Drug search for leishmaniasis: a virtual screening approach by grid computing.

PubMed

Ochoa, Rodrigo; Watowich, Stanley J; Flórez, Andrés; Mesa, Carol V; Robledo, Sara M; Muskus, Carlos

2016-07-01

The trypanosomatid protozoa Leishmania is endemic in ~100 countries, with infections causing ~2 million new cases of leishmaniasis annually. Disease symptoms can include severe skin and mucosal ulcers, fever, anemia, splenomegaly, and death. Unfortunately, therapeutics approved to treat leishmaniasis are associated with potentially severe side effects, including death. Furthermore, drug-resistant Leishmania parasites have developed in most endemic countries. To address an urgent need for new, safe and inexpensive anti-leishmanial drugs, we utilized the IBM World Community Grid to complete computer-based drug discovery screens (Drug Search for Leishmaniasis) using unique leishmanial proteins and a database of 600,000 drug-like small molecules. Protein structures from different Leishmania species were selected for molecular dynamics (MD) simulations, and a series of conformational "snapshots" were chosen from each MD trajectory to simulate the protein's flexibility. A Relaxed Complex Scheme methodology was used to screen ~2000 MD conformations against the small molecule database, producing >1 billion protein-ligand structures. For each protein target, a binding spectrum was calculated to identify compounds predicted to bind with highest average affinity to all protein conformations. Significantly, four different Leishmania protein targets were predicted to strongly bind small molecules, with the strongest binding interactions predicted to occur for dihydroorotate dehydrogenase (LmDHODH; PDB:3MJY). A number of predicted tight-binding LmDHODH inhibitors were tested in vitro and potent selective inhibitors of Leishmania panamensis were identified. These promising small molecules are suitable for further development using iterative structure-based optimization and in vitro/in vivo validation assays.

DITOP: drug-induced toxicity related protein database.

PubMed

Zhang, Jing-Xian; Huang, Wei-Juan; Zeng, Jing-Hua; Huang, Wen-Hui; Wang, Yi; Zhao, Rui; Han, Bu-Cong; Liu, Qing-Feng; Chen, Yu-Zong; Ji, Zhi-Liang

2007-07-01

Drug-induced toxicity related proteins (DITRPs) are proteins that mediate adverse drug reactions (ADRs) or toxicities through their binding to drugs or reactive metabolites. Collection of these proteins facilitates better understanding of the molecular mechanisms of drug-induced toxicity and the rational drug discovery. Drug-induced toxicity related protein database (DITOP) is such a database that is intending to provide comprehensive information of DITRPs. Currently, DITOP contains 1501 records, covering 618 distinct literature-reported DITRPs, 529 drugs/ligands and 418 distinct toxicity terms. These proteins were confirmed experimentally to interact with drugs or their reactive metabolites, thus directly or indirectly cause adverse effects or toxicities. Five major types of drug-induced toxicities or ADRs are included in DITOP, which are the idiosyncratic adverse drug reactions, the dose-dependent toxicities, the drug-drug interactions, the immune-mediated adverse drug effects (IMADEs) and the toxicities caused by genetic susceptibility. Molecular mechanisms underlying the toxicity and cross-links to related resources are also provided while available. Moreover, a series of user-friendly interfaces were designed for flexible retrieval of DITRPs-related information. The DITOP can be accessed freely at http://bioinf.xmu.edu.cn/databases/ADR/index.html. Supplementary data are available at Bioinformatics online.

CancerDR: cancer drug resistance database.

PubMed

Kumar, Rahul; Chaudhary, Kumardeep; Gupta, Sudheer; Singh, Harinder; Kumar, Shailesh; Gautam, Ankur; Kapoor, Pallavi; Raghava, Gajendra P S

2013-01-01

Cancer therapies are limited by the development of drug resistance, and mutations in drug targets is one of the main reasons for developing acquired resistance. The adequate knowledge of these mutations in drug targets would help to design effective personalized therapies. Keeping this in mind, we have developed a database "CancerDR", which provides information of 148 anti-cancer drugs, and their pharmacological profiling across 952 cancer cell lines. CancerDR provides comprehensive information about each drug target that includes; (i) sequence of natural variants, (ii) mutations, (iii) tertiary structure, and (iv) alignment profile of mutants/variants. A number of web-based tools have been integrated in CancerDR. This database will be very useful for identification of genetic alterations in genes encoding drug targets, and in turn the residues responsible for drug resistance. CancerDR allows user to identify promiscuous drug molecules that can kill wide range of cancer cells. CancerDR is freely accessible at http://crdd.osdd.net/raghava/cancerdr/

The Development of a Korean Drug Dosing Database

PubMed Central

Kim, Sun Ah; Kim, Jung Hoon; Jang, Yoo Jin; Jeon, Man Ho; Hwang, Joong Un; Jeong, Young Mi; Choi, Kyung Suk; Lee, Iyn Hyang; Jeon, Jin Ok; Lee, Eun Sook; Lee, Eun Kyung; Kim, Hong Bin; Chin, Ho Jun; Ha, Ji Hye; Kim, Young Hoon

2011-01-01

Objectives This report describes the development process of a drug dosing database for ethical drugs approved by the Korea Food & Drug Administration (KFDA). The goal of this study was to develop a computerized system that supports physicians' prescribing decisions, particularly in regards to medication dosing. Methods The advisory committee, comprised of doctors, pharmacists, and nurses from the Seoul National University Bundang Hospital, pharmacists familiar with drug databases, KFDA officials, and software developers from the BIT Computer Co. Ltd. analyzed approved KFDA drug dosing information, defined the fields and properties of the information structure, and designed a management program used to enter dosing information. The management program was developed using a web based system that allows multiple researchers to input drug dosing information in an organized manner. The whole process was improved by adding additional input fields and eliminating the unnecessary existing fields used when the dosing information was entered, resulting in an improved field structure. Results A total of 16,994 drugs sold in the Korean market in July 2009, excluding the exclusion criteria (e.g., radioactivity drugs, X-ray contrast medium), usage and dosing information were made into a database. Conclusions The drug dosing database was successfully developed and the dosing information for new drugs can be continually maintained through the management mode. This database will be used to develop the drug utilization review standards and to provide appropriate dosing information. PMID:22259729

Current situation and future usage of anticancer drug databases.

PubMed

Wang, Hongzhi; Yin, Yuanyuan; Wang, Peiqi; Xiong, Chenyu; Huang, Lingyu; Li, Sijia; Li, Xinyi; Fu, Leilei

2016-07-01

Cancer is a deadly disease with increasing incidence and mortality rates and affects the life quality of millions of people per year. The past 15 years have witnessed the rapid development of targeted therapy for cancer treatment, with numerous anticancer drugs, drug targets and related gene mutations been identified. The demand for better anticancer drugs and the advances in database technologies have propelled the development of databases related to anticancer drugs. These databases provide systematic collections of integrative information either directly on anticancer drugs or on a specific type of anticancer drugs with their own emphases on different aspects, such as drug-target interactions, the relationship between mutations in drug targets and drug resistance/sensitivity, drug-drug interactions, natural products with anticancer activity, anticancer peptides, synthetic lethality pairs and histone deacetylase inhibitors. We focus on a holistic view of the current situation and future usage of databases related to anticancer drugs and further discuss their strengths and weaknesses, in the hope of facilitating the discovery of new anticancer drugs with better clinical outcomes.

The CSB Incident Screening Database: description, summary statistics and uses.

PubMed

Gomez, Manuel R; Casper, Susan; Smith, E Allen

2008-11-15

This paper briefly describes the Chemical Incident Screening Database currently used by the CSB to identify and evaluate chemical incidents for possible investigations, and summarizes descriptive statistics from this database that can potentially help to estimate the number, character, and consequences of chemical incidents in the US. The report compares some of the information in the CSB database to roughly similar information available from databases operated by EPA and the Agency for Toxic Substances and Disease Registry (ATSDR), and explores the possible implications of these comparisons with regard to the dimension of the chemical incident problem. Finally, the report explores in a preliminary way whether a system modeled after the existing CSB screening database could be developed to serve as a national surveillance tool for chemical incidents.

Ligand.Info small-molecule Meta-Database.

