.

  13. Synthesis, antimalarial activity and molecular docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives.

    PubMed

    Bhat, Hans Raj; Singh, Udaya Pratap; Thakur, Anjali; Kumar Ghosh, Surajit; Gogoi, Kabita; Prakash, Anil; Singh, Ramendra K

    2015-10-01

    A series of novel hybrid 4-aminoquinoline 1,3,5-triazine derivatives was synthesized in a five-steps reaction and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (RKL-2) strains of Plasmodium falciparum. Entire synthetic derivatives showed higher antimalarial activity on the sensitive strain while two compounds, viz., 9a and 9c displayed good activity against both the strains of P. falciparum. The observed activity was further substantiated by docking study on both wild and qradruple mutant type P. falciparum dihydrofolate reductase-thymidylate synthase (pf-DHFR-TS).

  14. QSAR analyses of organophosphates for insecticidal activity and its in-silico validation using molecular docking study.

    PubMed

    Niraj, Ravi Ranjan Kumar; Saini, Vandana; Kumar, Ajit

    2015-11-01

    The present work was carried out to design and develop novel QSAR models using 2D-QSAR and 3D-QSAR with CoMFA methodology for prediction of insecticidal activity of organophosphate (OP) molecules. The models were validated on an entirely different external dataset of in-house generated combinatorial library of OPs, by completely different computational approach of molecular docking against the target AChE protein of Musca domestica. The dock scores were observed to be in good correlation with 2D-QSAR and 3D-QSAR with CoMFA predicted activities and had the correlation coefficients (r(2)) of -0.62 and -0.63, respectively. The activities predicted by 2D-QSAR and 3D-QSAR with CoMFA were also observed to be highly correlated with r(2)=0.82. Also, the combinatorial library molecules were screened for toxicity in non-target organisms and degradability using USEPA-EPI Suite. The work was first step towards computer aided design and development of novel OP pesticide candidates with good insecticidal property but lower toxicity in non-targeted organisms and having biodegradation potential.

  15. Pharmacophore modeling, 3D-QSAR and molecular docking studies of benzimidazole derivatives as potential FXR agonists.

    PubMed

    Sindhu, Thangaraj; Srinivasan, Pappu

    2014-08-01

    Farnesoid X receptor (FXR) is a potential therapeutic target for the treatment of diabetes mellitus. Atom-based three-dimensional quantitative structure activity relationship (3D-QSAR) models were developed for a series of 48 benzimidazole-based agonists of FXR. A total of five pharmacophore hypotheses were generated based on the survival score to build QSAR models. HHHRR was considered as a best model that consisted of three hydrophobic features (H) and two aromatic rings (R). The best hypothesis, HHHRR yielded a 3D-QSAR model with good statistical value (R(2)) of 0.8974 for a training set of 39 compounds and also showed good predictive power with correlation coefficient (Q(2)) of 0.7559 for a test set of nine compounds. Furthermore, molecular docking simulation was performed to understand the binding affinity of 48 benzimidazole-based compounds against the active site of human FXR protein. Docking results revealed that both the most active and least active compounds showed similar binding mode to the experimentally observed binding mode of co-crystallized ligand. The generated 3D contour maps revealed the structure activity relationship of the compounds. Substitution effects at different positions of benzimidazole derivatives would lead to the discovery of new agonists against human FXR protein.

  16. Inhibitory mode of indole-2-carboxamide derivatives against HLGPa: molecular docking and 3D-QSAR analyses.

    PubMed

    Liu, Guixia; Zhang, Zhenshan; Luo, Xiaomin; Shen, Jianhua; Liu, Hong; Shen, Xu; Chen, Kaixian; Jiang, Hualiang

    2004-08-01

    The interaction of a series of indole-2-carboxamide compounds with human liver glycogen phosphorylase a (HLGPa) have been studied employing molecular docking and 3D-QSAR approaches. The Lamarckian Genetic Algorithm (LGA) of AutoDock 3.0 was employed to locate the binding orientations and conformations of the inhibitors interacting with HLGPa. The binding models were demonstrated in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding. The very similar binding conformations of these inhibitors show that they interact with HLGPa in a very similar way. Good correlations between the calculated interaction free energies and experimental inhibitory activities suggest that the binding conformations of these inhibitors are reasonable. The structural and energetic differences in inhibitory potencies of indole-2-carboxamide compounds were reasonably explored. Using the binding conformations of indole-2-carboxamides, consistent and highly predictive 3D-QSAR models were developed by CoMFA and CoMSIA analyses. The q2 values are 0.697 and 0.622 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by four compounds that were not included in the training set. Mapping these models back to the topology of the active site of HLGPa leads to a better understanding of the vital indole-2-carboxamide-HLGPa interactions. Structure-based investigations and the final 3D-QSAR results provide clear guidelines and accurate activity predictions for novel inhibitor design.

  17. Anti-angiogenic potential of trypsin inhibitor purified from Cucumis melo seeds: Homology modeling and molecular docking perspective.

    PubMed

    Rasouli, Hassan; Parvaneh, Sharham; Mahnam, Azadeh; Rastegari-Pouyani, Mohsen; Hoseinkhani, Zohreh; Mansouri, Kamran

    2017-03-01

    Melons have a good source of protease inhibitors. Its fruit and seeds have been used as a traditional medicine. However, its effects on angiogenesis and mechanism of its action remain elusive. Herein trypsin inhibitor from aqueous extract of C. melo seeds (TICMS) was purified. Its effects on different steps of angiogenesis were evaluated. Also, we examined its effects on migration and angiogenesis of endothelial cells. Three dimensional model of TICMS protein was accurately built in which TICMS docked to αVβ3 integrin and VEGFR1. Electrophoresis analysis of the purified protein revealed a single band with a molecular mass of about 3kDa. Treatment with TICMS at six doses resulted in a significant decrease of endothelial cell proliferation with an IC50 value of about 20μg/ml. Tubulogenesis assay revealed that a dose dependent anti-angiogenic activity of TICMS (5-40μg/ml). Also, TICMS had inhibitory effects on VEGF, MMP-2 and MMP-9 secretion. Our docking result speculated that TICMS could bind to the cleft between the αVβ3 integrin and it able to decrease the activity of this receptor. The TICMS was also able to interact with VEGFR1 receptor, but with low probability. Based on our study, TICMS could be used as a specific angiogenesis inhibitor.

  18. Ionic liquid mediated synthesis of mono- and bis-spirooxindole-hexahydropyrrolidines as cholinesterase inhibitors and their molecular docking studies.

    PubMed

    Kia, Yalda; Osman, Hasnah; Kumar, Raju Suresh; Basiri, Alireza; Murugaiyah, Vikneswaran

    2014-02-15

    One pot, three-component reaction of 1-acryloyl-3,5-bisarylmethylidenepiperidin-4-ones with isatin and sarcosine in molar ratios of 1:1:1 and 1:2:2 furnished to mono- and bis-spiropyrrolidine heterocyclic hybrids comprising functionalized piperidine, pyrrolidine and oxindole structural motifs. Both mono and bis-spiropyrrolidines displayed good inhibitory activity against acetylcholinesterase (AChE) with IC₅₀ values of 2.36-9.43 μM. For butyrylcholinesterase (BChE), mono-cycloadducts in series 8 with IC₅₀ values of lower than 10 μM displayed better inhibitory activities than their bis-cycloadduct analogs in series 9 with IC₅₀ values of 7.44-19.12 μM. The cycloadducts 9j and 8e were found to be the most potent AChE and BChE inhibitors with IC₅₀ values of 2.35 and 3.21 μM, respectively. Compound 9j was found to be competitive inhibitor of AChE while compound 8e was a mixed-mode inhibitor of BChE with calculated Ki values of 2.01 and 6.76 μM, respectively. Molecular docking on Torpedo californica AChE and human BChE showed good correlation between IC₅₀ values and free binding energy values of the synthesized compounds docked into the active site of the enzymes.

  19. Spectroscopic and reactive properties of a newly synthesized quinazoline derivative: Combined experimental, DFT, molecular dynamics and docking study

    NASA Astrophysics Data System (ADS)

    El-Azab, Adel S.; Mary, Y. Shyma; Mary, Y. Sheena; Panicker, C. Yohannan; Abdel-Aziz, Alaa A.-M.; Mohamed, Menshawy A.; Armaković, Stevan; Armaković, Sanja J.; Van Alsenoy, Christian

    2017-04-01

    The molecular geometry, the normal mode wavenumbers and corresponding vibrational assignments, natural bond orbital analysis and the HOMO-LUMO analysis of 3-(4-oxo-phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)propanamide were performed by B3LYP level of theory using the 6-311++G(d,p)(5D,7F) basis set. The experimentally obtained wavenumbers are in agreement with the theoretically predicted wavenumbrs. From the MEP plot it is evident that the negative charge covers carbonyl group, mono substituted phenyl ring, O59 atom and the positive region is over the nitrogen atoms and hydrogen atoms. NLO behavior of the title molecule was investigated by the determination of the first and second order hyperpolarizabilities. The molecular orbitals and molecular electrostatic potential map are also reported. The NMR spectra and Fukui indices are also analyzed. Molecule sites important from the aspect of reactivity have been determined by calculations of average local ionization energy (ALIE), Fukui functions and bond dissociation energies (BDE). BDE for hydrogen abstraction served us to investigate the possibility for autoxidation mechanism of the investigated molecule. Molecular dynamics (MD) simulations were used in order to investigate which atoms of the title molecule have the most pronounced interactions with water molecules. Molecular docking studies reveal that the inhibitor forms a stable complex with HNE as is evident from the binding affinity -10.9 kcal/mol and the results suggest that the compound exhibit inhibitory activity against HNE.

  20. Experimental and molecular docking studies on DNA binding interaction of adefovir dipivoxil: Advances toward treatment of hepatitis B virus infections

    NASA Astrophysics Data System (ADS)

    Shahabadi, Nahid; Falsafi, Monireh

    The toxic interaction of adefovir dipivoxil with calf thymus DNA (CT-DNA) was investigated in vitro under simulated physiological conditions by multi-spectroscopic techniques and molecular modeling study. The fluorescence spectroscopy and UV absorption spectroscopy indicated drug interacted with CT-DNA in a groove binding mode. The binding constant of UV-visible and the number of binding sites were 3.33 ± 0.2 × 104 L mol-1and 0.99, respectively. The fluorimetric studies showed that the reaction between the drug and CT-DNA is exothermic (ΔH = 34.4 kJ mol-1; ΔS = 184.32 J mol-1 K-1). Circular dichroism spectroscopy (CD) was employed to measure the conformational change of CT-DNA in the presence of adefovir dipivoxil, which verified the groove binding mode. Furthermore, the drug induces detectable changes in its viscosity. The molecular modeling results illustrated that adefovir strongly binds to groove of DNA by relative binding energy of docked structure -16.83 kJ mol-1. This combination of multiple spectroscopic techniques and molecular modeling methods can be widely used in the investigation on the toxic interaction of small molecular pollutants and drugs with bio macromolecules, which contributes to clarify the molecular mechanism of toxicity or side effect in vivo.

  1. Molecular Dynamics in Mixed Solvents Reveals Protein-Ligand Interactions, Improves Docking, and Allows Accurate Binding Free Energy Predictions.

    PubMed

    Arcon, Juan Pablo; Defelipe, Lucas A; Modenutti, Carlos P; López, Elias D; Alvarez-Garcia, Daniel; Barril, Xavier; Turjanski, Adrián G; Martí, Marcelo A

    2017-03-31

    One of the most important biological processes at the molecular level is the formation of protein-ligand complexes. Therefore, determining their structure and underlying key interactions is of paramount relevance and has direct applications in drug development. Because of its low cost relative to its experimental sibling, molecular dynamics (MD) simulations in the presence of different solvent probes mimicking specific types of interactions have been increasingly used to analyze protein binding sites and reveal protein-ligand interaction hot spots. However, a systematic comparison of different probes and their real predictive power from a quantitative and thermodynamic point of view is still missing. In the present work, we have performed MD simulations of 18 different proteins in pure water as well as water mixtures of ethanol, acetamide, acetonitrile and methylammonium acetate, leading to a total of 5.4 μs simulation time. For each system, we determined the corresponding solvent sites, defined as space regions adjacent to the protein surface where the probability of finding a probe atom is higher than that in the bulk solvent. Finally, we compared the identified solvent sites with 121 different protein-ligand complexes and used them to perform molecular docking and ligand binding free energy estimates. Our results show that combining solely water and ethanol sites allows sampling over 70% of all possible protein-ligand interactions, especially those that coincide with ligand-based pharmacophoric points. Most important, we also show how the solvent sites can be used to significantly improve ligand docking in terms of both accuracy and precision, and that accurate predictions of ligand binding free energies, along with relative ranking of ligand affinity, can be performed.

  2. Synthesis, spectroscopic investigations (X-ray, NMR and TD-DFT), antimicrobial activity and molecular docking of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone.

    PubMed

    Barakat, Assem; Ghabbour, Hazem A; Al-Majid, Abdullah Mohammed; Soliman, Saied M; Ali, M; Mabkhot, Yahia Nasser; Shaik, Mohammed Rafi; Fun, Hoong-Kun

    2015-07-21

    The synthesis of 2,6-bis(hydroxy(phenyl)methyl)cyclohexanone 1 is described. The molecular structure of the title compound 1 was confirmed by NMR, FT-IR, MS, CHN microanalysis, and X-ray crystallography. The molecular structure was also investigated by a set of computational studies and found to be in good agreement with the experimental data obtained from the various spectrophotometric techniques. The antimicrobial activity and molecular docking of the synthesized compound was investigated.

  3. A mechanistic approach to explore novel HDAC1 inhibitor using pharmacophore modeling, 3D- QSAR analysis, molecular docking, density functional and molecular dynamics simulation study.

    PubMed

    Choubey, Sanjay K; Jeyaraman, Jeyakanthan

    2016-11-01

    Deregulated epigenetic activity of Histone deacetylase 1 (HDAC1) in tumor development and carcinogenesis pronounces it as promising therapeutic target for cancer treatment. HDAC1 has recently captured the attention of researchers owing to its decisive role in multiple types of cancer. In the present study a multistep framework combining ligand based 3D-QSAR, molecular docking and Molecular Dynamics (MD) simulation studies were performed to explore potential compound with good HDAC1 binding affinity. Four different pharmacophore hypotheses Hypo1 (AADR), Hypo2 (AAAH), Hypo3 (AAAR) and Hypo4 (ADDR) were obtained. The hypothesis Hypo1 (AADR) with two hydrogen bond acceptors (A), one hydrogen bond donor (D) and one aromatics ring (R) was selected to build 3D-QSAR model on the basis of statistical parameter. The pharmacophore hypothesis produced a statistically significant QSAR model, with co-efficient of correlation r(2)=0.82 and cross validation correlation co-efficient q(2)=0.70. External validation result displays high predictive power with r(2) (o) value of 0.88 and r(2) (m) value of 0.58 to carry out further in silico studies. Virtual screening result shows ZINC70450932 as the most promising lead where HDAC1 interacts with residues Asp99, His178, Tyr204, Phe205 and Leu271 forming seven hydrogen bonds. A high docking score (-11.17kcal/mol) and lower docking energy -37.84kcal/mol) displays the binding efficiency of the ligand. Binding free energy calculation was done using MM/GBSA to access affinity of ligands towards protein. Density Functional Theory was employed to explore electronic features of the ligands describing intramolcular charge transfer reaction. Molecular dynamics simulation studies at 50ns display metal ion (Zn)-ligand interaction which is vital to inhibit the enzymatic activity of the protein.

  4. Molecular docking of opiates and opioid peptides, a tool for the design of selective agonists and antagonists, and for the investigation of atypical ligand-receptor interactions.

    PubMed

    Gentilucci, L; Tolomelli, A; De Marco, R; Artali, R

    2012-01-01

    In the last years, molecular docking emerged as a powerful tool to investigate the interactions between opioid ligands and their receptors, thus driving the design and development of new selective agonists or antagonists of therapeutic interest. This review especially covers the most representative and recent comparative molecular docking analyses of structurally related compounds, as well as of agonists and antagonists within the active and inactive states of the receptors. The comparative analyses gave important information on the structural determinants responsible for the affinity and selectivity of the ligands, and defined the features responsible for the activation of the receptors. A special section is dedicated to the analyses of recently discovered, unusual agonists lacking of the tyramine pharmacophore, such as Salvinorin A, and the cyclopeptides which comprise the D-Trp-Phe pharmacophoric motif. For the atypical structure of these compounds, the docking proved to be essential to disclose how they interact with and activate the receptors.

  5. Interaction of human chymase with ginkgolides, terpene trilactones of Ginkgo biloba investigated by molecular docking simulations.

    PubMed

    Dubey, Amit; Marabotti, Anna; Ramteke, Pramod W; Facchiano, Angelo

    2016-04-29

    The search for natural chymase inhibitors has a good potential to provide a novel therapeutic approach against the cardiovascular diseases and other heart ailments. We selected from literature 20 promising Ginkgo biloba compounds, and tested them for their potential ability to bind chymase enzyme using docking and a deep analysis of surface pocket features. Docking results indicated that the compounds may interact with the active site of human chymase, with favorable distinct interactions with important residues Lys40, His57, Lys192, Phe191, Val146, Ser218, Gly216, and Ser195. In particular, proanthocyanidin is the one with the best-predicted binding energy, with seven hydrogen bonds. Interestingly, all active G. biloba compounds have formed the hydrogen bond interactions with the positively charged Lys192 residue at the active site, involved in the mechanism of pH enhancement for the cleavage of angiotensin I site. Ginkgolic acid and proanthocyanidin have better predicted binding energy towards chymase than other serine proteases, i.e kallikrein, tryptase and elastase, suggesting specificity for chymase inhibition. Our study suggests these G. biloba compounds are a promising starting point for developing chymase inhibitors for the potential development of future drugs.

  6. Molecular docking studies of anti-cancerous candidates in Hippophae rhamnoides and Hippophae salicifolia

    PubMed Central

    Usha, Talambedu; Middha, Sushil Kumar; Goyal, Arvind Kumar; Karthik, Mahesh; Manoj, DA; Faizan, Syed; Goyal, Peyush; Prashanth, HP; Pande, Veena

    2014-01-01

    Abstract Actinorhizal plants contain numerous antioxidants that may play a crucial role in preventing the formation of tumors. H-Ras p21, a member of the Ras-GTPase family, is a promising target to treat various kinds of cancers. An in silico docking study was carried out to identify the inhibitory potential of compounds of these plants against H-Ras by using Discovery Studio 3.5 and by using Autodock 4.2. Docking studies revealed that four compounds, isorhamnetin-7-rhamnoside, quercetin-3-glucoside-7-rhamnoside (present in H. rhamnoides), zeaxanthin, and translutein (present in H. salicifolia) significantly bind with binding energies −17.1534, −14.7936, −10.2105 and −17.2217 Kcal/mol, respectively, even though they slightly deviate from Lipinski's rule. Absorption, distribution, metabolism, excretion and toxicity (ADME/tox) analyses of these compounds and their stereoisomers showed that they were less toxic and non-mutagenic. Amongst them, isorhamntein-7-rhamnoside showed hepatotoxicity. Hence, these compounds can be further investigated in vivo to optimize their formulation and concentration and to develop potential chemical entities for the prevention and treatment of cancers. PMID:25332713

  7. Molecular Modeling and Docking Study to Elucidate Novel Chikungunya Virus nsP2 Protease Inhibitors.

    PubMed

    Agarwal, T; Asthana, Somya; Bissoyi, A

    2015-01-01

    Chikungunya is one of the tropical viral infections that severely affect the Asian and African countries. Absence of any suitable drugs or vaccines against Chikungunya virus till date makes it essential to identify and develop novel leads for the same. Recently, nsP2 cysteine protease has been classified as a crucial drug target to combat infections caused by Alphaviruses including Chikungunya virus due to its involvement viral replication. Here in, we investigated the structural aspects of the nsP2 protease through homology modeling based on nsP2 protease from Venezuelan equine encephalitis virus. Further, the ligands were virtually screened based on various pharmacological, ADME/Tox filters and subjected to docking with the modeled Chikungunya nsP2 protease using AutoDock4.2. The interaction profiling of ligand with the protein was carried out using LigPlot(+). The results demonstrated that the ligand with PubChem Id (CID_5808891) possessed highest binding affinity towards Chikungunya nsP2 protease with a good interaction profile with the active site residues. We hereby propose that these compounds could inhibit the nsP2 protease by binding to its active site. Moreover, they may provide structural scaffold for the design of novel leads with better efficacy and specificity for the nsP2 protease.

  8. Molecular docking and panicolytic effect of 8-prenylnaringenin in the elevated T-maze.

    PubMed

    Bagatin, Mariane Cristovão; Tozatti, Camila Santos Suniga; Abiko, Layara Akemi; Yamazaki, Diego Alberto dos Santos; Silva, Priscila Rebeca Alves; Perego, Leonardo Martins; Audi, Elisabeth Aparecida; Seixas, Flavio Augusto Vicente; Basso, Ernani Abicht; Gauze, Gisele de Freitas

    2014-01-01

    The purpose of this study was to investigate the effects of the chronic administration of a racemic mixture of 8-prenylnaringenin (8-PN) on rats submitted to the elevated T-maze (ETM) model of generalized anxiety and panic disorders. The selective serotonin (SERT) reuptake inhibitor fluoxetine was used as a positive control. Rat locomotion was assessed in a circular arena following each drug treatment. The administration of racemic 8-PN for 21 d in rats increased one-way escape latencies from the ETM open arm, indicating a panicolytic effect. To evaluate the interactions of 8-PN with monoamine transporters, a docking study was performed for both the R and S configurations of 8-PN towards SERT, norepinephrine (NET) and dopamine transporters (DAT). The application of the docking protocol showed that (R)-8-PN provides greater affinity to all transporters than does the S enantiomer. This result suggests that enantiomer (R)-8-PN is the active form in the in vivo test of the racemic mixture.

  9. Molecular Modeling and Docking Study to Elucidate Novel Chikungunya Virus nsP2 Protease Inhibitors

    PubMed Central

    Agarwal, T.; Asthana, Somya; Bissoyi, A.

    2015-01-01

    Chikungunya is one of the tropical viral infections that severely affect the Asian and African countries. Absence of any suitable drugs or vaccines against Chikungunya virus till date makes it essential to identify and develop novel leads for the same. Recently, nsP2 cysteine protease has been classified as a crucial drug target to combat infections caused by Alphaviruses including Chikungunya virus due to its involvement viral replication. Here in, we investigated the structural aspects of the nsP2 protease through homology modeling based on nsP2 protease from Venezuelan equine encephalitis virus. Further, the ligands were virtually screened based on various pharmacological, ADME/Tox filters and subjected to docking with the modeled Chikungunya nsP2 protease using AutoDock4.2. The interaction profiling of ligand with the protein was carried out using LigPlot+. The results demonstrated that the ligand with PubChem Id (CID_5808891) possessed highest binding affinity towards Chikungunya nsP2 protease with a good interaction profile with the active site residues. We hereby propose that these compounds could inhibit the nsP2 protease by binding to its active site. Moreover, they may provide structural scaffold for the design of novel leads with better efficacy and specificity for the nsP2 protease. PMID:26664062

  10. Studies of new fused benzazepine as selective dopamine D3 receptor antagonists using 3D-QSAR, molecular docking and molecular dynamics.

    PubMed

    Liu, Jing; Li, Yan; Zhang, Shuwei; Xiao, Zhengtao; Ai, Chunzhi

    2011-02-18

    In recent years, great interest has been paid to the development of compounds with high selectivity for central dopamine (DA) D3 receptors, an interesting therapeutic target in the treatment of different neurological disorders. In the present work, based on a dataset of 110 collected benzazepine (BAZ) DA D3 antagonists with diverse kinds of structures, a variety of in silico modeling approaches, including comparative molecular field analysis (CoMFA), comparative similarity indices analysis (CoMSIA), homology modeling, molecular docking and molecular dynamics (MD) were carried out to reveal the requisite 3D structural features for activity. Our results show that both the receptor-based (Q(2) = 0.603, R(2) (ncv) = 0.829, R(2) (pre) = 0.690, SEE = 0.316, SEP = 0.406) and ligand-based 3D-QSAR models (Q(2) = 0.506, R(2) (ncv) =0.838, R(2) (pre) = 0.794, SEE = 0.316, SEP = 0.296) are reliable with proper predictive capacity. In addition, a combined analysis between the CoMFA, CoMSIA contour maps and MD results with a homology DA receptor model shows that: (1) ring-A, position-2 and R(3) substituent in ring-D are crucial in the design of antagonists with higher activity; (2) more bulky R(1) substituents (at position-2 of ring-A) of antagonists may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory QSAR models; (4) key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251. To our best knowledge, this work is the first report on 3D-QSAR modeling of the new fused BAZs as DA D3 antagonists. These results might provide information for a better understanding of the mechanism of antagonism and thus be helpful in designing new potent DA D3 antagonists.

  11. rDock: A Fast, Versatile and Open Source Program for Docking Ligands to Proteins and Nucleic Acids

    PubMed Central

    Ruiz-Carmona, Sergio; Alvarez-Garcia, Daniel; Foloppe, Nicolas; Garmendia-Doval, A. Beatriz; Juhos, Szilveszter; Schmidtke, Peter; Barril, Xavier; Hubbard, Roderick E.; Morley, S. David

    2014-01-01

    Identification of chemical compounds with specific biological activities is an important step in both chemical biology and drug discovery. When the structure of the intended target is available, one approach is to use molecular docking programs to assess the chemical complementarity of small molecules with the target; such calculations provide a qualitative measure of affinity that can be used in virtual screening (VS) to rank order a list of compounds according to their potential to be active. rDock is a molecular docking program developed at Vernalis for high-throughput VS (HTVS) applications. Evolved from RiboDock, the program can be used against proteins and nucleic acids, is designed to be computationally very efficient and allows the user to incorporate additional constraints and information as a bias to guide docking. This article provides an overview of the program structure and features and compares rDock to two reference programs, AutoDock Vina (open source) and Schrödinger's Glide (commercial). In terms of computational speed for VS, rDock is faster than Vina and comparable to Glide. For binding mode prediction, rDock and Vina are superior to Glide. The VS performance of rDock is significantly better than Vina, but inferior to Glide for most systems unless pharmacophore constraints are used; in that case rDock and Glide are of equal performance. The program is released under the Lesser General Public License and is freely available for download, together with the manuals, example files and the complete test sets, at http://rdock.sourceforge.net/ PMID:24722481

  12. Molecular docking studies and anti-enzymatic activities of Thai mango seed kernel extract against snake venoms.

    PubMed

    Leanpolchareanchai, Jiraporn; Pithayanukul, Pimolpan; Bavovada, Rapepol; Saparpakorn, Patchreenart

    2009-03-31

    The ethanolic extract from seed kernels of Thai mango (MSKE) (Mangifera indica L. cv. 'Fahlun') (Anacardiaceae) and its major phenolic principle (pentagalloyl glucopyranose) exhibited dose-dependent inhibitory effects on enzymatic activities of phospholipase A(2) (PLA(2)), hyaluronidase and L-amino acid oxidase (LAAO) of Calloselasma rhodostoma (CR) and Naja naja kaouthia (NK)venoms by in vitro tests. The anti-hemorrhagic and anti-dermonecrotic activities of MSKE against both venoms were clearly supported by in vivo tests. Molecular docking studies indicated that the phenolic molecules of the MSKE could selectively bind to the active sites or their proximity, or modify conserved residues that are critical for the catalysis of PLA(2), and selectively bind to the LAAO binding pocket of both CR and NK venoms and thereby inhibit their enzymatic activities. The results imply a potential use of MSKE against snake venoms.

  13. Binding difference of fipronil with GABAARs in fruitfly and zebrafish: insights from homology modeling, docking, and molecular dynamics simulation studies.

    PubMed

    Zheng, Nan; Cheng, Jiagao; Zhang, Wei; Li, Weihua; Shao, Xusheng; Xu, Zhiping; Xu, Xiaoyong; Li, Zhong

    2014-11-05

    Fipronil, which targets GABAA receptors (GABAARs), is the first phenylpyrazole insecticide widely used in crop protection and public hygiene. However, its high toxicity on fishes greatly limited its applications. In the present study, a series of computational methods including homology modeling, docking, and molecular dynamics simulation studies were integrated to explore the binding difference of fipronil with GABAARs from fruitfly and zebrafish systems. It was found that, in the zebrafish system, the H-bond between 6'Thr and fipronil exerted key effects on the recognition of fipronil, which was absent in the fruitfly system. On the other hand, in the fruitfly system, strong electrostatic interaction between 2'Ala and fipronil was favorable to the binding of fipronil but detrimental to the binding in the zebrafish system. These findings marked the binding difference of fipronil with different GABAARs, which might be helpful in designing selective insecticides against pests instead of fishes.

  14. In Silico Molecular Docking and In Vitro Antidiabetic Studies of Dihydropyrimido[4,5-a]acridin-2-amines

    PubMed Central

    Bharathi, A.; Roopan, Selvaraj Mohana; Vasavi, C. S.; Munusami, Punnagai; Gayathri, G. A.; Gayathri, M.

    2014-01-01

    An in vitro antidiabetic activity on α-amylase and α–glucosidase activity of novel 10-chloro-4-(2-chlorophenyl)-12-phenyl-5,6-dihydropyrimido[4,5-a]acridin-2-amines (3a–3f) were evaluated. Structures of the synthesized molecules were studied by FT-IR, 1H NMR, 13C NMR, EI-MS, and single crystal X-ray structural analysis data. An in silico molecular docking was performed on synthesized molecules (3a–3f). Overall studies indicate that compound 3e is a promising compound leading to the development of selective inhibition of α-amylase and α-glucosidase. PMID:24991576

  15. Pharmacodynamics and potential synergistic effects of Mai-Luo-Ning injection on cardiovascular protection, based on molecular docking.

    PubMed

    Wu, Liang; Shen, Han-Yuan; Wu, Yu-Zheng; Yu, Xiao-Yi; Wang, Hong; Cheng, Xue-Fang; Wang, Guang-Ji; Hao, Hai-Ping

    2015-11-01

    As a computer-assisted approach, molecular docking has been universally applied in drug research and development and plays an important role in the investigation and evaluation of herbal medicines. Herein, the method was used to estimate the pharmacodynamics of Mai-Luo-Ning injection, a traditional Chinese compound herbal prescription. Through investigating the interactions between several important proteins in cardiovascular system and characteristic components of the formula, its effect on cardiovascular protection was evaluated. Results showed the differences in the interactions between each component and the selected target proteins and revealed the possible mechanisms for synergistic effects of various characteristic components on cardiovascular protection. The study provided scientific evidence supporting the mechanistic study of the interactions among multi-components and targets, offering a general approach to investigating the pharmacodynamics of complicated materials in compound herbal prescriptions.

  16. Dapson in heterocyclic chemistry part VI: synthesis and molecular docking of some novel sulfonebiscompounds of expected anticancer activity.

    PubMed

    Ghorab, M M; Al-Said, M S; Nissan, Y M

    2012-11-01

    To discover new bioactive lead compounds for medicinal purposes, herein, sulfone biscompounds bearing dihydrothiazoles (3-9, 14, 15), acrylamide (11), thiazolidinones (12, 13, 20), thiophenes (16, 17) and benzothiophene (19) were prepared and tested for their anticancer activity. The structures of the products were confirmed from elemental analysis as well as spectral data. All the synthesized compounds showed remarkable anticancer activity against human breast cancer cell line especially, compound (3) with IC50 value 23.02 µM which was better than that of Doxorubicin by three folds. In order to elucidate the mechanism of action of their cytotoxic activity molecular docking on the active sites of farnesyl transferase and arginine methyl transferase was performed for all synthesized compounds and good results were obtained.

  17. Structural investigations of E. Coli dihydrolipoamide dehydrogenase in solution: Small-angle X-ray scattering and molecular docking

    NASA Astrophysics Data System (ADS)

    Dadinova, L. A.; Rodina, E. V.; Vorobyeva, N. N.; Kurilova, S. A.; Nazarova, T. I.; Shtykova, E. V.

    2016-05-01

    Dihydrolipoamide dehydrogenase from Escherichia coli (LpD) is a bacterial enzyme that is involved in the central metabolism and shared in common between the pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes. In the crystal structure, E. coli LpD is known to exist as a dimer. The present work is focused on analyzing the solution structure of LpD by small-angle X-ray scattering, molecular docking, and analytical ultracentrifugation. It was shown that in solution LpD exists as an equilibrium mixture of a dimer and a tetramer. The presence of oligomeric forms is determined by the multifunctionality of LpD in the cell, in particular, the required stoichiometry in the complexes.

  18. Synthesis, in vitro evaluation and molecular docking studies of biscoumarin thiourea as a new inhibitor of α-glucosidases.

    PubMed

    Zawawi, Nik Khairunissa Nik Abdullah; Taha, Muhammad; Ahmat, Norizan; Ismail, Nor Hadiani; Wadood, Abdul; Rahim, Fazal; Rehman, Ashfaq Ur

    2015-12-01

    Biscoumarin analogs 1-18 have been synthesized, characterized by EI-MS and (1)H NMR and evaluated for α-glucosidase inhibitory potential. All compounds showed variety of α-glucosidase inhibitory potential ranging in between 13.5±0.39 and 104.62±0.3μM when compared with standard acarbose having IC50 value 774.5±1.94μM. The binding interactions of the most active analogs were confirmed through molecular docking. The compounds showed very good interactions with enzyme. All synthesized compounds 1-18 are new. Our synthesized compounds can further be studied to developed lead compounds.

  19. Synthesis, in vitro evaluation and molecular docking studies of novel coumarin-isatin derivatives as α-glucosidase inhibitors.

    PubMed

    Wang, Guangcheng; Wang, Jing; He, Dianxiong; Li, Xin; Li, Juan; Peng, Zhiyun

    2016-09-12

    This study synthesized a series of novel coumarin-isatin derivatives and evaluated them for α-glucosidase inhibitory activity. The majority of the screened compounds exhibited excellent inhibition activities with IC50 values of 2.56 ± 0.08-268.79 ± 3.04 μm, when compared to acarbose. Among the newly derivatives, compound 5p was found to be the most active compound in the library of coumarin-isatin derivatives. Furthermore, enzyme kinetic studies showed that compound 5p is a non-competitive inhibitor with a Ki of 2.14 μm. Molecular docking analysis revealed the existence of hydrophobic and hydrogen interactions between compound 5p and the active site of α-glucosidase. Our results indicate that coumarin-isatin derivatives as a new class of α-glucosidase inhibitors.

  20. Ionic liquid mediated synthesis and molecular docking study of novel aromatic embedded Schiff bases as potent cholinesterase inhibitors.

    PubMed

    Abd Razik, Basma M; Osman, Hasnah; Basiri, Alireza; Salhin, Abdussalam; Kia, Yalda; Ezzat, Mohammed Oday; Murugaiyah, Vikneswaran

    2014-12-01

    Novel aromatic embedded Schiff bases have been synthesized in ionic liquid [bmim]Br and evaluated in vitro for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes inhibitory activities. Among the newly synthesized compounds, 5f, 5h and 7j displayed higher AChE enzyme inhibitory activities than standard drug, galanthamine, with IC50 values of 1.88, 2.05 and 2.03μM, respectively. Interestingly, all the compounds except for compound 5c displayed higher BChE inhibitories than standard with IC50 values ranging from 3.49 to 19.86μM. Molecular docking analysis for 5f and 7j possessing the most potent AChE and BChE inhibitory activities, disclosed their binding interaction templates to the active site of AChE and BChE enzymes, respectively.

  1. Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors.

    PubMed

    Saeed, Aamer; Khan, Muhammad Siraj; Rafique, Hummera; Shahid, Mohammad; Iqbal, Jamshed

    2014-02-01

    Thioureas are exceptionally versatile building blocks towards the synthesis of wide variety of heterocyclic systems, which also possess extensive range of pharmacological activities. The substituted benzoic acids were converted into corresponding acid chlorides, these acid chlorides were then treated with potassium thiocyanate in acetone and then the reaction mixture was refluxed for 1-2h afford ethyl 4-(3-benzoylthioureido)benzoates thioureas in good yields. All the newly synthesized compounds were evaluated for their urease inhibitory activities and were found to be potent inhibitors of urease enzyme. Compounds 1f and 1g were identified as the most potent urease inhibitors (IC50 0.21 and 0.13 μM, respectively), and was 100-fold more potent than the standard inhibitors. Further molecular docking studies were carried out using the crystal structure of urease to find out the binding mode of the inhibitors with the enzyme.

  2. Probing the mechanism of interaction of metoprolol succinate with human serum albumin by spectroscopic and molecular docking analysis.

    PubMed

    Pawar, Suma K; Jaldappagari, Seetharamappa

    2017-02-24

    In the present work, the mechanism of the interaction between a β1 receptor blocker, metoprolol succinate (MS) and human serum albumin (HSA) under physiological conditions was investigated by spectroscopic techniques, namely fluorescence, Fourier transform infra-red spectroscopy (FT-IR), fluorescence lifetime decay and circular dichroism (CD) as well as molecular docking and cyclic voltammetric methods. The fluorescence and lifetime decay results indicated that MS quenched the intrinsic intensity of HSA through a static quenching mechanism. The Stern-Volmer quenching constants and binding constants for the MS-HSA system at 293, 298 and 303 K were obtained from the Stern-Volmer plot. Thermodynamic parameters for the interaction of MS with HSA were evaluated; negative values of entropy change (ΔG°) indicated the spontaneity of the MS and HSA interaction. Thermodynamic parameters such as negative ΔH° and positive ΔS° values revealed that hydrogen bonding and hydrophobic forces played a major role in MS-HSA interaction and stabilized the complex. The binding site for MS in HSA was identified by competitive site probe experiments and molecular docking studies. These results indicated that MS was bound to HSA at Sudlow's site I. The efficiency of energy transfer and the distance between the donor (HSA) and acceptor (MS) was calculated based on the theory of Fosters' resonance energy transfer (FRET). Three-dimensional fluorescence spectra and CD results revealed that the binding of MS to HSA resulted in an obvious change in the conformation of HSA. Cyclic voltammograms of the MS-HSA system also confirmed the interaction between MS and HSA. Furthermore, the effects of metal ions on the binding of MS to HSA were also studied.

  3. Spectroscopic and molecular docking studies of binding interaction of gefitinib, lapatinib and sunitinib with bovine serum albumin (BSA).

    PubMed

    Shen, Guo-Feng; Liu, Ting-Ting; Wang, Qi; Jiang, Min; Shi, Jie-Hua

    2015-12-01

    The binding interactions of three kinds of tyrosine kinase inhibitors (TKIs), such as gefitinib, lapatinib and sunitinib, with bovine serum albumin (BSA) were studied using ultraviolet spectrophotometry, fluorescence spectroscopy, circular dichroism (CD), Fourier transform infrared spectroscopy (FT-IR) and molecular docking methods. The experimental results showed that the intrinsic fluorescence quenching of BSA induced by the three TKIs resulted from the formation of stable TKIs-BSA complexes through the binding interaction of TKIs with BSA. The stoichiometry of three stable TKIs-BSA complexes was 1:1 and the binding constants (Kb) of the three TKIs-BSA complexes were in the order of 10(4)M(-1) at 310 K, indicating that there was a strong binding interaction of the three TKIs with BSA. Based on the analysis of the signs and magnitudes of the free energy change (ΔG(0)), enthalpic change (ΔH(0)) and entropic change (ΔS(0)) in the binding process, it can be deduced that the binding process of the three TKIs with BSA was spontaneous and enthalpy-driven process, and the main interaction forces between the three TKIs and BSA were van der Waals force and hydrogen bonding interaction. Moreover, from the results of CD, FT-IR and molecular docking, it can be concluded that there was a significant difference between the three TKIs in the binding site on BSA, lapatinib was located on site II (m) of BSA while gefitinib and sunitinib were bound on site I of BSA, and there were some changes in the BSA conformation when binding three TKIs to BSA but BSA still retains its secondary structure α-helicity.