PubMed

von Grotthuss, Marcin; Koczyk, Grzegorz; Pas, Jakub; Wyrwicz, Lucjan S; Rychlewski, Leszek

2004-12-01

Ligand.Info is a compilation of various publicly available databases of small molecules. The total size of the Meta-Database is over 1 million entries. The compound records contain calculated three-dimensional coordinates and sometimes information about biological activity. Some molecules have information about FDA drug approving status or about anti-HIV activity. Meta-Database can be downloaded from the http://Ligand.Info web page. The database can also be screened using a Java-based tool. The tool can interactively cluster sets of molecules on the user side and automatically download similar molecules from the server. The application requires the Java Runtime Environment 1.4 or higher, which can be automatically downloaded from Sun Microsystems or Apple Computer and installed during the first use of Ligand.Info on desktop systems, which support Java (Ms Windows, Mac OS, Solaris, and Linux). The Ligand.Info Meta-Database can be used for virtual high-throughput screening of new potential drugs. Presented examples showed that using a known antiviral drug as query the system was able to find others antiviral drugs and inhibitors.

When drug discovery meets web search: Learning to Rank for ligand-based virtual screening.

PubMed

Zhang, Wei; Ji, Lijuan; Chen, Yanan; Tang, Kailin; Wang, Haiping; Zhu, Ruixin; Jia, Wei; Cao, Zhiwei; Liu, Qi

2015-01-01

The rapid increase in the emergence of novel chemical substances presents a substantial demands for more sophisticated computational methodologies for drug discovery. In this study, the idea of Learning to Rank in web search was presented in drug virtual screening, which has the following unique capabilities of 1). Applicable of identifying compounds on novel targets when there is not enough training data available for these targets, and 2). Integration of heterogeneous data when compound affinities are measured in different platforms. A standard pipeline was designed to carry out Learning to Rank in virtual screening. Six Learning to Rank algorithms were investigated based on two public datasets collected from Binding Database and the newly-published Community Structure-Activity Resource benchmark dataset. The results have demonstrated that Learning to rank is an efficient computational strategy for drug virtual screening, particularly due to its novel use in cross-target virtual screening and heterogeneous data integration. To the best of our knowledge, we have introduced here the first application of Learning to Rank in virtual screening. The experiment workflow and algorithm assessment designed in this study will provide a standard protocol for other similar studies. All the datasets as well as the implementations of Learning to Rank algorithms are available at http://www.tongji.edu.cn/~qiliu/lor_vs.html. Graphical AbstractThe analogy between web search and ligand-based drug discovery.

Evaluation of the Triage TOX Drug Screen Assay for Detection of 11 Drugs of Abuse and Therapeutic Drugs.

PubMed

Bang, Hae In; Jang, Mi Ae; Lee, Yong Wha

2017-11-01

The demand for rapid and broad clinical toxicology screens is on the rise. Recently, a new rapid toxicology screening test, the Triage TOX Drug Screen (Alere Inc., USA), which can simultaneously detect 11 drugs of abuse and therapeutic drugs with an instrument-read cartridge, was developed. In the present study, we evaluated the efficacy of this new on-site immunoassay using 105 urine specimens; the results were compared with those obtained by using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-TMS). Precision was evaluated according to the CLSI EP12-A2 for analyte concentrations near the cutoff, including C₅₀ and±30% of C₅₀, for each drug using standard materials. The C₅₀ specimens yielded 35-65% positive results and the±30% concentration range of all evaluated drugs encompassed the C₅-C₉₅ interval. The overall percent agreement of the Triage TOX Drug Screen was 92.4-100% compared with UPLC-TMS; however, the Triage TOX Drug Screen results showed some discordant cases including acetaminophen, amphetamine, benzodiazepine, opiates, and tricyclic antidepressants. The overall performance of the Triage TOX Drug Screen assay was comparable to that of UPLC-TMS for screening of drug intoxication in hospitals. This assay could constitute a useful screening method for drugs of abuse and therapeutic drugs in urine. © The Korean Society for Laboratory Medicine.

Microfluidic Devices for Drug Delivery Systems and Drug Screening

PubMed Central

Kompella, Uday B.; Damiati, Safa A.

2018-01-01

Microfluidic devices present unique advantages for the development of efficient drug carrier particles, cell-free protein synthesis systems, and rapid techniques for direct drug screening. Compared to bulk methods, by efficiently controlling the geometries of the fabricated chip and the flow rates of multiphase fluids, microfluidic technology enables the generation of highly stable, uniform, monodispersed particles with higher encapsulation efficiency. Since the existing preclinical models are inefficient drug screens for predicting clinical outcomes, microfluidic platforms might offer a more rapid and cost-effective alternative. Compared to 2D cell culture systems and in vivo animal models, microfluidic 3D platforms mimic the in vivo cell systems in a simple, inexpensive manner, which allows high throughput and multiplexed drug screening at the cell, organ, and whole-body levels. In this review, the generation of appropriate drug or gene carriers including different particle types using different configurations of microfluidic devices is highlighted. Additionally, this paper discusses the emergence of fabricated microfluidic cell-free protein synthesis systems for potential use at point of care as well as cell-, organ-, and human-on-a-chip models as smart, sensitive, and reproducible platforms, allowing the investigation of the effects of drugs under conditions imitating the biological system. PMID:29462948

LactMed: New NLM Database on Drugs and Lactation

MedlinePlus

... Issues Research News From NIH LactMed: New NLM Database on Drugs and Lactation Past Issues / Summer 2006 ... Javascript on. Photo: Comstock LactMed, a free online database with information on drugs and lactation, is one ...

e-Drug3D: 3D structure collections dedicated to drug repurposing and fragment-based drug design.

PubMed

Pihan, Emilie; Colliandre, Lionel; Guichou, Jean-François; Douguet, Dominique

2012-06-01

In the drug discovery field, new uses for old drugs, selective optimization of side activities and fragment-based drug design (FBDD) have proved to be successful alternatives to high-throughput screening. e-Drug3D is a database of 3D chemical structures of drugs that provides several collections of ready-to-screen SD files of drugs and commercial drug fragments. They are natural inputs in studies dedicated to drug repurposing and FBDD. e-Drug3D collections are freely available at http://chemoinfo.ipmc.cnrs.fr/e-drug3d.html either for download or for direct in silico web-based screenings.

Traditional Medicine Collection Tracking System (TM-CTS): a database for ethnobotanically driven drug-discovery programs.

PubMed

Harris, Eric S J; Erickson, Sean D; Tolopko, Andrew N; Cao, Shugeng; Craycroft, Jane A; Scholten, Robert; Fu, Yanling; Wang, Wenquan; Liu, Yong; Zhao, Zhongzhen; Clardy, Jon; Shamu, Caroline E; Eisenberg, David M

2011-05-17

Ethnobotanically driven drug-discovery programs include data related to many aspects of the preparation of botanical medicines, from initial plant collection to chemical extraction and fractionation. The Traditional Medicine Collection Tracking System (TM-CTS) was created to organize and store data of this type for an international collaborative project involving the systematic evaluation of commonly used Traditional Chinese Medicinal plants. The system was developed using domain-driven design techniques, and is implemented using Java, Hibernate, PostgreSQL, Business Intelligence and Reporting Tools (BIRT), and Apache Tomcat. The TM-CTS relational database schema contains over 70 data types, comprising over 500 data fields. The system incorporates a number of unique features that are useful in the context of ethnobotanical projects such as support for information about botanical collection, method of processing, quality tests for plants with existing pharmacopoeia standards, chemical extraction and fractionation, and historical uses of the plants. The database also accommodates data provided in multiple languages and integration with a database system built to support high throughput screening based drug discovery efforts. It is accessed via a web-based application that provides extensive, multi-format reporting capabilities. This new database system was designed to support a project evaluating the bioactivity of Chinese medicinal plants. The software used to create the database is open source, freely available, and could potentially be applied to other ethnobotanically driven natural product collection and drug-discovery programs. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Traditional Medicine Collection Tracking System (TM-CTS): A Database for Ethnobotanically-Driven Drug-Discovery Programs

PubMed Central

Harris, Eric S. J.; Erickson, Sean D.; Tolopko, Andrew N.; Cao, Shugeng; Craycroft, Jane A.; Scholten, Robert; Fu, Yanling; Wang, Wenquan; Liu, Yong; Zhao, Zhongzhen; Clardy, Jon; Shamu, Caroline E.; Eisenberg, David M.