  4. Characterizing the binding interaction between antimalarial artemether (AMT) and bovine serum albumin (BSA): Spectroscopic and molecular docking methods.

    PubMed

    Shi, Jie-Hua; Pan, Dong-Qi; Wang, Xiou-Xiou; Liu, Ting-Ting; Jiang, Min; Wang, Qi

    2016-09-01

    Artemether (AMT), a peroxide sesquiterpenoides, has been widely used as an antimalarial for the treatment of multiple drug-resistant strains of plasmodium falciparum malaria. In this work, the binding interaction of AMT with bovine serum albumin (BSA) under the imitated physiological conditions (pH7.4) was investigated by UV spectroscopy, fluorescence emission spectroscopy, synchronous fluorescence spectroscopy, Fourier transform infrared spectroscopy (FT-IR), circular dichroism (CD), three-dimensional fluorescence spectroscopy and molecular docking methods. The experimental results indicated that there was a change in UV absorption of BSA along with a slight red shift of absorption wavelength, indicating that the interaction of AMT with BSA occurred. The intrinsic fluorescence of BSA was quenched by AMT due to the formation of AMT-BSA complex. The number of binding sites (n) and binding constant of AMT-BSA complex were about 1 and 2.63×10(3)M(-1) at 298K, respectively, suggesting that there was stronger binding interaction of AMT with BSA. Based on the analysis of the signs and magnitudes of the free energy change (ΔG(0)), enthalpic change (ΔH(0)) and entropic change (ΔS(0)) in the binding process, it can be concluded that the binding of AMT with BSA was enthalpy-driven process due to |ΔH°|>|TΔS°|. The results of experiment and molecular docking confirmed the main interaction forces between AMT and BSA were van der Waals force. And, there was a slight change in the BSA conformation after binding AMT but BSA still retains its secondary structure α-helicity. However, it had been confirmed that AMT binds on the interface between sub-domain IIA and IIB of BSA.

  5. Synthesis, anticancer activity and molecular docking studies on a series of heterocyclic trans-cyanocombretastatin analogues as antitubulin agents

    PubMed Central

    Penthala, Narsimha Reddy; Zong, Hongliang; Ketkar, Amit; Madadi, Nikhil Reddy; Janganati, Venumadav; Eoff, Robert L.; Guzman, Monica L.; Crooks, Peter A.

    2015-01-01

    A series of heterocyclic combretastatin analogues have been synthesized and evaluated for their anticancer activity against a panel of 60 human cancer cell lines. The most potent compounds were two 3,4,5-trimethoxy phenyl analogues containing either an (Z)-indol-2-yl (8) or (Z)-benzo[b]furan-2-yl (12) moiety; these compounds exhibited GI50 values of <10 nM against 74% and 70%, respectively, of the human cancer cell lines in the 60-cell panel. Compounds 8, and 12 and two previously reported compounds in the same structural class, i.e. 29 and 31, also showed potent anti-leukemic activity against leukemia MV4-11 cell lines with LD50 values = 44 nM, 47 nM, 18 nM, and 180 nM, respectively. From the NCI anti-cancer screening results and the data from the in vitro toxicity screening on cultured AML cells, seven compounds: 8, 12, 21, 23, 25, 29 and 31 were screened for their in vitro inhibitory activity on tubulin polymerization in MV4-11 AML cells; at 50 nM, 8 and 29 inhibited polymerization of tubulin by >50%. The binding modes of the three most active compounds (8, 12 and 29) to tubulin were also investigated utilizing molecular docking studies. All three molecules were observed to bind in the same hydrophobic pocket at the interface of α- and β-tubulin that is occupied by colchicine, and were stablized by van der Waals’ interactions with surrounding tubulin residues. The results from the tubulin polymerization and molecular docking studies indicate that compounds 8 and 29 are the most potent anti-leukemic compounds in this structural class, and are considered lead compounds for further development as anti-leukemic drugs. PMID:25557492

  6. Molecular basis of glucagon-like peptide 1 docking to its intact receptor studied with carboxyl-terminal photolabile probes.

    PubMed

    Chen, Quan; Pinon, Delia I; Miller, Laurence J; Dong, Maoqing

    2009-12-04

    The glucagon-like peptide 1 (GLP1) receptor is a member of Family B G protein-coupled receptors and represents an important drug target for type 2 diabetes. Despite recent solution of the structure of the amino-terminal domain of this receptor and that of several close family members, understanding of the molecular basis of natural ligand GLP1 binding to its intact receptor remains limited. The goal of this study was to explore spatial approximations between specific receptor residues within the carboxyl terminus of GLP1 and its receptor as normally docked. Therefore, we developed and characterized two high affinity, full-agonist photolabile GLP1 probes having sites for covalent attachment in positions 24 and 35. Both probes labeled the receptor specifically and saturably. Subsequent peptide mapping using chemical and proteinase cleavages of purified wild-type and mutant GLP1 receptor identified that the Arg(131)-Lys(136) segment at the juxtamembrane region of the receptor amino terminus contained the site of labeling for the position 24 probe, and the specific receptor residue labeled by this probe was identified as Glu(133) by radiochemical sequencing. Similarly, nearby residue Glu(125) within the same region of the receptor amino-terminal domain was identified as the site of labeling by the position 35 probe. These data represent the first direct demonstration of spatial approximation between GLP1 and its intact receptor as docked, providing two important constraints for the modeling of this interaction. This should expand our understanding of the molecular basis of natural agonist ligand binding to the GLP1 receptor and may be relevant to other family members.

  7. Heterodimerization of the Entamoeba histolytica EhCPADH virulence complex through molecular dynamics and protein-protein docking.

    PubMed

    Montaño, Sarita; Orozco, Esther; Correa-Basurto, José; Bello, Martiniano; Chávez-Munguía, Bibiana; Betanzos, Abigail

    2017-02-01

    EhCPADH is a protein complex involved in the virulence of Entamoeba histolytica, the protozoan responsible for human amebiasis. It is formed by the EhCP112 cysteine protease and the EhADH adhesin. To explore the molecular basis of the complex formation, three-dimensional models were built for both proteins and molecular dynamics simulations (MDS) and docking calculations were performed. Results predicted that the pEhCP112 proenzyme and the mEhCP112 mature enzyme were globular and peripheral membrane proteins. Interestingly, in pEhCP112, the propeptide appeared hiding the catalytic site (C167, H329, N348); while in mEhCP112, this site was exposed and its residues were found structurally closer than in pEhCP112. EhADH emerged as an extended peripheral membrane protein with high fluctuation in Bro1 and V shape domains. 500 ns-long MDS and protein-protein docking predictions evidenced different heterodimeric complexes with the lowest free energy. pEhCP112 interacted with EhADH by the propeptide and C-terminal regions and mEhCP112 by the C-terminal through hydrogen bonds. In contrast, EhADH bound to mEhCP112 by 442-479 residues, adjacent to the target cell-adherence region (480-600 residues), and by the Bro1 domain (9-349 residues). Calculations of the effective binding free energy and per residue free energy decomposition showed that EhADH binds to mEhCP112 with a higher binding energy than to pEhCP112, mainly through van der Waals interactions and the nonpolar part of solvation energy. The EhADH and EhCP112 structural relationship was validated in trophozoites by immunofluorescence, TEM, and immunoprecipitation assays. Experimental findings fair agreed with in silico results.

  8. Structural analysis and molecular docking of trypanocidal aryloxy-quinones in trypanothione and glutathione reductases: a comparison with biochemical data.

    PubMed

    Vera, Brenda; Vázquez, Karina; Mascayano, Carolina; Tapia, Ricardo A; Espinosa, Victoria; Soto-Delgado, Jorge; Salas, Cristian O; Paulino, Margot

    2016-07-15

    A set of aryloxy-quinones, previously synthesized and evaluated against Trypanosoma cruzi epimastigotes cultures, were found more potent and selective than nifurtimox. One of the possible mechanisms of the trypanocidal activity of these quinones could be inhibition of trypanothione reductase (TR). Considering that glutathione reductase (GR) is the equivalent of TR in humans, biochemical, kinetic, and molecular docking studies in TR and GR were envisaged and compared with the trypanocidal and cytotoxic data of a set of aryloxy-quinones. Biochemical assays indicated that three naphthoquinones (Nq-h, Nq-g, and Nq-d) selectively inhibit TR and the TR kinetic analyses indicated that Nq-h inhibit TR in a noncompetitive mechanism. Molecular dockings were performed in TR and GR in the following three putative binding sites: the catalytic site, the dimer interface, and the nicotinamide adenine dinucleotide phosphate-binding site. In TR and GR, the aryloxy-quinones were found to exhibit high affinity for a site near it cognate-binding site in a place in which the noncompetitive kinetics could be justified. Taking as examples the three compounds with TR specificity (TRS) (Nq-h, Nq-g, and Nq-d), the presence of a network of contacts with the quinonic ring sustained by the triad of Lys62, Met400', Ser464' residues, seems to contribute hardly to the TRS. Compound Nq-b, a naphthoquinone with nitrophenoxy substituent, proved to be the best scaffold for the design of trypanocidal compounds with low toxicity. However, the compound displayed only a poor and non-selective effect toward TR indicating that TR inhibition is not the main reason for the antiparasitic activity of the aryloxy-quinones.

  9. Structure Prediction, Molecular Dynamics Simulation and Docking Studies of D-Specific Dehalogenase from Rhizobium sp. RC1

    PubMed Central

    Sudi, Ismaila Yada; Wong, Ee Lin; Joyce-Tan, Kwee Hong; Shamsir, Mohd Shahir; Jamaluddin, Haryati; Huyop, Fahrul

    2012-01-01

    Currently, there is no three-dimensional structure of D-specific dehalogenase (DehD) in the protein database. We modeled DehD using ab initio technique, performed molecular dynamics (MD) simulation and docking of D-2-chloropropionate (D-2CP), D-2-bromopropionate (D-2BP), monochloroacetate (MCA), monobromoacetate (MBA), 2,2-dichloropropionate (2,2-DCP), D,L-2,3-dichloropropionate (D,L-2,3-DCP), and 3-chloropropionate (3-CP) into the DehD active site. The sequences of DehD and D-2-haloacid dehalogenase (HadD) from Pseudomonas putida AJ1 have 15% sequence similarity. The model had 80% of the amino acid residues in the most favored region when compared to the crystal structure of DehI from Pseudomonas putida PP3. Docking analysis revealed that Arg107, Arg134 and Tyr135 interacted with D-2CP, and Glu20 activated the water molecule for hydrolytic dehalogenation. Single residue substitutions at 25–30 °C showed that polar residues of DehD were stable when substituted with nonpolar residues and showed a decrease in activity within the same temperature range. The molecular dynamics simulation of DehD and its variants showed that in R134A variant, Arg107 interacted with D-2CP, while in Y135A, Gln221 and Arg231 interacted with D-2CP. It is our emphatic belief that the new model will be useful for the rational design of DehDs with enhanced potentials. PMID:23443090

  10. Interaction of a tyrosine kinase inhibitor, vandetanib with human serum albumin as studied by fluorescence quenching and molecular docking.

    PubMed

    Kabir, Md Zahirul; Feroz, Shevin R; Mukarram, Abdul Kadir; Alias, Zazali; Mohamad, Saharuddin B; Tayyab, Saad

    2016-08-01

    Interaction of a tyrosine kinase inhibitor, vandetanib (VDB), with the major transport protein in the human blood circulation, human serum albumin (HSA), was investigated using fluorescence spectroscopy, circular dichroism (CD) spectroscopy, and molecular docking analysis. The binding constant of the VDB-HSA system, as determined by fluorescence quenching titration method was found in the range, 8.92-6.89 × 10(3 )M(-1) at three different temperatures, suggesting moderate binding affinity. Furthermore, decrease in the binding constant with increasing temperature revealed involvement of static quenching mechanism, thus affirming the formation of the VDB-HSA complex. Thermodynamic analysis of the binding reaction between VDB and HSA yielded positive ΔS (52.76 J mol(-1) K(-1)) and negative ΔH (-6.57 kJ mol(-1)) values, which suggested involvement of hydrophobic interactions and hydrogen bonding in stabilizing the VDB-HSA complex. Far-UV and near-UV CD spectral results suggested alterations in both secondary and tertiary structures of HSA upon VDB-binding. Three-dimensional fluorescence spectral results also showed significant microenvironmental changes around the Trp residue of HSA consequent to the complex formation. Use of site-specific marker ligands, such as phenylbutazone (site I marker) and diazepam (site II marker) in competitive ligand displacement experiments indicated location of the VDB binding site on HSA as Sudlow's site I (subdomain IIA), which was further established by molecular docking results. Presence of some common metal ions, such as Ca(2+), Zn(2+), Cu(2+), Ba(2+), Mg(2+), and Mn(2+) in the reaction mixture produced smaller but significant alterations in the binding affinity of VDB to HSA.

  11. Fluorescence spectroscopic and molecular docking studies of the binding interaction between the new anaplastic lymphoma kinase inhibitor crizotinib and bovine serum albumin

    NASA Astrophysics Data System (ADS)

    Abdelhameed, Ali S.; Alanazi, Amer M.; Bakheit, Ahmed H.; Darwish, Hany W.; Ghabbour, Hazem A.; Darwish, Ibrahim A.

    2017-01-01

    Binding of the recently introduced anti-cancer drug, crizotinib (CRB) with the bovine serum albumin (BSA) was comprehensively studied with the aid of fluorescence and UV-Vis spectroscopic as well as molecular docking techniques. The collective results of the study under the simulated physiological conditions proposed a static type of binding occurring between the CRB and BSA with binding constants of 104 L mol- 1. BSA conformational changes were investigated using three dimensional (3D) and synchronous fluorescence measurements. Moreover, the results of site marker competitive experiments and molecular docking, it could be deduced that CRB was inserted into the subdomain IIA (site I) of BSA yielding a more stabilized system. This was further confirmed with the molecular docking results which revealed that CRB is located in the active site residues Try149, Glu152, Ser191, Arg194, Arg198, Trp213, Arg217, Arg256, His287, Ala290, Glu291, Ser343, Asp450 within a radius of 6 Å. Combining the molecular docking studies and the computed thermodynamic parameters, it can be inferred that hydrophobic and electrostatic interactions are the major binding forces involved in formation of the CRB-BSA complex.

  12. Fluorescence spectroscopic and molecular docking studies of the binding interaction between the new anaplastic lymphoma kinase inhibitor crizotinib and bovine serum albumin.

    PubMed

    Abdelhameed, Ali S; Alanazi, Amer M; Bakheit, Ahmed H; Darwish, Hany W; Ghabbour, Hazem A; Darwish, Ibrahim A

    2017-01-15

    Binding of the recently introduced anti-cancer drug, crizotinib (CRB) with the bovine serum albumin (BSA) was comprehensively studied with the aid of fluorescence and UV-Vis spectroscopic as well as molecular docking techniques. The collective results of the study under the simulated physiological conditions proposed a static type of binding occurring between the CRB and BSA with binding constants of 10(4)Lmol(-1). BSA conformational changes were investigated using three dimensional (3D) and synchronous fluorescence measurements. Moreover, the results of site marker competitive experiments and molecular docking, it could be deduced that CRB was inserted into the subdomain IIA (site I) of BSA yielding a more stabilized system. This was further confirmed with the molecular docking results which revealed that CRB is located in the active site residues Try149, Glu152, Ser191, Arg194, Arg198, Trp213, Arg217, Arg256, His287, Ala290, Glu291, Ser343, Asp450 within a radius of 6Å. Combining the molecular docking studies and the computed thermodynamic parameters, it can be inferred that hydrophobic and electrostatic interactions are the major binding forces involved in formation of the CRB-BSA complex.

  13. Atom-based 3D-QSAR, molecular docking and molecular dynamics simulation assessment of inhibitors for thyroid hormone receptor α and β.

    PubMed

    Gupta, Manish Kumar; Misra, Krishna

    2014-06-01

    The three-dimensional quantitative structure-activity relationship (3D-QSAR) for inhibitors of thyroid hormone receptors (TR) α and (TR) β was studied. The training set of the TRα model generated a correlation coefficient (R(2)) =  0.9535, with standard deviation (SD) =  0.3016. From the test set of the TRα model, a Q(2) value for the predicted activities (= 0.4303), squared correlation (random selection R(2)-CV  =  0.6929), Pearson-R (= 0.7294) and root mean square error (RMSE  =  0.6342) were calculated. The P-value for TRα (= 1.411e-96) and TRβ (= 2.108e-165) models indicate a high degree of self-reliance. For the TRβ model, the training set yielded R(2) = 0.9424 with SD = 0.3719. From the test set of TRβ, Q(2) value (= 0.5336), the squared correlation (R(2)-CV  =  0.7201), the Pearson-R (= 0.7852) and RMSE for test set predictions (= 0.8630) all strengthen the good predictive competence of the QSAR model derived. Examination of internal as well as external validation supports the rationality and good predictive ability of the best model. Molecular docking explained the conformations of molecules and important amino acid residues at the docking pocket, and a molecular dynamics simulation study further uncovered the binding process and validated the rationality of docking results. The findings not only lead to a better understanding of interactions between these antagonists and thyroid hormone receptors α and β, but also provide valuable information about the impact of structure on activity that will be very beneficial in the design of novel antagonists with preferred activity.

  14. Molecular Docking and in Vitro Antileishmanial Evaluation of Chromene-2-thione Analogues

    PubMed Central

    2012-01-01

    Leishmaniases are an epidemic in various countries, and the parasite is developing resistance against available drugs. Thus, development of new drugs against Leishmania is an open area of investigation for synthetic organic chemists. To meet this challenge, a series of chromene-2-thione derivatives have been synthesized and docked into the active site of trypanothione reductase (TryR) enzyme required for redox balance of the parasite. These were screened on promastigote, axenic amastigote, and intracellular amastigote stages of Leishmania donovani and found to show high levels of antileishmanial activity together with minimal toxicity to human peripheral blood mononuclear cells. Compounds 3b and 3k were found to be the most active among the tested compounds. Although the compounds show moderate antileishmanial activity, they identify a chemical space to design and develop drugs based on these chromene-2-thione derivatives against the Leishmania parasite. PMID:24936236

  15. Seven-membered azabridged neonicotinoids: synthesis, crystal structure, insecticidal assay, and molecular docking studies.

    PubMed

    Xu, Renbo; Luo, Ming; Xia, Rui; Meng, Xiaoqing; Xu, Xiaoyong; Xu, Zhiping; Cheng, Jiagao; Shao, Xusheng; Li, Houju; Li, Zhong

    2014-11-19

    To study the influence of the ring sizes, 37 novel seven-membered azabridged neonicotinoid analogues were synthesized by reactions of nitromethylene analogues, succinaldehyde, and aniline hydrochlorides. Most of the title compounds presented higher insecticidal activities than that of imidacloprid (IMI), cycloxaprid (CYC), and eight-membered compounds against cowpea aphid (Aphis craccivora), armyworm (Pseudaletia separata Walker), and brown planthopper (Nilaparvata lugens), which indicated that introducing the structure of a seven-membered azabridge could significantly improve the insecticidal activities of neonicotinoid analogues. Docking study and binding mode analysis also revealed that introducing methyl group into position 2 of phenyl ring could increase the hydrophobic interactions with receptor, which implied that position 2 might be the key site to get high insecticidal compounds.

  16. Comparative Molecular Docking Studies with ABCC1 and Aquaporin 9 in the Arsenite Complex Efflux

    PubMed Central

    Poojan, Shiv; Dhasmana, Anupam; Jamal, Qazi Mohammad Sajid; Haneef, Mohd; Lohani, Mohtashim

    2014-01-01

    Arsenic is the most toxic metalloid present in the natural environment in both organic and inorganic arsenic forms. Inorganic arsenic is often more hazardous than the organic form. Arsenite and arsenate compounds are the major inorganic forms which are toxic causing severe human health dysfunction including cancer. Excretion of arsenic from the system is found elusive. Therefore, it is of interest to screen channel proteins with the arsenic complex in the different combination of arsenic, GSH (glutathione) and arsenic, selenium using docking methods. The mode of arsenic removal. The complex structure revealed the mode of arsenic binding efficiency with the receptor aquaporine 9 and ABCC1 channel protein. This provides insights to understand the mechanism of arsenic efflux. These inferences find application in the design, identification and development of novel nutracetucal or any other formulation useful in the balance of arsenic efflux. PMID:25258480

  17. Identification and molecular docking analysis of active ingredients with medicinal properties from edible Baccaurea sapida

    PubMed Central

    Mann, Sonia; Sharma, Ankita; Biswas, Sagarika; Gupta, Rajinder K

    2015-01-01

    Underutilized plant species has started changing the conception of plants by expanding the use well beyond from foods and fibers to rich source of medicinally important secondary metabolites. Bioactive compounds from natural sources are gaining importance as potential drug candidates towards many inflammatory conditions like Rheumatoid Arthritis (RA). The focus of the present study has been centred to reveal the anti-inflammatory potential of an underutilized fruits of B. sapida. Further efforts towards its medicinal significance may provide relieve from symptoms of RA by reducing the side effects that are observed in available medications. Total 10 compounds in fruit crude methanol extract were identified and quantified by LC-MS/MS analysis followed by the agar well diffusion method for their anti microbial activity. Among all studied micro organism S. aureus was found to surmount the inflammation in RA through domain B of surface protein A (Staphylococcal surface protein A). Identified compounds (having anti-inflammatory properties) were scrutinized for their toxicity and quantitative structure–activity relationship (QSAR) using lazer toxicity and Molinspiration servers respectively. Further, docking studies have been carried out between domain B and studied compounds using AutoDock. Out of 6 anti-inflammtory compounds, quercetin has been identified as the most potent compound in reference to its inhibitory constant (47.01) and binding energy (-5.90 kcal/mol) to bacterial protein. Our data suggest that methanol extract of B. sapida fruit posses medicinally significant anti-inflammatory compounds and thus justifies the use of this fruit as folklore medicine for preventing inflammation related diseases. PMID:26527853

  18. Identification and molecular docking analysis of active ingredients with medicinal properties from edible Baccaurea sapida.

    PubMed

    Mann, Sonia; Sharma, Ankita; Biswas, Sagarika; Gupta, Rajinder K

    2015-01-01

    Underutilized plant species has started changing the conception of plants by expanding the use well beyond from foods and fibers to rich source of medicinally important secondary metabolites. Bioactive compounds from natural sources are gaining importance as potential drug candidates towards many inflammatory conditions like Rheumatoid Arthritis (RA). The focus of the present study has been centred to reveal the anti-inflammatory potential of an underutilized fruits of B. sapida. Further efforts towards its medicinal significance may provide relieve from symptoms of RA by reducing the side effects that are observed in available medications. Total 10 compounds in fruit crude methanol extract were identified and quantified by LC-MS/MS analysis followed by the agar well diffusion method for their anti microbial activity. Among all studied micro organism S. aureus was found to surmount the inflammation in RA through domain B of surface protein A (Staphylococcal surface protein A). Identified compounds (having anti-inflammatory properties) were scrutinized for their toxicity and quantitative structure-activity relationship (QSAR) using lazer toxicity and Molinspiration servers respectively. Further, docking studies have been carried out between domain B and studied compounds using AutoDock. Out of 6 anti-inflammtory compounds, quercetin has been identified as the most potent compound in reference to its inhibitory constant (47.01) and binding energy (-5.90 kcal/mol) to bacterial protein. Our data suggest that methanol extract of B. sapida fruit posses medicinally significant anti-inflammatory compounds and thus justifies the use of this fruit as folklore medicine for preventing inflammation related diseases.

  19. Combined 3D-QSAR, molecular docking, molecular dynamics simulation, and binding free energy calculation studies on the 5-hydroxy-2H-pyridazin-3-one derivatives as HCV NS5B polymerase inhibitors.

    PubMed

    Yu, Haijing; Fang, Yu; Lu, Xia; Liu, Yongjuan; Zhang, Huabei

    2014-01-01

    The NS5B RNA-dependent RNA polymerase (RdRP) is a promising therapeutic target for developing novel anti-hepatitis C virus (HCV) drugs. In this work, a combined molecular modeling study was performed on a series of 193 5-hydroxy-2H-pyridazin-3-one derivatives as inhibitors of HCV NS5B Polymerase. The best 3D-QSAR models, including CoMFA and CoMSIA, are based on receptor (or docking). Furthermore, a 40-ns molecular dynamics (MD) simulation and binding free energy calculations using docked structures of NS5B with ten compounds, which have diverse structures and pIC50 values, were employed to determine the detailed binding process and to compare the binding modes of the inhibitors with different activities. On one side, the stability and rationality of molecular docking and 3D-QSAR results were validated by MD simulation. The binding free energies calculated by the MM-PBSA method gave a good correlation with the experimental biological activity. On the other side, by analyzing some differences between the molecular docking and the MD simulation results, we can find that the MD simulation could also remedy the defects of molecular docking. The analyses of the combined molecular modeling results have identified that Tyr448, Ser556, and Asp318 are the key amino acid residues in the NS5B binding pocket. The results from this study can provide some insights into the development of novel potent NS5B inhibitors.

  20. A combination of pharmacophore modeling, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on PDE4 enzyme inhibitors.

    PubMed

    Tripuraneni, Naga Srinivas; Azam, Mohammed Afzal

    2016-11-01

    Phosphodiesterases 4 enzyme is an attractive target for the design of anti-inflammatory and bronchodilator agents. In the present study, pharmacophore and atom-based 3D-QSAR studies were carried out for pyrazolopyridine and quinoline derivatives using Schrödinger suite 2014-3. A four-point pharmacophore model was developed using 74 molecules having pIC50 ranging from 10.1 to 4.5. The best four feature model consists of one hydrogen bond acceptor, two aromatic rings, and one hydrophobic group. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a high correlation coefficient (R(2 )= .9949), cross validation coefficient (Q(2 )= .7291), and Pearson-r (.9107) at six component partial least square factor. The external validation indicated that our QSAR model possessed high predictive power with R(2) value of .88. The generated model was further validated by enrichment studies using the decoy test. Molecular docking, free energy calculation, and molecular dynamics (MD) simulation studies have been performed to explore the putative binding modes of these ligands. A 10-ns MD simulation confirmed the docking results of both stability of the 1XMU-ligand complex and the presumed active conformation. Outcomes of the present study provide insight in designing novel molecules with better PDE4 inhibitory activity.

  1. Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA.

    PubMed

    Mena-Ulecia, Karel; Tiznado, William; Caballero, Julio

    2015-01-01

    Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyanofluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P3 (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S1, S2, and S3 subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure-activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations. We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin-inhibitor complexes.

  2. Study of the Differential Activity of Thrombin Inhibitors Using Docking, QSAR, Molecular Dynamics, and MM-GBSA

    PubMed Central

    Mena-Ulecia, Karel; Tiznado, William; Caballero, Julio

    2015-01-01

    Non-peptidic thrombin inhibitors (TIs; 177 compounds) with diverse groups at motifs P1 (such as oxyguanidine, amidinohydrazone, amidine, amidinopiperidine), P2 (such as cyanofluorophenylacetamide, 2-(2-chloro-6-fluorophenyl)acetamide), and P3 (such as phenylethyl, arylsulfonate groups) were studied using molecular modeling to analyze their interactions with S1, S2, and S3 subsites of the thrombin binding site. Firstly, a protocol combining docking and three dimensional quantitative structure–activity relationship was performed. We described the orientations and preferred active conformations of the studied inhibitors, and derived a predictive CoMSIA model including steric, donor hydrogen bond, and acceptor hydrogen bond fields. Secondly, the dynamic behaviors of some selected TIs (compounds 26, 133, 147, 149, 162, and 177 in this manuscript) that contain different molecular features and different activities were analyzed by creating the solvated models and using molecular dynamics (MD) simulations. We used the conformational structures derived from MD to accomplish binding free energetic calculations using MM-GBSA. With this analysis, we theorized about the effect of van der Waals contacts, electrostatic interactions and solvation in the potency of TIs. In general, the contents reported in this article help to understand the physical and chemical characteristics of thrombin-inhibitor complexes. PMID:26599107

  3. 3D-QSAR, molecular dynamics simulations and molecular docking studies of benzoxazepine moiety as mTOR inhibitor for the treatment of lung cancer.

    PubMed

    Chaube, Udit; Chhatbar, Dhara; Bhatt, Hardik

    2016-02-01

    According to WHO statistics, lung cancer is one of the leading causes of death among all other types of cancer. Many genes get mutated in lung cancer but involvement of EGFR and KRAS are more common. Unavailability of drugs or resistance to the available drugs is the major problem in the treatment of lung cancer. In the present research, mTOR was selected as an alternative target for the treatment of lung cancer which involves PI3K/AKT/mTOR pathway. 28 synthetic mTOR inhibitors were selected from the literature. Ligand based approach (CoMFA and CoMSIA) and structure based approach (molecular dynamics simulations assisted molecular docking study) were applied for the identification of important features of benzoxazepine moiety, responsible for mTOR inhibition. Three different alignments were tried to obtain best QSAR model, of which, distil was found to be the best method, as it gave good statistical results. In CoMFA, Leave One Out (LOO) cross validated coefficients (q(2)), conventional coefficient (r(2)) and predicted correlation coefficient (r(2)pred) values were found to be 0.615, 0.990 and 0.930, respectively. Similarly in CoMSIA, q(2), r(2)ncv and r(2)pred values were found to be 0.748, 0.986 and 0.933, respectively. Molecular dynamics and simulations study revealed that B-chain of mTOR protein was stable at and above 500 FS with respect to temperature (at and above 298 K), Potential energy (at and above 7669.72 kJ/mol) and kinetic energy (at and above 4009.77 kJ/mol). Molecular docking study was performed on simulated protein of mTOR which helped to correlate interactions of amino acids surrounded to the ligand with contour maps generated by QSAR method. Important features of benzoxazepine were identified by contour maps and molecular docking study which would be useful to design novel molecules as mTOR inhibitors for the treatment of lung cancer.

  4. DOCKTITE-a highly versatile step-by-step workflow for covalent docking and virtual screening in the molecular operating environment.

    PubMed

    Scholz, Christoph; Knorr, Sabine; Hamacher, Kay; Schmidt, Boris

    2015-02-23

    The formation of a covalent bond with the target is essential for a number of successful drugs, yet tools for covalent docking without significant restrictions regarding warhead or receptor classes are rare and limited in use. In this work we present DOCKTITE, a highly versatile workflow for covalent docking in the Molecular Operating Environment (MOE) combining automated warhead screening, nucleophilic side chain attachment, pharmacophore-based docking, and a novel consensus scoring approach. The comprehensive validation study includes pose predictions of 35 protein/ligand complexes which resulted in a mean RMSD of 1.74 Å and a prediction rate of 71.4% with an RMSD below 2 Å, a virtual screening with an area under the curve (AUC) for the receiver operating characteristics (ROC) of 0.81, and a significant correlation between predicted and experimental binding affinities (ρ = 0.806, R(2) = 0.649, p < 0.005).

  5. Homology modeling, molecular docking and MD simulation studies to investigate role of cysteine protease from Xanthomonas campestris in degradation of Aβ peptide.

    PubMed

    Dhanavade, Maruti J; Jalkute, Chidambar B; Barage, Sagar H; Sonawane, Kailas D

    2013-12-01

    Cysteine protease is known to degrade amyloid beta peptide which is a causative agent of Alzheimer's disease. This cleavage mechanism has not been studied in detail at the atomic level. Hence, a three-dimensional structure of cysteine protease from Xanthomonas campestris was constructed by homology modeling using Geno3D, SWISS-MODEL, and MODELLER 9v7. All the predicted models were analyzed by PROCHECK and PROSA. Three-dimensional model of cysteine protease built by MODELLER 9v7 shows similarity with human cathepsin B crystal structure. This model was then used further for docking and simulation studies. The molecular docking study revealed that Cys17, His87, and Gln88 residues of cysteine protease form an active site pocket similar to human cathepsin B. Then the docked complex was refined by molecular dynamic simulation to confirm its stable behavior over the entire simulation period. The molecular docking and MD simulation studies showed that the sulfhydryl hydrogen atom of Cys17 of cysteine protease interacts with carboxylic oxygen of Lys16 of Aβ peptide indicating the cleavage site. Thus, the cysteine protease model from X. campestris having similarity with human cathepsin B crystal structure may be used as an alternate approach to cleave Aβ peptide a causative agent of Alzheimer's disease.

  6. Molecular Docking and Prediction of Pharmacokinetic Properties of Dual Mechanism Drugs that Block MAO-B and Adenosine A(2A) Receptors for the Treatment of Parkinson's Disease.

    PubMed

    Azam, Faizul; Madi, Arwa M; Ali, Hamed I

    2012-07-01

    Monoamine oxidase B (MAO-B) inhibitory potential of adenosine A(2A) receptor (AA(2A)R) antagonists has raised the possibility of designing dual-target-directed drugs that may provide enhanced symptomatic relief and that may also slow the progression of Parkinson's disease (PD) by protecting against further neurodegeneration. To explain the dual inhibition of MAO-B and AA(2A)R at the molecular level, molecular docking technique was employed. Lamarckian genetic algorithm methodology was used for flexible ligand docking studies. A good correlation (R(2)= 0.524 and 0.627 for MAO-B and AA(2A)R, respectively) was established between docking predicted and experimental K(i) values, which confirms that the molecular docking approach is reliable to study the mechanism of dual interaction of caffeinyl analogs with MAO-B and AA(2A)R. Parameters for Lipinski's "Rule-of-Five" were also calculated to estimate the pharmacokinetic properties of dual-target-directed drugs where both MAO-B inhibition and AA(2A)R antagonism exhibited a positive correlation with calculated LogP having a correlation coefficient R(2) of 0.535 and 0.607, respectively. These results provide some beneficial clues in structural modification for designing new inhibitors as dual-target-directed drugs with desired pharmacokinetic properties for the treatment of PD.

  7. A combined molecular docking-based and pharmacophore-based target prediction strategy with a probabilistic fusion method for target ranking.

    PubMed

    Li, Guo-Bo; Yang, Ling-Ling; Xu, Yong; Wang, Wen-Jing; Li, Lin-Li; Yang, Sheng-Yong

    2013-07-01

    Herein, a combined molecular docking-based and pharmacophore-based target prediction strategy is presented, in which a probabilistic fusion method is suggested for target ranking. Establishment and validation of the combined strategy are described. A target database, termed TargetDB, was firstly constructed, which contains 1105 drug targets. Based on TargetDB, the molecular docking-based target prediction and pharmacophore-based target prediction protocols were established. A probabilistic fusion method was then developed by constructing probability assignment curves (PACs) against a set of selected targets. Finally the workflow for the combined molecular docking-based and pharmacophore-based target prediction strategy was established. Evaluations of the performance of the combined strategy were carried out against a set of structurally different single-target compounds and a well-known multi-target drug, 4H-tamoxifen, which results showed that the combined strategy consistently outperformed the sole use of docking-based and pharmacophore-based methods. Overall, this investigation provides a possible way for improving the accuracy of in silico target prediction and a method for target ranking.

  8. Homology modeling, simulation and molecular docking studies of catechol-2, 3-Dioxygenase from Burkholderia cepacia: Involved in degradation of Petroleum hydrocarbons

    PubMed Central

    Ajao, AT; Kannan, M; Yakubu, SE; VJ, Umoh; JB, Ameh

    2012-01-01

    Catechol 2, 3-dioxygenase is present in several types of bacteria and undergoes degradation of environmental pollutants through an important key biochemical pathways. Specifically, this enzyme cleaves aromatic rings of several environmental pollutants such as toluene, xylene, naphthalene and biphenyl derivatives. Hence, the importance of Catechol 2, 3-dioxygenase and its role in the degradation of environmental pollutants made us to predict the three-dimensional structure of Catechol 2, 3-dioxygenase from Burkholderia cepacia. The 10ns molecular dynamics simulation was carried out to check the stability of the modeled Catechol 2, 3- dioxygenase. The results show that the model was energetically stable, and it attains their equilibrium within 2000 ps of production MD run. The docking of various petroleum hydrocarbons into the Catechol 2,3-dioxygenase reveals that the benzene, O-xylene, Toluene, Fluorene, Naphthalene, Carbazol, Pyrene, Dibenzothiophene, Anthracene, Phenanthrene, Biphenyl makes strong hydrogen bond and Van der waals interaction with the active site residues of H150, L152, W198, H206, H220, H252, I254, T255, Y261, E271, L276 and F309. Free energy of binding and estimated inhibition constant of these compounds demonstrates that they are energetically stable in their binding cavity. Chrysene shows positive energy of binding in the active site atom of Fe. Except Pyrene all the substrates made close contact with Fe atom by the distance ranges from 1.67 to 2.43 Å. In addition to that, the above mentioned substrate except pyrene all other made π-π stacking interaction with H252 by the distance ranges from 3.40 to 3.90 Å. All these docking results reveal that, except Chrysene all other substrate has good free energy of binding to hold enough in the active site and makes strong VdW interaction with Catechol-2,3-dioxygenase. These results suggest that, the enzyme is capable of catalyzing the above-mentioned substrate. PMID:23144539

  9. Molecular Docking, Molecular Dynamics, and Structure-Activity Relationship Explorations of 14-Oxygenated N-Methylmorphinan-6-ones as Potent μ-Opioid Receptor Agonists.

    PubMed

    Noha, Stefan M; Schmidhammer, Helmut; Spetea, Mariana

    2017-02-09

    Among opioids, morphinans are of major importance as the most effective analgesic drugs acting primarily via μ-opioid receptor (μ-OR) activation. Our long-standing efforts in the field of opioid analgesics from the class of morphinans led to N-methylmorphinan-6-ones differently substituted at positions 5 and 14 as μ-OR agonists inducing potent analgesia and fewer undesirable effects. Herein we present the first thorough molecular modeling study and structure-activity relationship (SAR) explorations aided by docking and molecular dynamics (MD) simulations of 14-oxygenated N-methylmorphinan-6-ones to gain insights into their mode of binding to the μ-OR and interaction mechanisms. The structure of activated μ-OR provides an essential model for how ligand/μ-OR binding is encoded within small chemical differences in otherwise structurally similar morphinans. We reveal important molecular interactions that these μ-agonists share and distinguish them. The molecular docking outcomes indicate the crucial role of the relative orientation of the ligand in the μ-OR binding site, influencing the propensity of critical non-covalent interactions that are required to facilitate ligand/μ-OR interactions and receptor activation. The MD simulations point out minor differences in the tendency to form hydrogen bonds by the 4,5α-epoxy group, along with the tendency to affect the 3-7 lock switch. The emerged SARs reveal the subtle interplay between the substituents at positions 5 and 14 in the morphinan scaffold by enabling the identification of key structural elements that determine the distinct pharmacological profiles. This study provides a significant structural basis for understanding ligand binding and μ-OR activation by the 14-oxygenated N-methylmorphinan-6-ones, which should be useful for guiding drug design.