2011-01-01

Aim of the study. Ethnobotanically-driven drug-discovery programs include data related to many aspects of the preparation of botanical medicines, from initial plant collection to chemical extraction and fractionation. The Traditional Medicine-Collection Tracking System (TM-CTS) was created to organize and store data of this type for an international collaborative project involving the systematic evaluation of commonly used Traditional Chinese Medicinal plants. Materials and Methods. The system was developed using domain-driven design techniques, and is implemented using Java, Hibernate, PostgreSQL, Business Intelligence and Reporting Tools (BIRT), and Apache Tomcat. Results. The TM-CTS relational database schema contains over 70 data types, comprising over 500 data fields. The system incorporates a number of unique features that are useful in the context of ethnobotanical projects such as support for information about botanical collection, method of processing, quality tests for plants with existing pharmacopoeia standards, chemical extraction and fractionation, and historical uses of the plants. The database also accommodates data provided in multiple languages and integration with a database system built to support high throughput screening based drug discovery efforts. It is accessed via a web-based application that provides extensive, multi-format reporting capabilities. Conclusions. This new database system was designed to support a project evaluating the bioactivity of Chinese medicinal plants. The software used to create the database is open source, freely available, and could potentially be applied to other ethnobotanically-driven natural product collection and drug-discovery programs. PMID:21420479

RAS - Screens & Assays - Drug Discovery

Cancer.gov

The RAS Drug Discovery group aims to develop assays that will reveal aspects of RAS biology upon which cancer cells depend. Successful assay formats are made available for high-throughput screening programs to yield potentially effective drug compounds.

Drug screening using model systems: some basics

PubMed Central

2016-01-01

ABSTRACT An increasing number of laboratories that focus on model systems are considering drug screening. Executing a drug screen is complicated enough. But the path for moving initial hits towards the clinic requires a different knowledge base and even a different mindset. In this Editorial I discuss the importance of doing some homework before you start screening. 'Lead hits', 'patentable chemical space' and 'druggability' are all concepts worth exploring when deciding which screening path to take. I discuss some of the lessons I learned that may be useful as you navigate the screening matrix. PMID:27821602

The prescribable drugs with efficacy in experimental epilepsies (PDE3) database for drug repurposing research in epilepsy.

PubMed

Sivapalarajah, Shayeeshan; Krishnakumar, Mathangi; Bickerstaffe, Harry; Chan, YikYing; Clarkson, Joseph; Hampden-Martin, Alistair; Mirza, Ahmad; Tanti, Matthew; Marson, Anthony; Pirmohamed, Munir; Mirza, Nasir

2018-02-01

Current antiepileptic drugs (AEDs) have several shortcomings. For example, they fail to control seizures in 30% of patients. Hence, there is a need to identify new AEDs. Drug repurposing is the discovery of new indications for approved drugs. This drug "recycling" offers the potential of significant savings in the time and cost of drug development. Many drugs licensed for other indications exhibit antiepileptic efficacy in animal models. Our aim was to create a database of "prescribable" drugs, approved for other conditions, with published evidence of efficacy in animal models of epilepsy, and to collate data that would assist in choosing the most promising candidates for drug repurposing. The database was created by the following: (1) computational literature-mining using novel software that identifies Medline abstracts containing the name of a prescribable drug, a rodent model of epilepsy, and a phrase indicating seizure reduction; then (2) crowdsourced manual curation of the identified abstracts. The final database includes 173 drugs and 500 abstracts. It is made freely available at www.liverpool.ac.uk/D3RE/PDE3. The database is reliable: 94% of the included drugs have corroborative evidence of efficacy in animal models (for example, evidence from multiple independent studies). The database includes many drugs that are appealing candidates for repurposing, as they are widely accepted by prescribers and patients-the database includes half of the 20 most commonly prescribed drugs in England-and they target many proteins involved in epilepsy but not targeted by current AEDs. It is important to note that the drugs are of potential relevance to human epilepsy-the database is highly enriched with drugs that target proteins of known causal human epilepsy genes (Fisher's exact test P-value < 3 × 10 -5 ). We present data to help prioritize the most promising candidates for repurposing from the database. The PDE3 database is an important new resource for drug

The DrugAge database of aging-related drugs.

PubMed

Barardo, Diogo; Thornton, Daniel; Thoppil, Harikrishnan; Walsh, Michael; Sharifi, Samim; Ferreira, Susana; Anžič, Andreja; Fernandes, Maria; Monteiro, Patrick; Grum, Tjaša; Cordeiro, Rui; De-Souza, Evandro Araújo; Budovsky, Arie; Araujo, Natali; Gruber, Jan; Petrascheck, Michael; Fraifeld, Vadim E; Zhavoronkov, Alexander; Moskalev, Alexey; de Magalhães, João Pedro

2017-06-01

Aging is a major worldwide medical challenge. Not surprisingly, identifying drugs and compounds that extend lifespan in model organisms is a growing research area. Here, we present DrugAge (http://genomics.senescence.info/drugs/), a curated database of lifespan-extending drugs and compounds. At the time of writing, DrugAge contains 1316 entries featuring 418 different compounds from studies across 27 model organisms, including worms, flies, yeast and mice. Data were manually curated from 324 publications. Using drug-gene interaction data, we also performed a functional enrichment analysis of targets of lifespan-extending drugs. Enriched terms include various functional categories related to glutathione and antioxidant activity, ion transport and metabolic processes. In addition, we found a modest but significant overlap between targets of lifespan-extending drugs and known aging-related genes, suggesting that some but not most aging-related pathways have been targeted pharmacologically in longevity studies. DrugAge is freely available online for the scientific community and will be an important resource for biogerontologists. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

A Public-Use, Full-Screen Interface for SPIRES Databases.

ERIC Educational Resources Information Center

Kriz, Harry M.

This paper describes the techniques for implementing a full-screen, custom SPIRES interface for a public-use library database. The database-independent protocol that controls the system is described in detail. Source code for an entire working application using this interface is included. The protocol, with less than 170 lines of procedural code,…

The application of knowledge discovery in databases to post-marketing drug safety: example of the WHO database.

PubMed

Bate, A; Lindquist, M; Edwards, I R

2008-04-01

After market launch, new information on adverse effects of medicinal products is almost exclusively first highlighted by spontaneous reporting. As data sets of spontaneous reports have become larger, and computational capability has increased, quantitative methods have been increasingly applied to such data sets. The screening of such data sets is an application of knowledge discovery in databases (KDD). Effective KDD is an iterative and interactive process made up of the following steps: developing an understanding of an application domain, creating a target data set, data cleaning and pre-processing, data reduction and projection, choosing the data mining task, choosing the data mining algorithm, data mining, interpretation of results and consolidating and using acquired knowledge. The process of KDD as it applies to the analysis of spontaneous reports can be exemplified by its routine use on the 3.5 million suspected adverse drug reaction (ADR) reports in the WHO ADR database. Examples of new adverse effects first highlighted by the KDD process on WHO data include topiramate glaucoma, infliximab vasculitis and the association of selective serotonin reuptake inhibitors (SSRIs) and neonatal convulsions. The KDD process has already improved our ability to highlight previously unsuspected ADRs for clinical review in spontaneous reporting, and we anticipate that such techniques will be increasingly used in the successful screening of other healthcare data sets such as patient records in the future.

[Benefits of large healthcare databases for drug risk research].

PubMed

Garbe, Edeltraut; Pigeot, Iris

2015-08-01

Large electronic healthcare databases have become an important worldwide data resource for drug safety research after approval. Signal generation methods and drug safety studies based on these data facilitate the prospective monitoring of drug safety after approval, as has been recently required by EU law and the German Medicines Act. Despite its large size, a single healthcare database may include insufficient patients for the study of a very small number of drug-exposed patients or the investigation of very rare drug risks. For that reason, in the United States, efforts have been made to work on models that provide the linkage of data from different electronic healthcare databases for monitoring the safety of medicines after authorization in (i) the Sentinel Initiative and (ii) the Observational Medical Outcomes Partnership (OMOP). In July 2014, the pilot project Mini-Sentinel included a total of 178 million people from 18 different US databases. The merging of the data is based on a distributed data network with a common data model. In the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCEPP) there has been no comparable merging of data from different databases; however, first experiences have been gained in various EU drug safety projects. In Germany, the data of the statutory health insurance providers constitute the most important resource for establishing a large healthcare database. Their use for this purpose has so far been severely restricted by the Code of Social Law (Section 75, Book 10). Therefore, a reform of this section is absolutely necessary.

Understanding drugs in breast cancer through drug sensitivity screening.