  10. Computer Aided Drug Design for Multi-Target Drug Design: SAR /QSAR, Molecular Docking and Pharmacophore Methods.

    PubMed

    Abdolmaleki, Azizeh; Ghasemi, Jahan B; Ghasemi, Fatemeh

    2017-01-01

    Multi-target drugs against particular multiple targets get better protection, resistance profiles and curative influence by cooperative rules of a key beneficial target with resistance behavior and compensatory elements. Computational techniques can assist us in the efforts to design novel drugs (ligands) with a preferred bioactivity outline and alternative bioactive molecules at an early stage. A number of in silico methods have been explored extensively in order to facilitate the investigation of individual target agents and to propose a selective drug. A different, progressively more significant field which is used to predict the bioactivity of chemical compounds is the data mining method. Some of the previously mentioned methods have been investigated for multi-target drug design (MTDD) to find drug leads interact simultaneously with multiple targets. Several cheminformatics methods and structure-based approaches try to extract information from units working cooperatively in a biomolecular system to fulfill their task. To dominate the difficulties of the experimental specification of ligand-target structures, rational methods, namely molecular docking, SAR and QSAR are vital substitutes to obtain knowledge for each structure in atomic insight. These procedures are logically successful for the prediction of binding affinity and have shown promising potential in facilitating MTDD. Here, we review some of the important features of the multi-target therapeutics discoveries using the computational approach, highlighting the SAR, QSAR, docking and pharmacophore methods to discover interactions between drug-target that could be leveraged for curative benefits. A summary of each, followed by examples of its applications in drug design has been provided. Computational efficiency of each method has been represented according to its main strengths and limitations.

  11. Homology modeling, molecular dynamics, e-pharmacophore mapping and docking study of Chikungunya virus nsP2 protease.

    PubMed

    Singh, Kh Dhanachandra; Kirubakaran, Palani; Nagarajan, Shanthi; Sakkiah, Sugunadevi; Muthusamy, Karthikeyan; Velmurgan, Devadasan; Jeyakanthan, Jeyaraman

    2012-01-01

    To date, no suitable vaccine or specific antiviral drug is available to treat Chikungunya viral (CHIKV) fever. Hence, it is essential to identify drug candidates that could potentially impede CHIKV infection. Here, we present the development of a homology model of nsP2 protein based on the crystal structure of the nsP2 protein of Venezuelan equine encephalitis virus (VEEV). The protein modeled was optimized using molecular dynamics simulation; the junction peptides of a nonstructural protein complex were then docked in order to investigate the possible protein-protein interactions between nsP2 and the proteins cleaved by nsP2. The modeling studies conducted shed light on the binding modes, and the critical interactions with the peptides provide insight into the chemical features needed to inhibit the CHIK virus infection. Energy-optimized pharmacophore mapping was performed using the junction peptides. Based on the results, we propose the pharmacophore features that must be present in an inhibitor of nsP2 protease. The resulting pharmacophore model contained an aromatic ring, a hydrophobic and three hydrogen-bond donor sites. Using these pharmacophore features, we screened a large public library of compounds (Asinex, Maybridge, TOSLab, Binding Database) to find a potential ligand that could inhibit the nsP2 protein. The compounds that yielded a fitness score of more than 1.0 were further subjected to Glide HTVS and Glide XP. Here, we report the best four compounds based on their docking scores; these compounds have IDs of 27943, 21362, ASN 01107557 and ASN 01541696. We propose that these compounds could bind to the active site of nsP2 protease and inhibit this enzyme. Furthermore, the backbone structural scaffolds of these four lead compounds could serve as building blocks when designing drug-like molecules for the treatment of Chikungunya viral fever.

  12. Comparative molecular docking analysis of cytoplasmic dynein light chain DYNLL1 with pilin to explore the molecular mechanism of pathogenesis caused by Pseudomonas aeruginosa PAO.

    PubMed

    Kausar, Samina; Asif, Muhammad; Bibi, Nousheen; Rashid, Sajid

    2013-01-01

    Cytoplasmic dynein light chain 1 (DYNLL1) is a component of large protein complex, which is implicated in cargo transport processes, and is known to interact with many cellular and viral proteins through its short consensus motif (K/R)XTQT. Still, it remains to be explored that bacterial proteins also exhibit similar recognition sequences to make them vulnerable to host defense mechanism. We employed multiple docking protocols including AUTODOCK, PatchDock, ZDOCK, DOCK/PIERR and CLUSPRO to explore the DYNLL1 and Pilin interaction followed by molecular dynamics simulation assays. Subsequent structural comparison of the predicted binding site for DYNLL1-Pilin complex against the experimentally verified DYNLL1 binding partners was performed to cross check the residual contributions and to determine the binding mode. On the basis of in silico analysis, here we describe a novel interaction of DYNLL1 and receptor binding domain of Pilin (the main protein constituent of bacterial type IV Pili) of gram negative bacteria Pseudomonas aeruginosa (PAO), which is the third most common nosocomial pathogen associated with the life-threatening infections. Evidently, our results underscore that Pilin specific motif (KSTQD) exhibits a close structural similarity to that of Vaccinia virus polymerase, P protein Rabies and P protein Mokola viruses. We speculate that binding of DYNLL1 to Pilin may trigger an uncontrolled inflammatory response of the host immune system during P. aeruginosa chronic infections thereby opening a new pioneering area to investigate the role of DYNLL1 in gram negative bacterial infections other than viral infections. Moreover, by manifesting a strict correspondence between sequence and function, our study anticipates a novel drug target site to control the complications caused by P. aeruginosa infections.

  13. Target guided isolation, in-vitro antidiabetic, antioxidant activity and molecular docking studies of some flavonoids from Albizzia Lebbeck Benth. bark

    PubMed Central

    2014-01-01

    Background Albizzia Lebbeck Benth. is traditionally important plant and is reported to possess a variety of pharmacological actions. The present research exertion was undertaken to isolate and characterized the flavonoids from the extract of stem bark of Albizzia Lebbeck Benth. and to evaluate the efficacy of the isolated flavonoids on in-vitro models of type-II diabetes. Furthermore, the results of in-vitro experimentation inveterate by the molecular docking studies of the isolated flavonoids on α-glucosidase and α-amylase enzymes. Methods Isolation of the flavonoids from the methanolic extract of stem bark of A. Lebbeck Benth was executed by the Silica gel (Si) column chromatography to yield different fractions. These fractions were then subjected to purification to obtain three important flavonoids. The isolated flavonoids were then structurally elucidated with the assist of 1H-NMR, 13C-NMR, and Mass spectroscopy. In-vitro experimentation was performed with evaluation of α-glucosidase, α-amylase and DPPH inhibition capacity. Molecular docking study was performed with GLIDE docking software. Results Three flavonoids, (1) 5-deoxyflavone (geraldone), (2) luteolin and (3) Isookanin were isolated from the EtOAc fraction of the methanolic extract of Albizzia lebbeck Benth bark. (ALD). All the compounds revealed to inhibit the α-glucosidase and α-amylase enzymes in in-vitro investigation correlating to reduce the plasma glucose level. Molecular docking study radically corroborates the binding affinity and inhibition of α-glucosidase and α-amylase enzymes. Conclusion The present research exertion demonstrates the anti-diabetic and antioxidant activity of the important isolated flavonoids with inhibition of α-glucosidase, α-amylase and DPPH which is further supported by molecular docking analysis. PMID:24886138

  14. Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules

    NASA Astrophysics Data System (ADS)

    Beckford, Floyd A.; Brock, Alyssa; Gonzalez-Sarrías, Antonio; Seeram, Navindra P.

    2016-10-01

    We have synthesized a trio of gallium complexes bearing 9-anthraldehyde thiosemicarbazones. The complexes were assessed for their anticancer activity and their biophysical reactivity was also investigated. The three complexes displayed good cytotoxic profiles against two human colon cancer cell lines, HCT-116 and Caco-2. The IC50 ranged from 4.7 to 44.1 μM with the complex having an unsubstituted amino group on the thiosemicarbazone being the most active. This particular complex also showed a high therapeutic index. All three complexes bind strongly to DNA via intercalation with binding constants ranging from 7.46 × 104 M-1 to 3.25 × 105 M-1. The strength of the binding cannot be directly related to the level of anticancer activity. The complexes also bind strongly to human serum albumin with binding constants on the order of 104-105 M-1 as well. The complexes act as chemical nucleases as evidenced by their ability to cleave pBR322 plasmid DNA. The binding constants along with the cleavage results may suggest that the extent of DNA interaction is not directly correlated with anticancer activity. The results of docking studies with DNA, ribonucleotide reductase and human serum albumin, however showed that the complex with the best biological activity had the largest binding constant to DNA.

  15. Design, Synthesis, Molecular Docking, and Antibacterial Evaluation of Some Novel Flouroquinolone Derivatives as Potent Antibacterial Agent

    PubMed Central

    Patel, Mehul M.; Patel, Laxman J.

    2014-01-01

    Objective. Quinolone moiety is an important class of nitrogen containing heterocycles widely used as key building blocks for medicinal agents. It exhibits a wide spectrum of pharmacophores and has bactericidal, antiviral, antimalarial, and anticancer activities. In view of the reported antimicrobial activity of various fluoroquinolones, the importance of the C-7 substituents is that they exhibit potent antimicrobial activities. Our objective was to synthesize newer quinolone analogues with increasing bulk at C-7 position of the main 6-fluoroquinolone scaffold to produce the target compounds which have potent antimicrobial activity. Methods. A novel series of 1-ethyl-6-fluoro-4-oxo-7-{4-[2-(4-substituted phenyl)-2-(substituted)-ethyl]-1-piperazinyl}-1,4-dihydroquinoline-3-carboxylic acid derivatives were synthesized. To understand the interaction of binding sites with bacterial protein receptor, the docking study was performed using topoisomerase II DNA gyrase enzymes (PDB ID: 2XCT) by Schrodinger's Maestro program. In vitro antibacterial activity of the synthesized compounds was studied and the MIC value was calculated by the broth dilution method. Results. Among all the synthesized compounds, some compounds showed potent antimicrobial activity. The compound 8g exhibited good antibacterial activity. Conclusion. This investigation identified the potent antibacterial agents against certain infections. PMID:25574496

  16. Synthesis, molecular docking and biological evaluation of new steroidal 4H-pyrans

    NASA Astrophysics Data System (ADS)

    Uzzaman, Shams; Dar, Ayaz Mahmood; Sohail, Aamir; Bhat, Sheraz; mustafa, Mir Faisal; Khan, Yusuf

    2014-01-01

    A series of new steroidal 4H-pyrans (4-6) have been synthesized from steroidal α, β-unsaturated ketones (1-3). The products (4-6) were characterized by IR, 1H NMR, 13C NMR, MS and analytical data. The interaction studies of compounds (4-6) with DNA were carried out by employing gel electrophoresis, UV-vis and fluorescence spectroscopy. The gel electrophoresis pattern revealed that compounds (4-6) bind to DNA and also demonstrated that the compound 6 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322. The compounds 4 and 5 bind to DNA preferentially through electrostatic and hydrophobic interactions with Kb values found to be 5.3 × 103 and 3.7 × 103 M-1, respectively, indicating the higher binding affinity of compound 4 towards DNA. The docking study suggested the intercalation of compounds in between the nucleotide base pairs. The cytotoxicity and genotoxicity of the newly synthesized compounds were checked by MTT and comet assay, respectively during which compound 6 showed potential behaviour.

  17. Steroidal pyrimidines: Synthesis, characterization, molecular docking studies with DNA and in vitro cytotoxicity

    NASA Astrophysics Data System (ADS)

    Shamsuzzaman; Dar, Ayaz Mahmood; Yaseen, Zahid; Alam, Khursheed; Hussain, Altaf; Gatoo, Manzoor Ahmad

    2013-08-01

    A series of new steroid pyrimidines (7-9) were synthesized by reacting steroidal thiosemicarbazones (4-6) with diethyl malonate. The new compounds were characterized by IR, 1H NMR, 13C NMR, MS and analytical data. The interaction studies of compounds (7-9) with DNA were carried out by employing gel electrophoresis, UV-vis and fluorescence spectroscopy. The acting force between the compounds (7-9) and DNA was mainly hydrophobic while the other interactions like van der Waals, hydrogen bonding cannot be ruled out. The gel electrophoresis pattern also demonstrated that the compound 7 alone or in presence of Cu (II) causes the nicking of supercoiled pBR322 and it seems to follow the mechanistic pathway involving generation of hydroxyl radicals that are responsible for initiating DNA strand scission. The docking study of compounds (7-9) suggested that the intercalation of compounds in between the nucleotide base pairs might be due to the presence of pyrimidine moiety in steroid molecule. MTT assay was carried out to check the toxicity of new compounds (7-9) against the different human cancer as well as non-cancer cell lines A545, MCF-7, HeLa, HL-60, SW480, HepG2, HT-29, A549, 184B5, MCF10A, NL-20, HPC and HPLF. Apoptotic degradation of DNA in presence of steroidal pyrimidines (7-9) was analyzed by agarose gel electrophoresis and visualized by ethidium bromide staining (comet assay).

  18. Synthesis biological screening and molecular docking studies of some tin (IV) Schiff base adducts.

    PubMed

    Rehman, Wajid; Yasmeen, Rehana; Rahim, Fazal; Waseem, Muhammad; Guo, Cun-Yue; Hassan, Zonera; Rashid, Umer; Ayub, Khurshid

    2016-11-01

    The search for an alternative to platinum anticancer agents is a major motivation for continuing investigations concerning the antitumor properties of other transition metal-based compounds. Keeping this in view, synthesis, antitumor and antimicrobial activity of diorganotin (IV) complexes was studied. A novel series of diorganotin (IV) complexes of the Schiff base ligand derived from 7-methoxy-2-hydroxy-1-naphthaldehyde, 1,2-phenylenediamine, Salicylaldehyde were synthesized. Physical and spectral examination was done through various techniques using elemental analyses, IR, (1)H, (13)C, (119)Sn NMR, and (119m)Sn Mössbauer techniques respectively. The results obtained are in good agreement with 1:1:1 stoichiometry of Schiff base and 2:1 stoichiometry of the complexes. Octahedral geometry was assigned to all the synthesized complexes within six (6) coordination number around the tin. Antitumor activity was screened against human oral epidermoid carcinoma (KB) cell line. The diethyltin (IV) complex 2 showed the most promising cytotoxic results (IC50=0.35μM) against the cell line which is comparable with cisplatin (IC50=0.37μM). Docking studies revealed that these complexes can bind favorably within cisplatin binding site and the binding energy of complex 2 is more than that of cisplatin. Furthermore, binding of these complexes on human topoisomerase IIα enzyme and revealed that these complexes intercalating within the inter-strand of DNA showing interactions with DNA as well as protein that may results in DNA damage and cell death.

  19. Modeling, molecular dynamics, and docking assessment of transcription factor rho: a potential drug target in Brucella melitensis 16M

    PubMed Central

    Pradeepkiran, Jangampalli Adi; Kumar, Konidala Kranthi; Kumar, Yellapu Nanda; Bhaskar, Matcha

    2015-01-01

    The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho) inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho’s structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO) as a template in MODELLER (v 9.10). The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9) and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial) database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds – ZINC24934545 and ZINC72319544 – that showed high binding affinity among 2,829 drug analogs that bind with key active-site residues; these residues are considered for protein-ligand binding and unbinding pathways via steered molecular dynamics simulations. Arg215 in the model plays an important role in the stability of the protein

  20. Docking, molecular dynamics and quantitative structure-activity relationship studies for HEPTs and DABOs as HIV-1 reverse transcriptase inhibitors.

    PubMed

    Mao, Yating; Li, Yan; Hao, Ming; Zhang, Shuwei; Ai, Chunzhi

    2012-05-01

    As a key component in combination therapy for acquired immunodeficiency syndrome (AIDS), non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been proven to be an essential way in stopping HIV-1 replication. In the present work, in silico studies were conducted on a series of 119 NNRTIs, including 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) and dihydroalkoxybenzyloxopyrimidine (DABO) derivatives by using the comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), docking simulations and molecular dynamics (MD). The statistical results of the optimal model, the ligand-based CoMSIA one (Q(2) = 0.48, R(ncv)(2) =0.847, R(pre)(2) = 0.745) validates its satisfactory predictive capacity both internally and externally. The contour maps, docking and MD results correlate well with each other, drawing conclusions as follows: 1) Compounds with bulky substituents in position-6 of ring A, hydrophobic groups around position- 1, 2, 6 are preferable to the biological activities; 2) Two hydrogen bonds between RT inhibitor and the Tyr 318, Lys 101 residues, respectively, and a π-π bond between the inhibitor and Trp 188 are formed and crucial to the orientation of the active conformation of the molecules; 3) The binding pocket is essentially hydrophobic, which are determined by residues such as Trp 229, Tyr 318, Val 179, Tyr 188 and Val 108, and hydrophobic substituents may bring an improvement to the biological activity; 4) DABO and HEPT derivatives have different structures but take a similar mechanism to inhibit RT. The potency difference between two isomers in HEPTs can be explained by the distinct locations of the 6-naphthylmethyl substituent and the reasons are explained in details. All these results could be employed to alter the structural scaffold in order to develop new HIV-1 RT inhibitors that have an improved biological property. To the best of our knowledge, this is the first report on 3D

  1. Modeling, molecular dynamics, and docking assessment of transcription factor rho: a potential drug target in Brucella melitensis 16M.

    PubMed

    Pradeepkiran, Jangampalli Adi; Kumar, Konidala Kranthi; Kumar, Yellapu Nanda; Bhaskar, Matcha

    2015-01-01

    The zoonotic disease brucellosis, a chronic condition in humans affecting renal and cardiac systems and causing osteoarthritis, is caused by Brucella, a genus of Gram-negative, facultative, intracellular pathogens. The mode of transmission and the virulence of the pathogens are still enigmatic. Transcription regulatory elements, such as rho proteins, play an important role in the termination of transcription and/or the selection of genes in Brucella. Adverse effects of the transcription inhibitors play a key role in the non-successive transcription challenges faced by the pathogens. In the investigation presented here, we computationally predicted the transcription termination factor rho (TtFRho) inhibitors against Brucella melitensis 16M via a structure-based method. In view the unknown nature of its crystal structure, we constructed a robust three-dimensional homology model of TtFRho's structure by comparative modeling with the crystal structure of the Escherichia coli TtFRho (Protein Data Bank ID: 1PVO) as a template in MODELLER (v 9.10). The modeled structure was optimized by applying a molecular dynamics simulation for 2 ns with the CHARMM (Chemistry at HARvard Macromolecular Mechanics) 27 force field in NAMD (NAnoscale Molecular Dynamics program; v 2.9) and then evaluated by calculating the stereochemical quality of the protein. The flexible docking for the interaction phenomenon of the template consists of ligand-related inhibitor molecules from the ZINC (ZINC Is Not Commercial) database using a structure-based virtual screening strategy against minimized TtFRho. Docking simulations revealed two inhibitors compounds - ZINC24934545 and ZINC72319544 - that showed high binding affinity among 2,829 drug analogs that bind with key active-site residues; these residues are considered for protein-ligand binding and unbinding pathways via steered molecular dynamics simulations. Arg215 in the model plays an important role in the stability of the protein-ligand complex

  2. CD4-gp120 interaction interface - a gateway for HIV-1 infection in human: molecular network, modeling and docking studies.

    PubMed

    Pandey, Deeksha; Podder, Avijit; Pandit, Mansi; Latha, Narayanan

    2016-09-29

    The major causative agent for Acquired Immune Deficiency Syndrome (AIDS) is Human Immunodeficiency Virus-1 (HIV-1). HIV-1 is a predominant subtype of HIV which counts on human cellular mechanism virtually in every aspect of its life cycle. Binding of viral envelope glycoprotein-gp120 with human cell surface CD4 receptor triggers the early infection stage of HIV-1. This study focuses on the interaction interface between these two proteins that play a crucial role for viral infectivity. The CD4-gp120 interaction interface has been studied through a comprehensive protein-protein interaction network (PPIN) analysis and highlighted as a useful step towards identifying potential therapeutic drug targets against HIV-1 infection. We prioritized gp41, Nef and Tat proteins of HIV-1 as valuable drug targets at early stage of viral infection. Lack of crystal structure has made it difficult to understand the biological implication of these proteins during disease progression. Here, computational protein modeling techniques and molecular dynamics simulations were performed to generate three-dimensional models of these targets. Besides, molecular docking was initiated to determine the desirability of these target proteins for already available HIV-1 specific drugs which indicates the usefulness of these protein structures to identify an effective drug combination therapy against AIDS.

  3. Exploring the interactions between isoprenoid chain and labdenediol diphosphate synthase based on molecular docking and quartz crystal microbalance.

    PubMed

    Liu, Wujun; Yang, Wei; Zhang, Yixin; Zhao, Zongbao Kent

    2014-12-01

    Many natural products and biosynthetic intermediates contain isoprenoid chains. Isoprenoid chains are believed to interact with some proteins in the biological systems, but such interactions remain poorly understood. Here labdenediol diphosphate synthase (LPPS) was used as a model to explore the molecular interactions involving isoprenoid chains. Both homology modeling and docking simulation results indicated that binding form between isoprenoid chain and LPPS is dominated by hydrophobic forces in one binding site. The interactions were also examined via quartz crystal microbalance (QCM) technology using synthetic isoprenoid chain-contained probes. The binding constant (1.51 μM(-1)), binding site number (n = 1) and key amino acid residues (Y196, F262, W266, F301, F308, W398, W439, and Y445) were obtained. Both computational and QCM results suggested that LPPS interacts strongly with farnesyl and geranylgeranyl groups. These interactions are primarily caused by hydrophobic and π-π interaction nature. Together, this study provided insightful information to understand molecular interactions between isoprenoid chains and proteins.

  4. Experimental, DFT and molecular docking studies on 2-(2-mercaptophenylimino)-4-methyl-2H-chromen-7-ol

    NASA Astrophysics Data System (ADS)

    Singh, Ashok Kumar; Singh, Ravindra Kumar

    2016-10-01

    A new coumarin derivative 2-(2-mercaptophenylimino)-4-methyl-2H-chromen-7-ol (COMSB) was synthesized and characterized with the help of 1H,13C NMR, FT-IR, FT-Raman and mass spectrometry. All quantum calculations were performed at DFT level of theory using B3LYP functional and 6-31G (d,p) as basis set. The UV-Vis spectrum studied by TD-DFT theory, with a hybrid exchange-correlation functional using Coulomb-attenuating method (CAM-B3LYP) in solvent phase gives similar pattern of bands, at energies and is consistent with that of experimental findings. The detailed analysis of vibrational (IR and Raman) spectra and their assignments has been done by computing Potential Energy Distribution (PED) using Gar2ped. Intra-molecular interactions were analyzed by 'Atoms in molecule' (AIM) approach. Computed first static hyperpolarizability (β0 = 8.583 × 10-30 esu) indicates non-linear optical (NLO) response of the molecule. Molecular docking studies show that the title molecule may act as potential acetylcholine esterase (AChE) inhibitor.

  5. Interaction of anticancer drug clofarabine with human serum albumin and human α-1 acid glycoprotein. Spectroscopic and molecular docking approach.

    PubMed

    Ajmal, Mohammad Rehan; Nusrat, Saima; Alam, Parvez; Zaidi, Nida; Khan, Mohsin Vahid; Zaman, Masihuz; Shahein, Yasser E; Mahmoud, Mohamed H; Badr, Gamal; Khan, Rizwan Hasan

    2017-02-20

    The binding interaction between clofarabine, an important anticancer drug and two important carrier proteins found abundantly in human plasma, Human Serum Albumin (HSA) and α-1 acid glycoprotein (AAG) was investigated by spectroscopic and molecular modeling methods. The results obtained from fluorescence quenching experiments demonstrated that the fluorescence intensity of HSA and AAG is quenched by clofarabine and the static mode of fluorescence quenching is operative. UV-vis spectroscopy deciphered the formation of ground state complex between anticancer drug and the two studied proteins. Clofarabine was found to bind at 298K with both AAG and HSA with the binding constant of 8.128×10(3) and 4.120×10(3) for AAG and HSA, respectively. There is stronger interaction of clofarabine with AAG as compared to HSA. The Gibbs free energy change was found to be negative for the interaction of clofarabine with AAG and HSA indicating that the binding process is spontaneous. Binding of clofarabine with HSA and AAG induced ordered structures in both proteins and lead to molecular compaction. Clofarabine binds to HSA near to drug site II. Hydrogen bonding and hydrophobic interactions were the main bonding forces between HSA-clofarabine and AAG-clofarabine as revealed by docking results. This study suggests the importance of binding of anticancer drug to AAG spatially in the diseases like cancers where the plasma concentration of AAG increases many folds. Design of drug dosage can be adjusted accordingly to achieve optimal treatment outcome.

  6. 3D-QSAR and molecular docking studies of selective agonists for the thyroid hormone receptor beta.

    PubMed

    Du, Juan; Qin, Jin; Liu, Huanxiang; Yao, Xiaojun

    2008-09-01

    Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) on a series of agonists of thyroid hormone receptor beta (TRbeta), which may lead to safe therapies for non-thyroid disorders while avoiding the cardiac side effects. The reasonable q(2) (cross-validated) values 0.600 and 0.616 and non-cross-validated r(2) values of 0.974 and 0.974 were obtained for CoMFA and CoMSIA models for the training set compounds, respectively. The predictive ability of two models was validated using a test set of 12 molecules which gave predictive correlation coefficients (r(pred)(2)) of 0.688 and 0.674, respectively. The Lamarckian Genetic Algorithm (LGA) of AutoDock 4.0 was employed to explore the binding mode of the compound at the active site of TRbeta. The results not only lead to a better understanding of interactions between these agonists and the thyroid hormone receptor beta but also can provide us some useful information about the influence of structures on the activity which will be very useful for designing some new agonist with desired activity.

  7. Multiple templates-based homology modeling enhances structure quality of AT1 receptor: validation by molecular dynamics and antagonist docking.

    PubMed

    Sokkar, Pandian; Mohandass, Shylajanaciyar; Ramachandran, Murugesan

    2011-07-01

    We present a comparative account on 3D-structures of human type-1 receptor (AT1) for angiotensin II (AngII), modeled using three different methodologies. AngII activates a wide spectrum of signaling responses via the AT1 receptor that mediates physiological control of blood pressure and diverse pathological actions in cardiovascular, renal, and other cell types. Availability of 3D-model of AT1 receptor would significantly enhance the development of new drugs for cardiovascular diseases. However, templates of AT1 receptor with low sequence similarity increase the complexity in straightforward homology modeling, and hence there is a need to evaluate different modeling methodologies in order to use the models for sensitive applications such as rational drug design. Three models were generated for AT1 receptor by, (1) homology modeling with bovine rhodopsin as template, (2) homology modeling with multiple templates and (3) threading using I-TASSER web server. Molecular dynamics (MD) simulation (15 ns) of models in explicit membrane-water system, Ramachandran plot analysis and molecular docking with antagonists led to the conclusion that multiple template-based homology modeling outweighs other methodologies for AT1 modeling.

  8. Structural studies of a vasorelaxant lectin from Dioclea reflexa Hook seeds: Crystal structure, molecular docking and dynamics.

    PubMed

    Pinto-Junior, Vanir Reis; Osterne, Vinicius José Silva; Santiago, Mayara Queiroz; Correia, Jorge Luis Almeida; Pereira-Junior, Francisco Nascimento; Leal, Rodrigo Bainy; Pereira, Maria Gonçalves; Chicas, Larissa Silva; Nagano, Celso Shiniti; Rocha, Bruno Anderson Matias; Silva-Filho, José Caetano; Ferreira, Wandemberg Paiva; Rocha, Cíntia Renata Costa; Nascimento, Kyria Santiago; Assreuy, Ana Maria Sampaio; Cavada, Benildo Sousa

    2017-05-01

    The three-dimensional structure of Dioclea reflexa seed lectin (DrfL) was studied in detail by a combination of X-ray crystallography, molecular docking and molecular dynamics. DrfL was purified by affinity chromatography using Sephadex G-50 matrix. Its primary structure was obtained by mass spectrometry, and crystals belonging to orthorhombic space group P212121 were grown by the vapor diffusion method at 293K. The crystal structure was solved at 1.765Å and was very similar to that of other lectins from the same subtribe. The structure presented Rfactor and Rfree of 21.69% and 24.89%, respectively, with no residues in nonallowed regions of Ramachandran plot. Similar to other Diocleinae lectins, DrfL was capable of relaxing aortic rings via NO induction, with CRD participation, albeit with low intensity (32%). In silico analysis results demonstrated that DrfL could strongly interact with complex N-glycans, components of blood vessel glycoconjugates. Despite the high similarity among Diocleinae lectins, it was also reported that each lectin has unique CRD properties that influence carbohydrate binding, resulting in different biological effects presented by these molecules.

  9. Influence of bromoethyl group on biological activity of 5-fluorouracil prodrug: Insights from X-ray crystallography and molecular docking

    NASA Astrophysics Data System (ADS)

    Li, Xian-Chuan; Liu, Kuan-Guan; Qin, Da-An; Cheng, Chen-Chen; Chen, Bing-Xiong; Hu, Mao-Lin

    2012-11-01

    To develop alkyl halides for a promising prodrug system, a 5-fluorouracil prodrug containing a bromoethyl group (5-FUBr) was synthesized and its hydrophobicity, cytotoxicity and DNA-bonding ability were investigated in detail. Compare with 5-fluorouracil, 5-FUBr exhibits a great advantage of hydrophobicity and shows significant reduction in toxic side effect. To explore the mechanism of action of 5-FUBr at the molecular level, X-ray crystallography and molecular docking were exploited to make a more detailed analysis of the bromoethyl contribution to the construction of meaningful structure-activity relationship. Details of X-ray crystal structure of 5-FUBr suggest that 5-fluorouracil may be more apt to be released from 5-FUBr. The appearance of the bromoethyl group in 5-FUBr makes a remarkable impact on inhibition of thymidylate synthase (TS), and the impact of subtle structural variation between 5-fluorouracil and 5-FUBr should be taken into account in the process of developing this family of 5-fluorouracil prodrugs.

  10. In Silico Drug-Designing Studies on Flavanoids as Anticolon Cancer Agents: Pharmacophore Mapping, Molecular Docking, and Monte Carlo Method-Based QSAR Modeling.

    PubMed

    Simon, Lalitha; Imane, Abdelli; Srinivasan, K K; Pathak, Lokesh; Daoud, I

    2016-04-08

    In silico molecular modeling studies were carried out on some newly synthesized flavanoid analogues. Search for potential targets for these compounds was performed using pharmacophore-mapping algorithm employing inverse screening of some representative compounds to a large set of pharmacophore models constructed from human target proteins. Further, molecular docking studies were carried out to assess binding affinity of these compounds to proteins mediating tumor growth. In vitro anticancer studies were carried out on colon cancer cell lines (HCT116) to assess validity of this approach for target identification of the new compounds. Further important structural features of compounds for anticolon cancer activity were assessed using Monte Carlo-based SMILES and hydrogen graph-Based QSAR studies. In conclusion this study have depicted successful and stepwise application of pharmacophore mapping, molecular docking, and QSAR studies in target identification and lead optimization of flavonoids.

  11. Atomic insight into designed carbamate-based derivatives as acetylcholine esterase (AChE) inhibitors: a computational study by multiple molecular docking and molecular dynamics simulation.

    PubMed

    Mohammadi, Tecush; Ghayeb, Yousef

    2017-01-11

    Over 100 variants have been designed and studied, using multiple docking methods such as Autodock Vina, ArgusLab, Molegro Virtual Docker, and Hex-Cuda, to study the effect of alteration in the structure of carbamate-based acetylcholyne esterase (AChE) inhibitors. Sixteen selected systems were then subjected to 14 ns molecular dynamics (MD) simulations. Results from all the docking methods are in agreement. Variants that involved biphenyl substituents possess the most negative binding energies in the -37.64 to -39.31 kJ mol(-1) range due to their π-π interactions with AChE aromatic residues. The root mean square deviation values showed that all of these components achieved equilibration after 6 ns. Gyration radius (Rg) and solvent accessibility surface area were calculated to further investigate the AChE conformational changes in the presence of these components. MD simulation results suggested that these components might interact with AChE, possibly with no major changes in AChE secondary and tertiary structures.

  12. Molecular docking studies of (X-methylphenyl)-5-nitro-6-amino-3-pyridinecarboxmide (X=2,3,4,5,6) as potential inhibitors for Alzheimer's disease

    NASA Astrophysics Data System (ADS)

    Premkumar, S.; Asath, R. Mohamed; Rekha, T. N.; Jawahar, A.; Mathavan, T.; Benial, A. Milton Franklin

    2016-05-01

    An insilico and density functional theory (DFT) calculations were carried out for (X-methylphenyl)-5-nitro-6-amino-3-pyridinecarboxmide (X-MPNAPC),{X=2,3,4,5,6} to evaluate the potential inhibitors for Alzheimer's disease. The molecular structure of 2-MPNAPC, 3-MPNAPC, 4-MPNAPC, 5-MPNAPC and 6-MPNAPC molecules was optimized by the DFT/B3LYP method with cc-pVTZ basis set using the Gaussian 09 program. The inhibitory nature of the molecules against enzyme acetylcholinesterase (AChE) catalyzes was evaluated by molecular docking studies. The molecular docking parameters such as binding energy, inhibition constant and intermolecular energy were calculated by the AutoDock 4.0 software. The higher binding energy, intermolecular energy and lower inhibition constant values suggested that the 2-MPNAPC molecule has higher inhibitory nature against the AChE catalyzes, which confirm that the 2-MPNAPC molecule is a potential inhibitor for the Alzheimer's disease. The molecular reactivity was also studied by the frontier molecular orbitals analysis.

  13. A combined spectroscopic, docking and molecular dynamics simulation approach to probing binding of a Schiff base complex to human serum albumin

    NASA Astrophysics Data System (ADS)

    Fani, N.; Bordbar, A. K.; Ghayeb, Y.

    2013-02-01

    The molecular mechanism of a Schiff base complex ((E)-((E)-2-(3-((E)-((E)-3(mercapto (methylthio) methylene)cyclopentylidene) amino) propylimino) cyclopentylidene) (methylthio) methanethiol) binding to Human Serum Albumin (HSA) was investigated by fluorescence quenching, absorption spectroscopy, molecular docking and molecular dynamics (MD) simulation procedures. The fluorescence emission of HSA was quenched by this Schiff base complex that has been analyzed for estimation of binding parameters. The titration of Schiff base solution by various amount of HSA was also followed by UV-Vis absorption spectroscopy and the corresponding data were analyzed by suitable models. The results revealed that this Schiff base has an ability to bind strongly to HSA and formed 1:1 complex. Energy transfer mechanism of quenching was discussed and the value of 5.45 ± 0.06 nm was calculated as the mean distance between the bound complex and the Trp residue. This is implying the high possibility of energy transfer from HSA to this Schiff base complex. Molecular docking results indicated that the main active binding site for this Schiff base complex is site III in subdomain IB. Moreover, MD simulation results suggested that this Schiff base complex can interact with HSA, without affecting the secondary structure of HSA but probably with a slight modification of its tertiary structure. MD simulations, molecular docking and experimental data reciprocally supported each other.

  14. A combined spectroscopic, docking and molecular dynamics simulation approach to probing binding of a Schiff base complex to human serum albumin.

    PubMed

    Fani, N; Bordbar, A K; Ghayeb, Y

    2013-02-15

    The molecular mechanism of a Schiff base complex ((E)-((E)-2-(3-((E)-((E)-3(mercapto (methylthio) methylene)cyclopentylidene) amino) propylimino) cyclopentylidene) (methylthio) methanethiol) binding to Human Serum Albumin (HSA) was investigated by fluorescence quenching, absorption spectroscopy, molecular docking and molecular dynamics (MD) simulation procedures. The fluorescence emission of HSA was quenched by this Schiff base complex that has been analyzed for estimation of binding parameters. The titration of Schiff base solution by various amount of HSA was also followed by UV-Vis absorption spectroscopy and the corresponding data were analyzed by suitable models. The results revealed that this Schiff base has an ability to bind strongly to HSA and formed 1:1 complex. Energy transfer mechanism of quenching was discussed and the value of 5.45 ± 0.06 nm was calculated as the mean distance between the bound complex and the Trp residue. This is implying the high possibility of energy transfer from HSA to this Schiff base complex. Molecular docking results indicated that the main active binding site for this Schiff base complex is site III in subdomain IB. Moreover, MD simulation results suggested that this Schiff base complex can interact with HSA, without affecting the secondary structure of HSA but probably with a slight modification of its tertiary structure. MD simulations, molecular docking and experimental data reciprocally supported each other.