PubMed

Uhr, Katharina; Prager-van der Smissen, Wendy J C; Heine, Anouk A J; Ozturk, Bahar; Smid, Marcel; Göhlmann, Hinrich W H; Jager, Agnes; Foekens, John A; Martens, John W M

2015-01-01

With substantial numbers of breast tumors showing or acquiring treatment resistance, it is of utmost importance to develop new agents for the treatment of the disease, to know their effectiveness against breast cancer and to understand their relationships with other drugs to best assign the right drug to the right patient. To achieve this goal drug screenings on breast cancer cell lines are a promising approach. In this study a large-scale drug screening of 37 compounds was performed on a panel of 42 breast cancer cell lines representing the main breast cancer subtypes. Clustering, correlation and pathway analyses were used for data analysis. We found that compounds with a related mechanism of action had correlated IC50 values and thus grouped together when the cell lines were hierarchically clustered based on IC50 values. In total we found six clusters of drugs of which five consisted of drugs with related mode of action and one cluster with two drugs not previously connected. In total, 25 correlated and four anti-correlated drug sensitivities were revealed of which only one drug, Sirolimus, showed significantly lower IC50 values in the luminal/ERBB2 breast cancer subtype. We found expected interactions but also discovered new relationships between drugs which might have implications for cancer treatment regimens.

Stereoselective virtual screening of the ZINC database using atom pair 3D-fingerprints.

PubMed

Awale, Mahendra; Jin, Xian; Reymond, Jean-Louis

2015-01-01

Tools to explore large compound databases in search for analogs of query molecules provide a strategically important support in drug discovery to help identify available analogs of any given reference or hit compound by ligand based virtual screening (LBVS). We recently showed that large databases can be formatted for very fast searching with various 2D-fingerprints using the city-block distance as similarity measure, in particular a 2D-atom pair fingerprint (APfp) and the related category extended atom pair fingerprint (Xfp) which efficiently encode molecular shape and pharmacophores, but do not perceive stereochemistry. Here we investigated related 3D-atom pair fingerprints to enable rapid stereoselective searches in the ZINC database (23.2 million 3D structures). Molecular fingerprints counting atom pairs at increasing through-space distance intervals were designed using either all atoms (16-bit 3DAPfp) or different atom categories (80-bit 3DXfp). These 3D-fingerprints retrieved molecular shape and pharmacophore analogs (defined by OpenEye ROCS scoring functions) of 110,000 compounds from the Cambridge Structural Database with equal or better accuracy than the 2D-fingerprints APfp and Xfp, and showed comparable performance in recovering actives from decoys in the DUD database. LBVS by 3DXfp or 3DAPfp similarity was stereoselective and gave very different analogs when starting from different diastereomers of the same chiral drug. Results were also different from LBVS with the parent 2D-fingerprints Xfp or APfp. 3D- and 2D-fingerprints also gave very different results in LBVS of folded molecules where through-space distances between atom pairs are much shorter than topological distances. 3DAPfp and 3DXfp are suitable for stereoselective searches for shape and pharmacophore analogs of query molecules in large databases. Web-browsers for searching ZINC by 3DAPfp and 3DXfp similarity are accessible at www.gdb.unibe.ch and should provide useful assistance to drug

A national database for essential drugs in South Africa.

PubMed

Zweygarth, M; Summers, R S

2000-06-01

In the process of drafting standard treatment guidelines for adults and children at hospital level, the Secretariat of the National Essential Drugs List Committee made use of a database designed with technical support from the School of Pharmacy, MEDUNSA. The database links the current 697 drugs on the Essential Drugs List with Standard Treatment Guidelines for over 400 conditions. It served to streamline the inclusion of different drugs and dosage forms in the various guidelines, and provided concise, updated information to other departments involved in drug procurement. From information on drug prices and morbidity, it can also be used to calculate drug consumption and cost estimates and compare them with actual figures.

Comprehensive Urine Drug Screen by Gas Chromatography/Mass Spectrometry (GC/MS).

PubMed

Ramoo, Bheemraj; Funke, Melissa; Frazee, Clint; Garg, Uttam

2016-01-01

Drug screening is an essential component of clinical toxicology laboratory service. Some laboratories use only automated chemistry analyzers for limited screening of drugs of abuse and few other drugs. Other laboratories use a combination of various techniques such as immunoassays, colorimetric tests, and mass spectrometry to provide more detailed comprehensive drug screening. Mass spectrometry, gas or liquid, can screen for hundreds of drugs and is often considered the gold standard for comprehensive drug screening. We describe an efficient and rapid gas chromatography/mass spectrometry (GC/MS) method for comprehensive drug screening in urine which utilizes a liquid-liquid extraction, sample concentration, and analysis by GC/MS.

Microfluidic cell chips for high-throughput drug screening

PubMed Central

Chi, Chun-Wei; Ahmed, AH Rezwanuddin; Dereli-Korkut, Zeynep; Wang, Sihong

2016-01-01

The current state of screening methods for drug discovery is still riddled with several inefficiencies. Although some widely used high-throughput screening platforms may enhance the drug screening process, their cost and oversimplification of cell–drug interactions pose a translational difficulty. Microfluidic cell-chips resolve many issues found in conventional HTS technology, providing benefits such as reduced sample quantity and integration of 3D cell culture physically more representative of the physiological/pathological microenvironment. In this review, we introduce the advantages of microfluidic devices in drug screening, and outline the critical factors which influence device design, highlighting recent innovations and advances in the field including a summary of commercialization efforts on microfluidic cell chips. Future perspectives of microfluidic cell devices are also provided based on considerations of present technological limitations and translational barriers. PMID:27071838

Applications of chemogenomic library screening in drug discovery.

PubMed

Jones, Lyn H; Bunnage, Mark E

2017-04-01

The allure of phenotypic screening, combined with the industry preference for target-based approaches, has prompted the development of innovative chemical biology technologies that facilitate the identification of new therapeutic targets for accelerated drug discovery. A chemogenomic library is a collection of selective small-molecule pharmacological agents, and a hit from such a set in a phenotypic screen suggests that the annotated target or targets of that pharmacological agent may be involved in perturbing the observable phenotype. In this Review, we describe opportunities for chemogenomic screening to considerably expedite the conversion of phenotypic screening projects into target-based drug discovery approaches. Other applications are explored, including drug repositioning, predictive toxicology and the discovery of novel pharmacological modalities.

DrugBank 5.0: a major update to the DrugBank database for 2018.

PubMed

Wishart, David S; Feunang, Yannick D; Guo, An C; Lo, Elvis J; Marcu, Ana; Grant, Jason R; Sajed, Tanvir; Johnson, Daniel; Li, Carin; Sayeeda, Zinat; Assempour, Nazanin; Iynkkaran, Ithayavani; Liu, Yifeng; Maciejewski, Adam; Gale, Nicola; Wilson, Alex; Chin, Lucy; Cummings, Ryan; Le, Diana; Pon, Allison; Knox, Craig; Wilson, Michael

2018-01-04

DrugBank (www.drugbank.ca) is a web-enabled database containing comprehensive molecular information about drugs, their mechanisms, their interactions and their targets. First described in 2006, DrugBank has continued to evolve over the past 12 years in response to marked improvements to web standards and changing needs for drug research and development. This year's update, DrugBank 5.0, represents the most significant upgrade to the database in more than 10 years. In many cases, existing data content has grown by 100% or more over the last update. For instance, the total number of investigational drugs in the database has grown by almost 300%, the number of drug-drug interactions has grown by nearly 600% and the number of SNP-associated drug effects has grown more than 3000%. Significant improvements have been made to the quantity, quality and consistency of drug indications, drug binding data as well as drug-drug and drug-food interactions. A great deal of brand new data have also been added to DrugBank 5.0. This includes information on the influence of hundreds of drugs on metabolite levels (pharmacometabolomics), gene expression levels (pharmacotranscriptomics) and protein expression levels (pharmacoprotoemics). New data have also been added on the status of hundreds of new drug clinical trials and existing drug repurposing trials. Many other important improvements in the content, interface and performance of the DrugBank website have been made and these should greatly enhance its ease of use, utility and potential applications in many areas of pharmacological research, pharmaceutical science and drug education. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Discovery of Novel HIV-1 Integrase Inhibitors Using QSAR-Based Virtual Screening of the NCI Open Database.

PubMed

Ko, Gene M; Garg, Rajni; Bailey, Barbara A; Kumar, Sunil

2016-01-01

Quantitative structure-activity relationship (QSAR) models can be used as a predictive tool for virtual screening of chemical libraries to identify novel drug candidates. The aims of this paper were to report the results of a study performed for descriptor selection, QSAR model development, and virtual screening for identifying novel HIV-1 integrase inhibitor drug candidates. First, three evolutionary algorithms were compared for descriptor selection: differential evolution-binary particle swarm optimization (DE-BPSO), binary particle swarm optimization, and genetic algorithms. Next, three QSAR models were developed from an ensemble of multiple linear regression, partial least squares, and extremely randomized trees models. A comparison of the performances of three evolutionary algorithms showed that DE-BPSO has a significant improvement over the other two algorithms. QSAR models developed in this study were used in consensus as a predictive tool for virtual screening of the NCI Open Database containing 265,242 compounds to identify potential novel HIV-1 integrase inhibitors. Six compounds were predicted to be highly active (plC50 > 6) by each of the three models. The use of a hybrid evolutionary algorithm (DE-BPSO) for descriptor selection and QSAR model development in drug design is a novel approach. Consensus modeling may provide better predictivity by taking into account a broader range of chemical properties within the data set conducive for inhibition that may be missed by an individual model. The six compounds identified provide novel drug candidate leads in the design of next generation HIV- 1 integrase inhibitors targeting drug resistant mutant viruses.

Microfluidics-assisted in vitro drug screening and carrier production

PubMed Central

Tsui, Jonathan H.; Lee, Woohyuk; Pun, Suzie H.; Kim, Jungkyu; Kim, Deok-Ho

2013-01-01

Microfluidic platforms provide several unique advantages for drug development. In the production of drug carriers, physical properties such as size and shape, and chemical properties such as drug composition and pharmacokinetic parameters, can be modified simply and effectively by tuning the flow rate and geometries. Large numbers of carriers can then be fabricated with minimal effort and with little to no batch-to-batch variation. Additionally, cell or tissue culture models in microfluidic systems can be used as in vitro drug screening tools. Compared to in vivo animal models, microfluidic drug screening platforms allow for high-throughput and reproducible screening at a significantly lower cost, and when combined with current advances in tissue engineering, are also capable of mimicking native tissues. In this review, various microfluidic platforms for drug and gene carrier fabrication are reviewed to provide guidelines for designing appropriate carriers. In vitro microfluidic drug screening platforms designed for high-throughput analysis and replication of in vivo conditions are also reviewed to highlight future directions for drug research and development. PMID:23856409

SFINX-a drug-drug interaction database designed for clinical decision support systems.

PubMed

Böttiger, Ylva; Laine, Kari; Andersson, Marine L; Korhonen, Tuomas; Molin, Björn; Ovesjö, Marie-Louise; Tirkkonen, Tuire; Rane, Anders; Gustafsson, Lars L; Eiermann, Birgit

2009-06-01

The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.

Clinical evaluation and use of urine screening for drug abuse.

PubMed Central

Saxon, A J; Calsyn, D A; Haver, V M; Delaney, C J

1988-01-01

Urine drug screening is indicated to evaluate patients who show mental status or behavioral changes and to monitor the abstinence of drug abusers. The appropriate timing for collecting urine specimens may vary depending on the suspected drug of abuse and on laboratory factors. Laboratories use a variety of techniques to do urine screens, and these must be understood by clinicians ordering the screens to interpret results correctly. In treating drug-abusing patients, clinicians must apply structured reinforcement in conjunction with urine screen results to aid patients in achieving abstinence. PMID:3176489

Evaluation of personal digital assistant drug information databases for the managed care pharmacist.

PubMed

Lowry, Colleen M; Kostka-Rokosz, Maria D; McCloskey, William W

2003-01-01

Personal digital assistants (PDAs) are becoming a necessity for practicing pharmacists. They offer a time-saving and convenient way to obtain current drug information. Several software companies now offer general drug information databases for use on hand held computers. PDAs priced less than 200 US dollars often have limited memory capacity; therefore, the user must choose from a growing list of general drug information database options in order to maximize utility without exceeding memory capacity. This paper reviews the attributes of available general drug information software databases for the PDA. It provides information on the content, advantages, limitations, pricing, memory requirements, and accessibility of drug information software databases. Ten drug information databases were subjectively analyzed and evaluated based on information from the product.s Web site, vendor Web sites, and from our experience. Some of these databases have attractive auxiliary features such as kinetics calculators, disease references, drug-drug and drug-herb interaction tools, and clinical guidelines, which may make them more useful to the PDA user. Not all drug information databases are equal with regard to content, author credentials, frequency of updates, and memory requirements. The user must therefore evaluate databases for completeness, currency, and cost effectiveness before purchase. In addition, consideration should be given to the ease of use and flexibility of individual programs.

Screening emergency department patients for opioid drug use: A qualitative systematic review.

PubMed

Sahota, Preet Kaur; Shastry, Siri; Mukamel, Dana B; Murphy, Linda; Yang, Narisu; Lotfipour, Shahram; Chakravarthy, Bharath

2018-05-24

The opioid drug epidemic is a major public health concern and an economic burden in the United States. The purpose of this systematic review is to assess the reliability and validity of screening instruments used in emergency medicine settings to detect opioid use in patients and to assess psychometric data for each screening instrument. PubMed/MEDLINE, PsycINFO, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, Cumulative Index to Nursing and Allied Health Literature and ClinicalTrials.gov were searched for articles published up to May 2018. The extracted articles were independently screened for eligibility by two reviewers. We extracted 1555 articles for initial screening and 95 articles were assessed for full-text eligibility. Six articles were extracted from the full-text assessment. Six instruments were identified from the final article list: Screener and Opioid Assessment for Patients with Pain - Revised; Drug Abuse Screening Test; Opioid Risk Tool; Current Opioid Misuse Measure; an Emergency Medicine Providers Clinician Assessment Questionnaire; and an Emergency Provider Impression Data Collection Form. Screening instrument characteristics, and reliability and validity data were extracted from the six studies. A meta-analysis was not conducted due to heterogeneity between the studies. There is a lack of validity and reliability evidence in all six articles; and sensitivity, specificity and predictive values varied between the different instruments. These instruments cannot be validated for use in emergency medicine settings. There is no clear evidence to state which screening instruments are appropriate for use in detecting opioid use disorders in emergency medicine patients. There is a need for brief, reliable, valid and feasible opioid use screening instruments in the emergency medicine setting. Copyright © 2018 Elsevier Ltd. All rights reserved.

Hierarchical virtual screening approaches in small molecule drug discovery.

PubMed

Kumar, Ashutosh; Zhang, Kam Y J

2015-01-01

Virtual screening has played a significant role in the discovery of small molecule inhibitors of therapeutic targets in last two decades. Various ligand and structure-based virtual screening approaches are employed to identify small molecule ligands for proteins of interest. These approaches are often combined in either hierarchical or parallel manner to take advantage of the strength and avoid the limitations associated with individual methods. Hierarchical combination of ligand and structure-based virtual screening approaches has received noteworthy success in numerous drug discovery campaigns. In hierarchical virtual screening, several filters using ligand and structure-based approaches are sequentially applied to reduce a large screening library to a number small enough for experimental testing. In this review, we focus on different hierarchical virtual screening strategies and their application in the discovery of small molecule modulators of important drug targets. Several virtual screening studies are discussed to demonstrate the successful application of hierarchical virtual screening in small molecule drug discovery. Copyright © 2014 Elsevier Inc. All rights reserved.

MPD3: a useful medicinal plants database for drug designing.

PubMed

Mumtaz, Arooj; Ashfaq, Usman Ali; Ul Qamar, Muhammad Tahir; Anwar, Farooq; Gulzar, Faisal; Ali, Muhammad Amjad; Saari, Nazamid; Pervez, Muhammad Tariq

2017-06-01

Medicinal plants are the main natural pools for the discovery and development of new drugs. In the modern era of computer-aided drug designing (CADD), there is need of prompt efforts to design and construct useful database management system that allows proper data storage, retrieval and management with user-friendly interface. An inclusive database having information about classification, activity and ready-to-dock library of medicinal plant's phytochemicals is therefore required to assist the researchers in the field of CADD. The present work was designed to merge activities of phytochemicals from medicinal plants, their targets and literature references into a single comprehensive database named as Medicinal Plants Database for Drug Designing (MPD3). The newly designed online and downloadable MPD3 contains information about more than 5000 phytochemicals from around 1000 medicinal plants with 80 different activities, more than 900 literature references and 200 plus targets. The designed database is deemed to be very useful for the researchers who are engaged in medicinal plants research, CADD and drug discovery/development with ease of operation and increased efficiency. The designed MPD3 is a comprehensive database which provides most of the information related to the medicinal plants at a single platform. MPD3 is freely available at: http://bioinform.info .