  15. Cinnamide Derivatives as Mammalian Arginase Inhibitors: Synthesis, Biological Evaluation and Molecular Docking

    PubMed Central

    Pham, Thanh-Nhat; Bordage, Simon; Pudlo, Marc; Demougeot, Céline; Thai, Khac-Minh; Girard-Thernier, Corine

    2016-01-01

    Arginases are enzymes that are involved in many human diseases and have been targeted for new treatments. Here a series of cinnamides was designed, synthesized and evaluated in vitro and in silico for their inhibitory activity against mammalian arginase. Using a microassay on purified liver bovine arginase (b-ARG I), (E)-N-(2-phenylethyl)-3,4-dihydroxycinnamide, also named caffeic acid phenylamide (CAPA), was shown to be slightly more active than our natural reference inhibitor, chlorogenic acid (IC50 = 6.9 ± 1.3 and 10.6 ± 1.6 µM, respectively) but it remained less active that the synthetic reference inhibitor Nω-hydroxy-nor-l-arginine nor-NOHA (IC50 = 1.7 ± 0.2 µM). Enzyme kinetic studies showed that CAPA was a competitive inhibitor of arginase with Ki = 5.5 ± 1 µM. Whereas the activity of nor-NOHA was retained (IC50 = 5.7 ± 0.6 µM) using a human recombinant arginase I (h-ARG I), CAPA showed poorer activity (IC50 = 60.3 ± 7.8 µM). However, our study revealed that the cinnamoyl moiety and catechol function were important for inhibitory activity. Docking results on h-ARG I demonstrated that the caffeoyl moiety could penetrate into the active-site pocket of the enzyme, and the catechol function might interact with the cofactor Mn2+ and several crucial amino acid residues involved in the hydrolysis mechanism of arginase. The results of this study suggest that 3,4-dihydroxycinnamides are worth being considered as potential mammalian arginase inhibitors, and could be useful for further research on the development of new arginase inhibitors. PMID:27690022

  16. Molecular docking simulation studies on potent butyrylcholinesterase inhibitors obtained from microbial transformation of dihydrotestosterone

    PubMed Central

    2013-01-01

    Background Biotransformation is an effective technique for the synthesis of libraries of bioactive compounds. Current study on microbial transformation of dihydrotestosterone (DHT) (1) was carried out to produce various functionalized metabolites. Results Microbial transformation of DHT (1) by using two fungal cultures resulted in potent butyrylcholinesterase (BChE) inhibitors. Biotransformation with Macrophomina phaseolina led to the formation of two known products, 5α-androstan-3β,17β-diol (2), and 5β-androstan-3α,17β-diol (3), while biotransformation with Gibberella fujikuroi yielded six known metabolites, 11α,17β-dihydroxyandrost-4-en-3-one (4), androst-1,4-dien-3,17-dione (5), 11α-hydroxyandrost-4-en-3,17-dione (6), 11α-hydroxyandrost-1,4-dien-3,17-dione (7), 12β-hydroxyandrost-1,4-dien-3,17-dione (8), and 16α-hydroxyandrost-1,4-dien-3,17-dione (9). Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme. Metabolites 5–7 were identified as significant inhibitors of BChE. Furthermore, predicted results from docking simulation studies were in complete agreement with experimental data. Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors. Compounds 8 and 9 were not evaluated for enzyme inhibition activity both in vitro and in silico, due to lack of sufficient quantities. Conclusion Biotransformation of DHT (1) with two fungal cultures produced eight known metabolites. Metabolites 5–7 effectively inhibited the BChE activity. Cholinesterase inhibition is among the key strategies in the management of Alzheimer’s disease (AD). The experimental findings were further validated by in silico inhibition studies and possible modes of action were deduced. PMID:24103815

  17. The 3D Structure of the Binding Pocket of the Human Oxytocin Receptor for Benzoxazine Antagonists, Determined by Molecular Docking, Scoring Functions and 3D-QSAR Methods

    NASA Astrophysics Data System (ADS)

    Jójárt, Balázs; Martinek, Tamás A.; Márki, Árpád

    2005-05-01

    Molecular docking and 3D-QSAR studies were performed to determine the binding mode for a series of benzoxazine oxytocin antagonists taken from the literature. Structural hypotheses were generated by docking the most active molecule to the rigid receptor by means of AutoDock 3.05. The cluster analysis yielded seven possible binding conformations. These structures were refined by using constrained simulated annealing, and the further ligands were aligned in the refined receptor by molecular docking. A good correlation was found between the estimated Δ G bind and the p K i values for complex F. The Connolly-surface analysis, CoMFA and CoMSIA models q CoMFA 2 = 0.653, q CoMSA 2 = 0.630 and r pred,CoMFA 2 = 0.852 , r pred,CoMSIA 2 = 0.815) confirmed the scoring function results. The structural features of the receptor-ligand complex and the CoMFA and CoMSIA fields are in closely connected. These results suggest that receptor-ligand complex F is the most likely binding hypothesis for the studied benzoxazine analogs.

  18. In silico prediction of estrogen receptor subtype binding affinity and selectivity using statistical methods and molecular docking with 2-arylnaphthalenes and 2-arylquinolines.

    PubMed

    Wang, Zhizhong; Li, Yan; Ai, Chunzhi; Wang, Yonghua

    2010-09-20

    Over the years development of selective estrogen receptor (ER) ligands has been of great concern to researchers involved in the chemistry and pharmacology of anticancer drugs, resulting in numerous synthesized selective ER subtype inhibitors. In this work, a data set of 82 ER ligands with ERα and ERβ inhibitory activities was built, and quantitative structure-activity relationship (QSAR) methods based on the two linear (multiple linear regression, MLR, partial least squares regression, PLSR) and a nonlinear statistical method (Bayesian regularized neural network, BRNN) were applied to investigate the potential relationship of molecular structural features related to the activity and selectivity of these ligands. For ERα and ERβ, the performances of the MLR and PLSR models are superior to the BRNN model, giving more reasonable statistical properties (ERα: for MLR, R(tr) (2) = 0.72, Q(te) (2) = 0.63; for PLSR, R(tr) (2) = 0.92, Q(te) (2) = 0.84. ERβ: for MLR, R(tr) (2) = 0.75, Q(te) (2) = 0.75; for PLSR, R(tr) (2) = 0.98, Q(te) (2) = 0.80). The MLR method is also more powerful than other two methods for generating the subtype selectivity models, resulting in R(tr) (2) = 0.74 and Q(te) (2) = 0.80. In addition, the molecular docking method was also used to explore the possible binding modes of the ligands and a relationship between the 3D-binding modes and the 2D-molecular structural features of ligands was further explored. The results show that the binding affinity strength for both ERα and ERβ is more correlated with the atom fragment type, polarity, electronegativites and hydrophobicity. The substitutent in position 8 of the naphthalene or the quinoline plane and the space orientation of these two planes contribute the most to the subtype selectivity on the basis of similar hydrogen bond interactions between binding ligands and both ER subtypes. The QSAR models built together with the docking procedure should be of great advantage for screening and

  19. Molecular dynamics modeling the synthetic and biological polymers interactions pre-studied via docking: anchors modified polyanions interference with the HIV-1 fusion mediator.

    PubMed

    Tsvetkov, Vladimir B; Serbin, Alexander V

    2014-06-01

    In previous works we reported the design, synthesis and in vitro evaluations of synthetic anionic polymers modified by alicyclic pendant groups (hydrophobic anchors), as a novel class of inhibitors of the human immunodeficiency virus type 1 (HIV-1) entry into human cells. Recently, these synthetic polymers interactions with key mediator of HIV-1 entry-fusion, the tri-helix core of the first heptad repeat regions [HR1]3 of viral envelope protein gp41, were pre-studied via docking in terms of newly formulated algorithm for stepwise approximation from fragments of polymeric backbone and side-group models toward real polymeric chains. In the present article the docking results were verified under molecular dynamics (MD) modeling. In contrast with limited capabilities of the docking, the MD allowed of using much more large models of the polymeric ligands, considering flexibility of both ligand and target simultaneously. Among the synthesized polymers the dinorbornen anchors containing alternating copolymers of maleic acid were selected as the most representative ligands (possessing the top anti-HIV activity in vitro in correlation with the highest binding energy in the docking). To verify the probability of binding of the polymers with the [HR1]3 in the sites defined via docking, various starting positions of polymer chains were tried. The MD simulations confirmed the main docking-predicted priority for binding sites, and possibilities for axial and belting modes of the ligands-target interactions. Some newly MD-discovered aspects of the ligand's backbone and anchor units dynamic cooperation in binding the viral target clarify mechanisms of the synthetic polymers anti-HIV activity and drug resistance prevention.

  20. Design, synthesis, biological evaluation, molecular docking and QSAR studies of 2,4-dimethylacridones as anticancer agents.

    PubMed

    Murahari, Manikanta; Kharkar, Prashant S; Lonikar, Nitin; Mayur, Y C

    2017-04-21

    Drug resistance in cancer is an unmet medical challenge and a major drawback for the failure of many chemotherapeutic drugs. Search for targeted, effective drug with minimum toxicity is an urgent need. Acridone which is an alkaloid derivative has been attributed as molecule in reversing drug resistance in cancer cells for a long time now. In the present investigation, an attempt has been made to explore the chemosensitizing ability of 2,4-dimethylacridones with alkyl side chain containing terminally substituted tertiary amino groups. Considering the structural features required for the MDR reversal activity, acridone derivatives have been synthesized with propyl and butyl side chain containing morpholinyl, piperidinyl, N-methylpiperazinyl, N,N-diethylamino, N-diethanolamino, N-[(β-hydroxylethyl)]piperazino at the terminus of the alkyl side chain. cLogP values for the synthesized compounds ranged from 2.96 to 4.72 for the propyl derivatives and 3.41 to 5.15 for the butyl derivatives. All the compounds were screened against breast cancer sensitive MCF7 and resistant MCF7/ADR cell lines. Compounds 12e and 12f have shown better cytotoxicity profiles with IC50 of 4 ± 0.05 and 2 ± 0.03 μM against MCF7 cells, 5.21 ± 0.13 and 2.56 ± 0.05 μM against MCF7/ADR cells. Photolabelling studies with [(3)H]-azidopine and molecular docking studies have identified that 2,4-dimethylacridones have potential to modulate the P-gp mediated multidrug resistance. Docking studies identified that compounds have shown favorable interactions with P-gp. QSAR equation was derived for cytotoxicity vs molecular descriptors of acridone derivatives. Best models with good predictive ability have been generated with very high square correlation coefficient (R(2)) values of 0.889, 0.964 and 0.983.

  1. "Vibrational spectroscopic analysis and molecular docking studies of (E)-4-methoxy-N‧-(4-methylbenzylidene) benzohydrazide by DFT"

    NASA Astrophysics Data System (ADS)

    Maheswari, R.; Manjula, J.

    2016-07-01

    (E)-4-methoxy-N‧-(4-methylbenzylidene)benzohydrazide (4MN'MBH) a novel, organic, hydrazone Schiff base compound was synthesized and its structure was characterized by Fourier Transform Infrared (4000-400 cm-1), Fourier Transform Raman (3500-50 cm-1), Ultraviolet-Visible (200-800 nm) and 1H and 13C NMR spectroscopic analysis. Optimized molecular structure, vibrational frequencies and corresponding vibrational assignments regarding 4MN'MBH has become screened tentatively as well as hypothetically utilizing Gaussian09Wprogram package. Potential energy distributions of the normal modes of vibrations connected with vibrations are generally accomplished by applying VEDA program. Natural Bonding Orbital (NBO) assessment was completed with a reason to clarify charge transfer or conjugative interaction, the intra-molecular-hybridization and delocalization of electron density within the molecule. Electronic transitions were studied employing UV-Visible spectrum and the observed values were compared with theoretical values. 1H and13C NMR spectral assessment had been made with choosing structure property relationship by chemical shifts along with magnetic shielding effects of title compound. The first order hyperpolarizability (β0) and related properties (β, α0 and Δα) of 4MN'MBH were calculated. The computed first order hyperpolarizability commensurate with the documented worth of very similar structure and could be an interesting thing for more experiments on non linear optics. Molecular docking study has been performed by in silico method to analysis their antituberculosis aspects against Enoyl acyl carrier protein reductase (Mycobacterium tuberculosis InhA) protein.

  2. Studies of the interaction between FNC and human hemoglobin: a spectroscopic analysis and molecular docking.

    PubMed

    Li, Huiyi; Dou, Huanjing; Zhang, Yuhai; Li, Zhigang; Wang, Ruiyong; Chang, Junbiao

    2015-02-05

    FNC (2'-deoxy-2'-bfluoro-4'-azidocytidine) is a novel nucleoside analogue with pharmacologic effects on several human diseases. In this work, the binding of FNC to human hemoglobin (HHb) have been investigated by absorption spectroscopy, fluorescence quenching technique, synchronous fluorescence, three-dimensional fluorescence and molecular modeling methods. Analysis of fluorescence data showed that the binding of FNC to HHb occurred via a static quenching mechanism. Thermodynamic analysis and molecular modeling suggest that hydrogen bond and van der Waals force are the mainly binding force in the binding of FNC to HHb.

  3. Computational docking, molecular dynamics simulation and subsite structure analysis of a maltogenic amylase from Bacillus lehensis G1 provide insights into substrate and product specificity.

    PubMed

    Manas, Nor Hasmaliana Abdul; Bakar, Farah Diba Abu; Illias, Rosli Md

    2016-06-01

    Maltogenic amylase (MAG1) from Bacillus lehensis G1 displayed the highest hydrolysis activity on β-cyclodextrin (β-CD) to produce maltose as a main product and exhibited high transglycosylation activity on malto-oligosaccharides with polymerization degree of three and above. These substrate and product specificities of MAG1 were elucidated from structural point of view in this study. A three-dimensional structure of MAG1 was constructed using homology modeling. Docking of β-CD and malto-oligosaccharides was then performed in the MAG1 active site. An aromatic platform in the active site was identified which is responsible in substrate recognition especially in determining the enzyme's preference toward β-CD. Molecular dynamics (MD) simulation showed MAG1 structure is most stable when docked with β-CD and least stable when docked with maltose. The docking analysis and MD simulation showed that the main subsites for substrate stabilization in the active site are -2, -1, +1 and +2. A bulky residue, Trp359 at the +2 subsite was identified to cause steric interference to the bound linear malto-oligosaccharides thus prevented it to occupy subsite +3, which can only be reached by a highly bent glucose molecule such as β-CD. The resulted modes of binding from docking simulation show a good correlation with the experimentally determined hydrolysis pattern. The subsite structure generated from this study led to a possible mode of action that revealed how maltose was mainly produced during hydrolysis. Furthermore, maltose only occupies subsite +1 and +2, therefore could not be hydrolyzed or transglycosylated by the enzyme. This important knowledge has paved the way for a novel structure-based molecular design for modulation of its catalytic activities.

  4. Molecular modeling studies of [6,6,5] Tricyclic Fused Oxazolidinones as FXa inhibitors using 3D-QSAR, Topomer CoMFA, molecular docking and molecular dynamics simulations.

    PubMed

    Xu, Cheng; Ren, Yujie

    2015-10-15

    Coagulation factor Xa (Factor Xa, FXa) is a particularly promising target for novel anticoagulant therapy. The first oral factor Xa inhibitor has been approved in the EU and Canada in 2008. In this work, 38 [6,6,5] Tricyclic Fused Oxazolidinones were studied using a combination of molecular modeling techniques including three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, molecular dynamics and Topomer CoMFA (comparative molecular field analysis) were used to build 3D-QSAR models. The results show that the best CoMFA model has q(2)=0.511 and r(2)=0.984, the best CoMSIA (comparative molecular similarity indices analysis) model has q(2)=0.700 and r(2)=0.993 and the Topomer CoMFA analysis has q(2)=0.377 and r(2)=0.886. The results indicated the steric, hydrophobic, H-acceptor and electrostatic fields play key roles in models. Molecular docking and molecular dynamics explored the binding relationship of the ligand and the receptor protein.

  5. Binding properties of the natural red dye carthamin with human serum albumin: Surface plasmon resonance, isothermal titration microcalorimetry, and molecular docking analysis.

    PubMed

    He, Jiawei; Li, Shanshan; Xu, Kailin; Tang, Bin; Yang, Hongqin; Wang, Qing; Li, Hui

    2017-04-15

    The interaction between carthamin and human serum albumin (HSA) was investigated by multiple spectroscopic analyses, surface plasmon resonance (SPR), isothermal titration microcalorimetry (ITC), and molecular docking studies. Fluorescence lifetime measurements implied that carthamin quenched the intrinsic fluorescence of HSA with the formation of a new complex via static mode. Binding affinities regarding this interaction were obtained from SPR analysis. Results demonstrated that carthamin could form a 1:1 complex with HSA at the binding affinity of KD=8.726×10(-5)M and that a high temperature was unfavourable for the interaction. ITC analyses and molecular docking results illustrated that HSA shaped a proper cavity (site I) to embed the whole carthamin molecule and that the complex was formed depending on intermolecular forces, including hydrophobic interaction, hydrogen bonding, and electrostatic force. Moreover, circular dichroism and 3D fluorescence demonstrated that carthamin slightly disturbed the microenvironment of amino residues and affected the secondary structure of HSA.

  6. Spectroscopic and molecular docking study on the interaction between salicylic acid and the induced disease-resistant protein OsAAA1 of rice

    NASA Astrophysics Data System (ADS)

    Chen, Ya H.; Dai, Kang; Zhang, Hua; Wu, Yun H.; Wang, Chun T.; Liu, Xue Q.; Liu, Xin Q.

    2017-02-01

    The interaction between salicylic acid (SA) and the induced disease-resistant protein OsAAA1 in rice was studied using spectroscopy and molecular docking. Ultraviolet (UV) absorption spectroscopy demonstrated an interaction between OsAAA1 protein and SA. Spectroscopy showed that this interaction was a dynamic quenching process. Synchronous fluorescence spectroscopy (SFS) further revealed that this interaction caused changes in the microenvironment of tyrosine and tryptophan and that the interaction site was closer to the tryptophan residue. The structural model of protein OsAAA1 was determined by homology modeling method, and the molecular docking simulation diagram of OsAAA1 with SA was obtained. These models, in combination with a Ramachandran plot analysis, showed amino acid residues ranging from position 240 to position 420 as the possible site interacting with SA. Among them, Gly389, Lys257 and Glu425 might be three key amino acids that can form hydrogen bonds with SA.

  7. Molecular modeling of NK-CT1, from Indian monocellate cobra (Naja kaouthia) and its docking interaction with human DNA topoisomerase II alpha

    PubMed Central

    Bandopadhyay, Pathikrit; Halder, Soma; Sarkar, Mrinmoy; Kumar Bhunia, Sujay; Dey, Sananda; Gomes, Antony; Giri, Biplab

    2016-01-01

    A 6.76 kDa molecular weight cardio and cytotoxic protein of 60 amino acids in length called NK-CT1, was purified from the venom of Indian monocellate cobra (Naja kaouthia) by ion-exchange chromatography and HPLC as described in our earlier report. Therefore it is of interest to utlize the sequence of NK-CT1 for further functional inference using molecular modeling and docking. Thus homology model of NK-CT1 is described in this report. The anti-proliferative activity of the protein, binding with human DNA topoisomerase-II alpha was demonstrated using docking data with AUTODOCK and AUTODOCK MGL tools. Data shows that M26, V27 and S28 of NK-CT1 is in close contact with the nucleotides of the oligonucleotide, bound with topoisomerase-II alpha complex. PMID:28149043

  8. Spectroscopic and molecular docking study on the interaction between salicylic acid and the induced disease-resistant protein OsAAA1 of rice.

    PubMed

    Chen, Ya H; Dai, Kang; Zhang, Hua; Wu, Yun H; Wang, Chun T; Liu, Xue Q; Liu, Xin Q

    2017-02-15

    The interaction between salicylic acid (SA) and the induced disease-resistant protein OsAAA1 in rice was studied using spectroscopy and molecular docking. Ultraviolet (UV) absorption spectroscopy demonstrated an interaction between OsAAA1 protein and SA. Spectroscopy showed that this interaction was a dynamic quenching process. Synchronous fluorescence spectroscopy (SFS) further revealed that this interaction caused changes in the microenvironment of tyrosine and tryptophan and that the interaction site was closer to the tryptophan residue. The structural model of protein OsAAA1 was determined by homology modeling method, and the molecular docking simulation diagram of OsAAA1 with SA was obtained. These models, in combination with a Ramachandran plot analysis, showed amino acid residues ranging from position 240 to position 420 as the possible site interacting with SA. Among them, Gly389, Lys257 and Glu425 might be three key amino acids that can form hydrogen bonds with SA.

  9. Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies.

    PubMed

    Hao, Ming; Li, Yan; Zhang, Shu-Wei; Yang, Wei

    2011-12-01

    Recently, benzothiophenes attract much attention of interest due to its possible inhibitory activity targeting FIXa, a blood coagulation factor that is essential for the amplification or consolidation phase of blood coagulation. To explore this inhibitory mechanism, three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) studies on a series of 84 benzothiophene analogues, for the first time, were performed. As a result, a highly predictive CoMFA model was developed with the q(2) = 0.52, r(2) = 0.97 and r(2)(pred) = 0.81, respectively. The CoMFA contour maps, the docking analysis, as well as the MD simulation results are all in a good agreement, proving the reliability and robustness of the model. These models and the information, we hoped, would be helpful in screening and development of novel drugs against thrombosis prior to synthesis.

  10. Synthesis, vibrational spectroscopic investigations, molecular docking, antibacterial and antimicrobial studies of 5-ethylsulphonyl-2-(p-aminophenyl)benzoxazole

    NASA Astrophysics Data System (ADS)

    Parveen S, Shana; Al-Alshaikh, Monirah A.; Panicker, C. Yohannan; El-Emam, Ali A.; Arisoy, Mustafa; Temiz-Arpaci, Ozlem; Van Alsenoy, C.