Computer-aided identification of potential TYK2 inhibitors from drug database

NASA Astrophysics Data System (ADS)

Zhang, Wei; Li, Jianzong; Huang, Zhixin; Wang, Haiyang; Luo, Hao; Wang, Xin; Zhou, Nan; Wu, Chuanfang; Bao, Jinku

2016-10-01

TYK2 is a member of JAKs family protein tyrosine kinase activated in response to various cytokines. It plays a crucial role in transducing signals downstream of various cytokine receptors, which are involved in proinflammatory responses associated with immunological diseases. Thus, the study of selective TYK2 inhibitors is one of the most popular fields in anti-inflammation drug development. Herein, we adopted molecular docking, molecular dynamics simulation and MM-PBSA binding free energy calculation to screen potential TYK2-selective inhibitors from ZINC Drug Database. Finally, three small molecule drugs ZINC12503271 (Gemifloxacin), ZINC05844792 (Nebivolol) and ZINC00537805 (Glyburide) were selected as potential TYK2-selective inhibitors. Compared to known inhibitor 2,6-dichloro-N-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}benzamide, these three candidates had better Grid score and Amber score from molecular docking and preferable results from binding free energy calculation as well. What's more, the ATP-binding site and A-loop motif had been identified to play key roles in TYK2-targeted inhibitor discovery. It is expected that our study will pave the way for the design of potent TYK2 inhibitors of new drugs to treat a wide variety of immunological diseases such as inflammatory diseases, multiple sclerosis, psoriasis inflammatory bowel disease (IBD) and so on.

Drugs and Drug-Like Compounds: Discriminating Approved Pharmaceuticals from Screening-Library Compounds

NASA Astrophysics Data System (ADS)

Schierz, Amanda C.; King, Ross D.

Compounds in drug screening-libraries should resemble pharmaceuticals. To operationally test this, we analysed the compounds in terms of known drug-like filters and developed a novel machine learning method to discriminate approved pharmaceuticals from “drug-like” compounds. This method uses both structural features and molecular properties for discrimination. The method has an estimated accuracy of 91% in discriminating between the Maybridge HitFinder library and approved pharmaceuticals, and 99% between the NATDiverse collection (from Analyticon Discovery) and approved pharmaceuticals. These results show that Lipinski’s Rule of 5 for oral absorption is not sufficient to describe “drug-likeness” and be the main basis of screening-library design.

Biomedical Informatics Approaches to Identifying Drug-Drug Interactions: Application to Insulin Secretagogues

PubMed Central

Han, Xu; Chiang, ChienWei; Leonard, Charles E.; Bilker, Warren B.; Brensinger, Colleen M.; Li, Lang; Hennessy, Sean

2017-01-01

Background Drug-drug interactions with insulin secretagogues are associated with increased risk of serious hypoglycemia in patients with type 2 diabetes. We aimed to systematically screen for drugs that interact with the five most commonly used secretagogues―glipizide, glyburide, glimepiride, repaglinide, and nateglinide―to cause serious hypoglycemia. Methods We screened 400 drugs frequently co-prescribed with the secretagogues as candidate interacting precipitants. We first predicted the drug–drug interaction potential based on the pharmacokinetics of each secretagogue–precipitant pair. We then performed pharmacoepidemiologic screening for each secretagogue of interest, and for metformin as a negative control, using an administrative claims database and the self-controlled case series design. The overall rate ratios (RRs) and those for four predefined risk periods were estimated using Poisson regression. The RRs were adjusted for multiple estimation using semi-Bayes method, and then adjusted for metformin results to distinguish native effects of the precipitant from a drug–drug interaction. Results We predicted 34 pharmacokinetic drug–drug interactions with the secretagogues, nine moderate and 25 weak. There were 140 and 61 secretagogue–precipitant pairs associated with increased rates of serious hypoglycemia before and after the metformin adjustment, respectively. The results from pharmacokinetic prediction correlated poorly with those from pharmacoepidemiologic screening. Conclusions The self-controlled case series design has the potential to be widely applicable to screening for drug–drug interactions that lead to adverse outcomes identifiable in healthcare databases. Coupling pharmacokinetic prediction with pharmacoepidemiologic screening did not notably improve the ability to identify drug–drug interactions in this case. PMID:28169935

Screening for alcohol and drug use in pregnancy.

PubMed

Seib, Charrlotte A; Daglish, Mark; Heath, Renée; Booker, Catriona; Reid, Carol; Fraser, Jennifer

2012-12-01

this study examined the clinical utility and precision of routine screening for alcohol and other drug use among women attending a public antenatal service. a survey of clients and audit of clinical charts. clients attending an antenatal clinic of a large tertiary hospital in Queensland, Australia, from October to December 2009. data were collected from two sources. First, 32 women who reported use of alcohol or other drugs during pregnancy at initial screening were then asked to complete a full substance use survey. Second, data were collected from charts of 349 new clients who attended the antenatal clinic during the study period. Both sensitivity (86%, 67%) and positive predictive value (100%, 92%) for alcohol and other drug use respectively, were high. Only 15% of surveyed women were uncomfortable about being screened for substance use in pregnancy, yet the chart audit revealed poor staff compliance. During the study period, 25% of clients were either not screened adequately or not at all. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTISE: despite recommended universal screening in pregnancy and the apparent acceptance by our participants, alcohol and other drug (A&OD) screening in the antenatal setting remains problematic. Investigation into the reasons behind, and ways to overcome, the low screening rate could improve health outcomes for mothers and children in this at-risk group. Targeted education and training for midwives may form part of the solution as these clinicians have a key role in implementing prevention and early intervention strategies. Copyright © 2011 Elsevier Ltd. All rights reserved.

Development of a replicated database of DHCP data for evaluation of drug use.

PubMed

Graber, S E; Seneker, J A; Stahl, A A; Franklin, K O; Neel, T E; Miller, R A

1996-01-01

This case report describes development and testing of a method to extract clinical information stored in the Veterans Affairs (VA) Decentralized Hospital Computer System (DHCP) for the purpose of analyzing data about groups of patients. The authors used a microcomputer-based, structured query language (SQL)-compatible, relational database system to replicate a subset of the Nashville VA Hospital's DHCP patient database. This replicated database contained the complete current Nashville DHCP prescription, provider, patient, and drug data sets, and a subset of the laboratory data. A pilot project employed this replicated database to answer questions that might arise in drug-use evaluation, such as identification of cases of polypharmacy, suboptimal drug regimens, and inadequate laboratory monitoring of drug therapy. These database queries included as candidates for review all prescriptions for all outpatients. The queries demonstrated that specific drug-use events could be identified for any time interval represented in the replicated database.

Urine drug screening in the medical setting.

PubMed

Hammett-Stabler, Catherine A; Pesce, Amadeo J; Cannon, Donald J

2002-01-01

The term drug screen is a misnomer since it implies screening for all drugs, which is not possible. Current practice is to limit the testing to the examination of serum for several drugs such as ethanol, acetaminophen, salicylate, and of urine for several specific drugs or classes of drugs. In the emergency setting the screen should be performed in less than one hour. Controversies continue to exist regarding the value of urine drug testing in the medical setting. The reasons for these include the drugs involved, the sample, the methods utilized to perform the tests, and the level of understanding of the physician using the data, all of which are closely related to the other. Current automated methods provide rapid results demanded in emergency situations, but are often designed for, or adapted from, workplace testing and are not necessarily optimized for clinical applications. Furthermore, the use of these methods without consideration of the frequency in which the drugs are found in a given area is not cost-effective. The laboratory must understand the limitations of the assays used and provide this information to the physician. Additionally, the laboratory and the physicians using the data must cooperate to determine which drugs are appropriate and necessary to measure for their institution and clinical setting. In doing so it should be remembered that for many drugs, the sample, urine, contains the end product(s) of drug metabolism, not the parent drug. Furthermore, it is necessary to understand the pharmacokinetic parameters of the drug of interest when interpreting data. Finally, while testing for some drugs may not appear cost-effective, the prevention or reduction of morbidity and mortality may offset any laboratory costs. While the literature is replete with studies concerning new methods and a few regarding physician understanding, there are none that we could find that thoroughly, objectively, and fully addressed the issues of utility and cost-effectiveness.

A single-question screening test for drug use in primary care.

PubMed

Smith, Peter C; Schmidt, Susan M; Allensworth-Davies, Donald; Saitz, Richard

2010-07-12

Drug use (illicit drug use and nonmedical use of prescription drugs) is common but underrecognized in primary care settings. We validated a single-question screening test for drug use and drug use disorders in primary care. Adult patients recruited from primary care waiting rooms were asked the single screening question, "How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?" A response of at least 1 time was considered positive for drug use. They were also asked the 10-item Drug Abuse Screening Test (DAST-10). The reference standard was the presence or absence of current (past year) drug use or a drug use disorder (abuse or dependence) as determined by a standardized diagnostic interview. Drug use was also determined by oral fluid testing for common drugs of abuse. Of 394 eligible primary care patients, 286 (73%) completed the interview. The single screening question was 100% sensitive (95% confidence interval [CI], 90.6%-100%) and 73.5% specific (95% CI, 67.7%-78.6%) for the detection of a drug use disorder. It was less sensitive for the detection of self-reported current drug use (92.9%; 95% CI, 86.1%-96.5%) and drug use detected by oral fluid testing or self-report (81.8%; 95% CI, 72.5%-88.5%). Test characteristics were similar to those of the DAST-10 and were affected very little by participant demographic characteristics. The single screening question accurately identified drug use in this sample of primary care patients, supporting the usefulness of this brief screen in primary care.

Role of Open Source Tools and Resources in Virtual Screening for Drug Discovery.

PubMed

Karthikeyan, Muthukumarasamy; Vyas, Renu

2015-01-01

Advancement in chemoinformatics research in parallel with availability of high performance computing platform has made handling of large scale multi-dimensional scientific data for high throughput drug discovery easier. In this study we have explored publicly available molecular databases with the help of open-source based integrated in-house molecular informatics tools for virtual screening. The virtual screening literature for past decade has been extensively investigated and thoroughly analyzed to reveal interesting patterns with respect to the drug, target, scaffold and disease space. The review also focuses on the integrated chemoinformatics tools that are capable of harvesting chemical data from textual literature information and transform them into truly computable chemical structures, identification of unique fragments and scaffolds from a class of compounds, automatic generation of focused virtual libraries, computation of molecular descriptors for structure-activity relationship studies, application of conventional filters used in lead discovery along with in-house developed exhaustive PTC (Pharmacophore, Toxicophores and Chemophores) filters and machine learning tools for the design of potential disease specific inhibitors. A case study on kinase inhibitors is provided as an example.

Development of a replicated database of DHCP data for evaluation of drug use.

PubMed Central

Graber, S E; Seneker, J A; Stahl, A A; Franklin, K O; Neel, T E; Miller, R A

1996-01-01

This case report describes development and testing of a method to extract clinical information stored in the Veterans Affairs (VA) Decentralized Hospital Computer System (DHCP) for the purpose of analyzing data about groups of patients. The authors used a microcomputer-based, structured query language (SQL)-compatible, relational database system to replicate a subset of the Nashville VA Hospital's DHCP patient database. This replicated database contained the complete current Nashville DHCP prescription, provider, patient, and drug data sets, and a subset of the laboratory data. A pilot project employed this replicated database to answer questions that might arise in drug-use evaluation, such as identification of cases of polypharmacy, suboptimal drug regimens, and inadequate laboratory monitoring of drug therapy. These database queries included as candidates for review all prescriptions for all outpatients. The queries demonstrated that specific drug-use events could be identified for any time interval represented in the replicated database. PMID:8653451

Rationale and uses of a public HIV drug-resistance database.

PubMed

Shafer, Robert W

2006-09-15

Knowledge regarding the drug resistance of human immunodeficiency virus (HIV) is critical for surveillance of drug resistance, development of antiretroviral drugs, and management of infections with drug-resistant viruses. Such knowledge is derived from studies that correlate genetic variation in the targets of therapy with the antiretroviral treatments received by persons from whom the variant was obtained (genotype-treatment), with drug-susceptibility data on genetic variants (genotype-phenotype), and with virological and clinical response to a new treatment regimen (genotype-outcome). An HIV drug-resistance database is required to represent, store, and analyze the diverse forms of data underlying our knowledge of drug resistance and to make these data available to the broad community of researchers studying drug resistance in HIV and clinicians using HIV drug-resistance tests. Such genotype-treatment, genotype-phenotype, and genotype-outcome correlations are contained in the Stanford HIV RT and Protease Sequence Database and have specific usefulness.

GEAR: A database of Genomic Elements Associated with drug Resistance.

PubMed

Wang, Yin-Ying; Chen, Wei-Hua; Xiao, Pei-Pei; Xie, Wen-Bin; Luo, Qibin; Bork, Peer; Zhao, Xing-Ming

2017-03-15

Drug resistance is becoming a serious problem that leads to the failure of standard treatments, which is generally developed because of genetic mutations of certain molecules. Here, we present GEAR (A database of Genomic Elements Associated with drug Resistance) that aims to provide comprehensive information about genomic elements (including genes, single-nucleotide polymorphisms and microRNAs) that are responsible for drug resistance. Right now, GEAR contains 1631 associations between 201 human drugs and 758 genes, 106 associations between 29 human drugs and 66 miRNAs, and 44 associations between 17 human drugs and 22 SNPs. These relationships are firstly extracted from primary literature with text mining and then manually curated. The drug resistome deposited in GEAR provides insights into the genetic factors underlying drug resistance. In addition, new indications and potential drug combinations can be identified based on the resistome. The GEAR database can be freely accessed through http://gear.comp-sysbio.org.

GEAR: A database of Genomic Elements Associated with drug Resistance

PubMed Central

Wang, Yin-Ying; Chen, Wei-Hua; Xiao, Pei-Pei; Xie, Wen-Bin; Luo, Qibin; Bork, Peer; Zhao, Xing-Ming

2017-01-01

Drug resistance is becoming a serious problem that leads to the failure of standard treatments, which is generally developed because of genetic mutations of certain molecules. Here, we present GEAR (A database of Genomic Elements Associated with drug Resistance) that aims to provide comprehensive information about genomic elements (including genes, single-nucleotide polymorphisms and microRNAs) that are responsible for drug resistance. Right now, GEAR contains 1631 associations between 201 human drugs and 758 genes, 106 associations between 29 human drugs and 66 miRNAs, and 44 associations between 17 human drugs and 22 SNPs. These relationships are firstly extracted from primary literature with text mining and then manually curated. The drug resistome deposited in GEAR provides insights into the genetic factors underlying drug resistance. In addition, new indications and potential drug combinations can be identified based on the resistome. The GEAR database can be freely accessed through http://gear.comp-sysbio.org. PMID:28294141

CREDO: a structural interactomics database for drug discovery

PubMed Central

Schreyer, Adrian M.; Blundell, Tom L.

2013-01-01

CREDO is a unique relational database storing all pairwise atomic interactions of inter- as well as intra-molecular contacts between small molecules and macromolecules found in experimentally determined structures from the Protein Data Bank. These interactions are integrated with further chemical and biological data. The database implements useful data structures and algorithms such as cheminformatics routines to create a comprehensive analysis platform for drug discovery. The database can be accessed through a web-based interface, downloads of data sets and web services at http://www-cryst.bioc.cam.ac.uk/credo. Database URL: http://www-cryst.bioc.cam.ac.uk/credo PMID:23868908

TCMSP: a database of systems pharmacology for drug discovery from herbal medicines.

PubMed

Ru, Jinlong; Li, Peng; Wang, Jinan; Zhou, Wei; Li, Bohui; Huang, Chao; Li, Pidong; Guo, Zihu; Tao, Weiyang; Yang, Yinfeng; Xu, Xue; Li, Yan; Wang, Yonghua; Yang, Ling

2014-01-01

Modern medicine often clashes with traditional medicine such as Chinese herbal medicine because of the little understanding of the underlying mechanisms of action of the herbs. In an effort to promote integration of both sides and to accelerate the drug discovery from herbal medicines, an efficient systems pharmacology platform that represents ideal information convergence of pharmacochemistry, ADME properties, drug-likeness, drug targets, associated diseases and interaction networks, are urgently needed. The traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) was built based on the framework of systems pharmacology for herbal medicines. It consists of all the 499 Chinese herbs registered in the Chinese pharmacopoeia with 29,384 ingredients, 3,311 targets and 837 associated diseases. Twelve important ADME-related properties like human oral bioavailability, half-life, drug-likeness, Caco-2 permeability, blood-brain barrier and Lipinski's rule of five are provided for drug screening and evaluation. TCMSP also provides drug targets and diseases of each active compound, which can automatically establish the compound-target and target-disease networks that let users view and analyze the drug action mechanisms. It is designed to fuel the development of herbal medicines and to promote integration of modern medicine and traditional medicine for drug discovery and development. The particular strengths of TCMSP are the composition of the large number of herbal entries, and the ability to identify drug-target networks and drug-disease networks, which will help revealing the mechanisms of action of Chinese herbs, uncovering the nature of TCM theory and developing new herb-oriented drugs. TCMSP is freely available at http://sm.nwsuaf.edu.cn/lsp/tcmsp.php.