    2016-07-01

    The optimized molecular structure, vibrational wavenumbers, corresponding vibrational assignments of 5-ethylsulphonyl-2-(p-aminophenyl)benzoxazole have been investigated experimentally and theoretically based on density functional theory. Synthesis and antibacterial and antimicrobial activities of the title compound were reported. The FT-IR and FT-Raman spectra were recorded in solid phase and the experimental bands were assigned and characterized on the basis of potential energy distribution. The HOMO and LUMO energies show that the charge transfer occur within the molecule. Stability arising from hyperconjugative interactions and charge delocalization were analysed using natural bond orbital analysis. Binding free energy of -9.8 kcal/mol as predicted by docking studies suggests good binding affinity and the inhibitor forms a stable complex with FAK as is evident from the ligand-receptor interactions. The title compound possesses lower activity against Candida albicans with MIC value of 64 μg/ml than the compared reference drugs as fluconazole and amphotericin B and possesses the same activity with value of 64 μg/ml against Candida krusei as the reference drug, fluconazole.

  11. Spectroscopic and molecular docking studies on the interaction of human serum albumin with copper(II) complexes

    NASA Astrophysics Data System (ADS)

    Guhathakurta, Bhargab; Pradhan, Ankur Bikash; Das, Suman; Bandyopadhyay, Nirmalya; Lu, Liping; Zhu, Miaoli; Naskar, Jnan Prakash

    2017-02-01

    Two osazone based ligands, butane-2,3-dione bis(2‧-pyridylhydrazone) (BDBPH) and hexane-3,4-dione bis(2‧-pyridylhydrazone) (HDBPH), were synthesized out of the 2:1 M Schiff base condensation of 2-hydrazino pyridine respectively with 2,3-butanedione and 3,4-hexanedione. The X-ray crystal structures of both the ligands have been determined. The copper(II) complex of HDBPH has also been synthesized and structurally characterized. HDBPH and its copper(II) complex have thoroughly been characterized through various spectroscopic and analytical techniques. The X-ray crystal structure of the copper complex of HDBPH shows that it is a monomeric Cu(II) complex having 'N4O2' co-ordination chromophore. Interaction of human serum albumin (HSA) with these ligands and their monomeric copper(II) complexes have been studied by various spectroscopic means. The experimental findings show that the ligands as well as their copper complexes are good HSA binders. Molecular docking investigations have also been done to unravel the mode of binding of the species with HSA.

  12. In silico interaction of methyl isocyanate with immune protein responsible for Mycobacterium tuberculosis infection using molecular docking.

    PubMed

    Shrivastava, Rahul; Yasir, Mohammad; Tripathi, Manish; Singh, Pushpendra

    2016-01-01

    This article reports in silico analysis of methyl isocyanate (MIC) on different key immune proteins against Mycobacterium tuberculosis. The analysis shows that MIC is released in the Bhopal gas tragedy in 1984, which is highly toxic and extremely hazardous to human health. In this study, we have selected immune proteins to perform molecular docking with the help of Autodock 4.0. Results show that the CD40 ligand and alpha5beta1 integrin have higher inhibition compared to plasminogen activator urokinase, human glutathione synthetase, mitogen-activated protein kinase (P38 MAPK 14), surfactant protein-B, -D (SP-D), and pulmonary SP-D. MIC interacted with His-125, Try-146 residue of CD40 ligand and Ala-149, and Arg-152 residue of alpha5beta1 integrin and affects the proteins functioning by binding on their active sites. These inhibitory conformations were energetically and statistically favored and supported the evidence from wet laboratory experiments reported in the literature. We can conclude that MIC directly or indirectly affects these proteins, which shows that survivals of the disaster suffer from the diseases like tuberculosis infection and lung cancer.

  13. A new insight into mushroom tyrosinase inhibitors: docking, pharmacophore-based virtual screening, and molecular modeling studies.

    PubMed

    Bagherzadeh, Kowsar; Shirgahi Talari, Faezeh; Sharifi, Amirhossein; Ganjali, Mohammad Reza; Saboury, Ali Akbar; Amanlou, Massoud

    2015-01-01

    Tyrosinase, a widely spread enzyme in micro-organisms, animals, and plants, participates in two rate-limiting steps in melanin formation pathway which is responsible for skin protection against UV lights' harm whose functional deficiency result in serious dermatological diseases. This enzyme seems to be responsible for neuromelanin formation in human brain as well. In plants, the enzyme leads the browning pathway which is commonly observed in injured tissues that is economically very unfavorable. Among different types of tyrosinase, mushroom tyrosinase has the highest homology with the mammalian tyrosinase and the only commercial tyrosinase available. In this study, ligand-based pharmacophore drug discovery method was applied to rapidly identify mushroom tyrosinase enzyme inhibitors using virtual screening. The model pharmacophore of essential interactions was developed and refined studying already experimentally discovered potent inhibitors employing Docking analysis methodology. After pharmacophore virtual screening and binding modes prediction, 14 compounds from ZINC database were identified as potent inhibitors of mushroom tyrosinase which were classified into five groups according to their chemical structures. The inhibition behavior of the discovered compounds was further studied through Classical Molecular Dynamic Simulations and the conformational changes induced by the presence of the studied ligands were discussed and compared to those of the substrate, tyrosine. According to the obtained results, five novel leads are introduced to be further optimized or directly used as potent inhibitors of mushroom tyrosinase.

  14. Synthesis, anti-microbial and molecular docking studies of quinazolin-4(3H)-one derivatives.

    PubMed

    Mabkhot, Yahia Nasser; Al-Har, Munirah S; Barakat, Assem; Aldawsari, Fahad D; Aldalbahi, Ali; Ul-Haq, Zaheer

    2014-06-25

    In this work, synthesis, antimicrobial activities and molecular docking studies of some new series of substituted quinazolinone 2a-h and 3a-d were described. Starting form 2-aminobenzamide derivatives 1, a new series of quinazolinone derivatives has been synthesized, in high yields, assisted by microwave and classical methods. Some of these substituted quinazolinones were tested for their antimicrobial activity against Gram-negative bacteria (Pseudomonas aeruginosa and Esherichia coli) and Gram-positive bacteria (Staphylococcus aureus, and Bacillus subtilis), and anti-fungal activity against (Aspergillus fumigatus, Saccharomyces cervevisiae, and Candida albicans) using agar well diffusion method. Among the prepared products, 3-benzyl-2-(4-chlorophenyl)quinazolin-4(3H)-one (3a) was found to exhibits the most potent in vitro anti-microbial activity with MICs of 25.6±0.5, 24.3±0.4, 30.1±0.6, and 25.1±0.5 µg/mL against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa and Esherichia coli, respectively. Compound 3a was found to exhibits the most potent in vitro anti-fungal activity with MICs of 18.3±0.6, 23.1±0.4, and 26.1±0.5 µg/mL against Aspergillus fumigatus, Saccharomyces cervevisiae, and Candidaal bicans, respectively.

  15. Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents.

    PubMed

    Revathi, Rajappan; Venkatesha Perumal, Ramachandran; Pai, Karkala Sreedhara Ranganath; Arunkumar, Govindakarnavar; Sriram, Dharmarajan; Kini, Suvarna Ganesh

    2015-01-01

    Tuberculosis remains one of the major grievous diseases worldwide. The emergence of resistance to antituberculosis drugs emphasize the necessity to discover new therapeutic agents for preferential tuberculosis therapy. In this study, various novel 1-(1H-benzimidazol-2-ylmethyl) piperidin-4-imine derivatives were developed and checked for favorable pharmacokinetic parameters based on drug-likeness explained by Lipinski's rule of five. All 20 of the novel chemical entities were found to possess a favorable pharmacokinetic profile since they were not violating Lipinski's rule of five. The title compounds were also synthesized, characterized, and tested for ex vivo antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The results revealed that four compounds (2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene] hydrazinecarbothioamide, 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]-N-hydroxy-hydrazinecarbo-thioamide, 1-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]guanidine, and 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]hydrazinecarboxamide) were the most potent (minimum inhibitory concentration 6.25 µg/mL) antitubercular agents, with less toxicity (selectivity index more than 10). The molecules were also subjected to three-dimensional molecular docking on the crystal structure of enoyl-acyl carrier protein (EACP) reductase enzyme (code 1ZID, Protein Data Bank), which represents a good prediction of the interactions between the molecules and EACP reductase with minimum binding energy.

  16. Spectroscopic and molecular docking studies on the interaction of human serum albumin with copper(II) complexes.

    PubMed

    Guhathakurta, Bhargab; Pradhan, Ankur Bikash; Das, Suman; Bandyopadhyay, Nirmalya; Lu, Liping; Zhu, Miaoli; Naskar, Jnan Prakash

    2017-02-15

    Two osazone based ligands, butane-2,3-dione bis(2'-pyridylhydrazone) (BDBPH) and hexane-3,4-dione bis(2'-pyridylhydrazone) (HDBPH), were synthesized out of the 2:1M Schiff base condensation of 2-hydrazino pyridine respectively with 2,3-butanedione and 3,4-hexanedione. The X-ray crystal structures of both the ligands have been determined. The copper(II) complex of HDBPH has also been synthesized and structurally characterized. HDBPH and its copper(II) complex have thoroughly been characterized through various spectroscopic and analytical techniques. The X-ray crystal structure of the copper complex of HDBPH shows that it is a monomeric Cu(II) complex having 'N4O2' co-ordination chromophore. Interaction of human serum albumin (HSA) with these ligands and their monomeric copper(II) complexes have been studied by various spectroscopic means. The experimental findings show that the ligands as well as their copper complexes are good HSA binders. Molecular docking investigations have also been done to unravel the mode of binding of the species with HSA.

  17. Probing into the binding interaction between medroxyprogesterone acetate and bovine serum albumin (BSA): spectroscopic and molecular docking methods.

    PubMed

    Fang, Fang; Pan, Dong-Qi; Qiu, Min-Jie; Liu, Ting-Ting; Jiang, Min; Wang, Qi; Shi, Jie-Hua

    2016-09-01

    To further understand the mechanism of action and pharmacokinetics of medroxyprogesterone acetate (MPA), the binding interaction of MPA with bovine serum albumin (BSA) under simulated physiological conditions (pH 7.4) was studied using fluorescence emission spectroscopy, synchronous fluorescence spectroscopy, circular dichroism and molecular docking methods. The experimental results reveal that the fluorescence of BSA quenches due to the formation of MPA-BSA complex. The number of binding sites (n) and the binding constant for MPA-BSA complex are ~1 and 4.6 × 10(3)  M(-1) at 310 K, respectively. However, it can be concluded that the binding process of MPA with BSA is spontaneous and the main interaction forces between MPA and BSA are van der Waals force and hydrogen bonding interaction due to the negative values of ΔG(0) , ΔH(0) and ΔS(0) in the binding process of MPA with BSA. MPA prefers binding on the hydrophobic cavity in subdomain IIIA (site II'') of BSA resulting in a slight change in the conformation of BSA, but BSA retaining the α-helix structure. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Synthesis, biological evaluation and molecular docking of novel chalcone-coumarin hybrids as anticancer and antimalarial agents.

    PubMed

    Pingaew, Ratchanok; Saekee, Amporn; Mandi, Prasit; Nantasenamat, Chanin; Prachayasittikul, Supaluk; Ruchirawat, Somsak; Prachayasittikul, Virapong

    2014-10-06

    A new series of chalcone-coumarin derivatives (9-19) linked by the 1,2,3-triazole ring were synthesized through the azide/alkyne dipolar cycloaddition. Hybrid molecules were evaluated for their cytotoxic activity against four cancer cell lines (e.g., HuCCA-1, HepG2, A549 and MOLT-3) and antimalarial activity toward Plasmodium falciparum. Most of the synthesized hybrids, except for analogs 10 and 16, displayed cytotoxicity against MOLT-3 cell line without affecting normal cells. Analogs (10, 11, 16 and 18) exhibited higher inhibitory efficacy than the control drug, etoposide, in HepG2 cells. Significantly, the high cytotoxic potency of the hybrid 11 was shown to be non-toxic to normal cells. Interestingly, the chalcone-coumarin 18 was the most potent antimalarial compound affording IC50 value of 1.60 μM. Molecular docking suggested that the cytotoxicity of reported hybrids could be possibly due to their dual inhibition of α- and β-tubulins at GTP and colchicine binding sites, respectively. Furthermore, falcipain-2 was identified to be a plausible target site of the hybrids given their antimalarial potency.

  19. Novel quinazoline-urea analogues as modulators for Aβ-induced mitochondrial dysfunction: design, synthesis, and molecular docking study.

    PubMed

    Elkamhawy, Ahmed; Lee, Jiyoun; Park, Beoung-Geon; Park, Insun; Pae, Ae Nim; Roh, Eun Joo

    2014-09-12

    A novel series of twenty-six quinazoline-urea derivatives was designed and synthesized. Their blocking activities against β-amyloid peptide (Aβ) induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measured the change of mitochondrial membrane potential. Seven compounds showed better inhibitory activities than the standard Cyclosporin A (CsA). The most active analogues were tested by MTT assay to evaluate their toxicity on the cellular survival; they revealed excellent cellular viability. To explain the difference in inhibitory activity, molecular docking study using (GOLD) program was performed for selected sets of the most active and inactive compounds on cyclophilin D (CypD) receptor as a major component of mPTP. Moreover, ADME profiling, in silico toxicity, drug-likeness, and drug-score studies were discussed. From these results, we report compound 31 as the most active nonpeptidyl mPTP blocker possessing quinazoline-urea scaffold; 2 folds of CsA activity, which would constitute a new direction for the design of novel mPTP modulators.

  20. Synthesis, spectroscopy, X-ray crystallography, DFT calculations, DNA binding and molecular docking of a propargyl arms containing Schiff base.

    PubMed

    Balakrishnan, C; Subha, L; Neelakantan, M A; Mariappan, S S

    2015-11-05

    A propargyl arms containing Schiff base (L) was synthesized by the condensation of 1-[2-hydroxy-4-(prop-2-yn-1-yloxy)phenyl]ethanone with trans-1,2-diaminocyclohexane. The structure of L was characterized by IR, (1)H NMR, (13)C NMR and UV-Vis spectroscopy and by single crystal X-ray diffraction analysis. The UV-Visible spectral behavior of L in different solvents exhibits positive solvatochromism. Density functional calculation of the L in gas phase was performed by using DFT (B3LYP) method with 6-31G basis set. The computed vibrational frequencies and NMR signals of L were compared with the experimental data. Tautomeric stability study inferred that the enolimine is more stable than the ketoamine form. The charge delocalization has been analyzed using natural bond orbital (NBO) analysis. Electronic absorption and emission spectral studies were used to study the binding of L with CT-DNA. The molecular docking was done to identify the interaction of L with A-DNA and B-DNA.

  1. Discovery of CREBBP Bromodomain Inhibitors by High-Throughput Docking and Hit Optimization Guided by Molecular Dynamics.

    PubMed

    Xu, Min; Unzue, Andrea; Dong, Jing; Spiliotopoulos, Dimitrios; Nevado, Cristina; Caflisch, Amedeo

    2016-02-25

    We have identified two chemotypes of CREBBP bromodomain ligands by fragment-based high-throughput docking. Only 17 molecules from the original library of two-million compounds were tested in vitro. Optimization of the two low-micromolar hits, the 4-acylpyrrole 1 and acylbenzene 9, was driven by molecular dynamics results which suggested improvement of the polar interactions with the Arg1173 side chain at the rim of the binding site. The synthesis of only two derivatives of 1 yielded the 4-acylpyrrole 6 which shows a single-digit micromolar affinity for the CREBBP bromodomain and a ligand efficiency of 0.34 kcal/mol per non-hydrogen atom. Optimization of the acylbenzene hit 9 resulted in a series of derivatives with nanomolar potencies, good ligand efficiency and selectivity (see Unzue, A.; Xu, M.; Dong, J.; Wiedmer, L.; Spiliotopoulos, D.; Caflisch, A.; Nevado, C.Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00172). The in silico predicted binding mode of the acylbenzene derivative 10 was validated by solving the structure of the complex with the CREBBP bromodomain.

  2. Asp32 and Asp228 determine the selective inhibition of BACE1 as shown by docking and molecular dynamics simulations.

    PubMed

    Hernández-Rodríguez, Maricarmen; Correa-Basurto, José; Gutiérrez, Antonia; Vitorica, Javier; Rosales-Hernández, Martha C

    2016-11-29

    Inhibition of β-site amyloid-β-protein precursor cleaving enzyme 1 (BACE1) represents a promising approach for the treatment of Alzheimer's disease (AD). However, the development of a selective BACE1 inhibitor is difficult due to its highly flexible catalytic site and homology to other aspartic proteases, including BACE2 and Cathepsin D (CTSD). Aiming to better understand the structural factors responsible for selective BACE1 inhibition, we performed alignment studies, molecular dynamics (MD) simulations and docking studies to explore the recognition of four selective BACE1 inhibitors by aspartyl proteases. The results show that selective BACE1 inhibition may be due to the formation of strong electrostatic interactions with Asp32 and Asp228 and a large number of hydrogen bonds, π-π and Van der Waals interactions with the amino acid residues located inside the catalytic cavity, which has different volume and shape compared to BACE2 and CTSD. Hindrance effects avoid the accommodation of ligands in the small catalytic site of BACE2, resulting in a lower affinity and the high cavity of CTSD results in the formation of a small number of interactions with the ligands, although they show a similar binding mode with BACE1. These results might help to rationalize the design of selective BACE1 inhibitors.

  3. Evaluating the binding efficiency of pheromone binding protein with its natural ligand using molecular docking and fluorescence analysis

    NASA Astrophysics Data System (ADS)

    Ilayaraja, Renganathan; Rajkumar, Ramalingam; Rajesh, Durairaj; Muralidharan, Arumugam Ramachandran; Padmanabhan, Parasuraman; Archunan, Govindaraju

    2014-06-01

    Chemosignals play a crucial role in social and sexual communication among inter- and intra-species. Chemical cues are bound with protein that is present in the pheromones irrespective of sex are commonly called as pheromone binding protein (PBP). In rats, the pheromone compounds are bound with low molecular lipocalin protein α2u-globulin (α2u). We reported farnesol is a natural endogenous ligand (compound) present in rat preputial gland as a bound volatile compound. In the present study, an attempt has been made through computational method to evaluating the binding efficiency of α2u with the natural ligand (farnesol) and standard fluorescent molecule (2-naphthol). The docking analysis revealed that the binding energy of farnesol and 2-naphthol was almost equal and likely to share some binding pocket of protein. Further, to extrapolate the results generated through computational approach, the α2u protein was purified and subjected to fluorescence titration and binding assay. The results showed that the farnesol is replaced by 2-naphthol with high hydrophobicity of TYR120 in binding sites of α2u providing an acceptable dissociation constant indicating the binding efficiency of α2u. The obtained results are in corroboration with the data made through computational approach.

  4. Further Insights in the Binding Mode of Selective Inhibitors to Human PDE4D Enzyme Combining Docking and Molecular Dynamics

    PubMed Central

    D'Ursi, Pasqualina; Guariento, Sara; Trombetti, Gabriele; Orro, Alessandro; Cichero, Elena; Milanesi, Luciano; Bruno, Olga

    2016-01-01

    Abstract Alzheimer′s disease has recently emerged as a possible field of application for PDE4D inhibitors (PDE4DIs). The great structure similarity among the various PDE4 isoforms and, furthermore, the lack of the full length crystal structure of the enzyme, impaired the rational design of new selective PDE4DIs. In this paper, with the aim of exploring new insights into the PDE4D binding, we tackled the problem by performing a computational study based on docking simulations combined with molecular dynamics (D‐MD). Our work uniquely identified the binding mode and the key residues involved in the interaction with a number of in‐house catechol iminoether derivatives, acting as PDE4DIs. Moreover, the new binding mode was tested using a series of analogues previously reported by us and it was used to confirm their key structural features to allow PDE4D in