Applications of SHAPES screening in drug discovery.

PubMed

Lepre, Christopher A; Peng, Jeffrey; Fejzo, Jasna; Abdul-Manan, Norzehan; Pocas, Jennifer; Jacobs, Marc; Xie, Xiaoling; Moore, Jonathan M

2002-12-01

The SHAPES strategy combines nuclear magnetic resonance (NMR) screening of a library of small drug-like molecules with a variety of complementary methods, such as virtual screening, high throughput enzymatic assays, combinatorial chemistry, X-ray crystallography, and molecular modeling, in a directed search for new medicinal chemistry leads. In the past few years, the SHAPES strategy has found widespread utility in pharmaceutical research. To illustrate a variety of different implementations of the method, we will focus in this review on recent applications of the SHAPES strategy in several drug discovery programs at Vertex Pharmaceuticals.

Biomimetic three-dimensional tissue models for advanced high-throughput drug screening

PubMed Central

Nam, Ki-Hwan; Smith, Alec S.T.; Lone, Saifullah; Kwon, Sunghoon; Kim, Deok-Ho

2015-01-01

Most current drug screening assays used to identify new drug candidates are 2D cell-based systems, even though such in vitro assays do not adequately recreate the in vivo complexity of 3D tissues. Inadequate representation of the human tissue environment during a preclinical test can result in inaccurate predictions of compound effects on overall tissue functionality. Screening for compound efficacy by focusing on a single pathway or protein target, coupled with difficulties in maintaining long-term 2D monolayers, can serve to exacerbate these issues when utilizing such simplistic model systems for physiological drug screening applications. Numerous studies have shown that cell responses to drugs in 3D culture are improved from those in 2D, with respect to modeling in vivo tissue functionality, which highlights the advantages of using 3D-based models for preclinical drug screens. In this review, we discuss the development of microengineered 3D tissue models which accurately mimic the physiological properties of native tissue samples, and highlight the advantages of using such 3D micro-tissue models over conventional cell-based assays for future drug screening applications. We also discuss biomimetic 3D environments, based-on engineered tissues as potential preclinical models for the development of more predictive drug screening assays for specific disease models. PMID:25385716

DockScreen: A database of in silico biomolecular interactions to support computational toxicology

EPA Science Inventory

We have developed DockScreen, a database of in silico biomolecular interactions designed to enable rational molecular toxicological insight within a computational toxicology framework. This database is composed of chemical/target (receptor and enzyme) binding scores calculated by...

Reverse screening methods to search for the protein targets of chemopreventive compounds

NASA Astrophysics Data System (ADS)

Huang, Hongbin; Zhang, Guigui; Zhou, Yuquan; Lin, Chenru; Chen, Suling; Lin, Yutong; Mai, Shangkang; Huang, Zunnan

2018-05-01

This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn and

Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds.

PubMed

Huang, Hongbin; Zhang, Guigui; Zhou, Yuquan; Lin, Chenru; Chen, Suling; Lin, Yutong; Mai, Shangkang; Huang, Zunnan

2018-01-01

This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget, and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB, and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn

Reverse Screening Methods to Search for the Protein Targets of Chemopreventive Compounds

PubMed Central

Huang, Hongbin; Zhang, Guigui; Zhou, Yuquan; Lin, Chenru; Chen, Suling; Lin, Yutong; Mai, Shangkang; Huang, Zunnan

2018-01-01

This article is a systematic review of reverse screening methods used to search for the protein targets of chemopreventive compounds or drugs. Typical chemopreventive compounds include components of traditional Chinese medicine, natural compounds and Food and Drug Administration (FDA)-approved drugs. Such compounds are somewhat selective but are predisposed to bind multiple protein targets distributed throughout diverse signaling pathways in human cells. In contrast to conventional virtual screening, which identifies the ligands of a targeted protein from a compound database, reverse screening is used to identify the potential targets or unintended targets of a given compound from a large number of receptors by examining their known ligands or crystal structures. This method, also known as in silico or computational target fishing, is highly valuable for discovering the target receptors of query molecules from terrestrial or marine natural products, exploring the molecular mechanisms of chemopreventive compounds, finding alternative indications of existing drugs by drug repositioning, and detecting adverse drug reactions and drug toxicity. Reverse screening can be divided into three major groups: shape screening, pharmacophore screening and reverse docking. Several large software packages, such as Schrödinger and Discovery Studio; typical software/network services such as ChemMapper, PharmMapper, idTarget, and INVDOCK; and practical databases of known target ligands and receptor crystal structures, such as ChEMBL, BindingDB, and the Protein Data Bank (PDB), are available for use in these computational methods. Different programs, online services and databases have different applications and constraints. Here, we conducted a systematic analysis and multilevel classification of the computational programs, online services and compound libraries available for shape screening, pharmacophore screening and reverse docking to enable non-specialist users to quickly learn

Molecular Quantum Similarity, Chemical Reactivity and Database Screening of 3D Pharmacophores of the Protein Kinases A, B and G from Mycobacterium tuberculosis.

PubMed

Morales-Bayuelo, Alejandro

2017-06-21

Mycobacterium tuberculosis remains one of the world's most devastating pathogens. For this reason, we developed a study involving 3D pharmacophore searching, selectivity analysis and database screening for a series of anti-tuberculosis compounds, associated with the protein kinases A, B, and G. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these compounds, with anti-tuberculosis activity. Using the Molecular Quantum Similarity field and reactivity descriptors supported in the Density Functional Theory, it was possible to measure the quantification of the steric and electrostatic effects through the Overlap and Coulomb quantitative convergence (alpha and beta) scales. In addition, an analysis of reactivity indices using global and local descriptors was developed, identifying the binding sites and selectivity on these anti-tuberculosis compounds in the active sites. Finally, the reported pharmacophores to PKn A, B and G, were used to carry out database screening, using a database with anti-tuberculosis drugs from the Kelly Chibale research group (http://www.kellychibaleresearch.uct.ac.za/), to find the compounds with affinity for the specific protein targets associated with PKn A, B and G. In this regard, this hybrid methodology (Molecular Mechanic/Quantum Chemistry) shows new insights into drug design that may be useful in the tuberculosis treatment today.

Phenotypic screening in cancer drug discovery - past, present and future.

PubMed

Moffat, John G; Rudolph, Joachim; Bailey, David

2014-08-01

There has been a resurgence of interest in the use of phenotypic screens in drug discovery as an alternative to target-focused approaches. Given that oncology is currently the most active therapeutic area, and also one in which target-focused approaches have been particularly prominent in the past two decades, we investigated the contribution of phenotypic assays to oncology drug discovery by analysing the origins of all new small-molecule cancer drugs approved by the US Food and Drug Administration (FDA) over the past 15 years and those currently in clinical development. Although the majority of these drugs originated from target-based discovery, we identified a significant number whose discovery depended on phenotypic screening approaches. We postulate that the contribution of phenotypic screening to cancer drug discovery has been hampered by a reliance on 'classical' nonspecific drug effects such as cytotoxicity and mitotic arrest, exacerbated by a paucity of mechanistically defined cellular models for therapeutically translatable cancer phenotypes. However, technical and biological advances that enable such mechanistically informed phenotypic models have the potential to empower phenotypic drug discovery in oncology.

Use of a single alcohol screening question to identify other drug use.

PubMed

Smith, Peter C; Cheng, Debbie M; Allensworth-Davies, Donald; Winter, Michael R; Saitz, Richard

2014-06-01

People who consume unhealthy amounts of alcohol are more likely to use illicit drugs. We tested the ability of a screening test for unhealthy alcohol use to simultaneously detect drug use. Adult English speaking patients (n=286) were enrolled from a primary care waiting room. They were asked the screening question for unhealthy alcohol use "How many times in the past year have you had X or more drinks in a day?", where X is 5 for men and 4 for women, and a response of one or more is considered positive. A standard diagnostic interview was used to determine current (past year) drug use or a drug use disorder (abuse or dependence). Oral fluid testing was also used to detect recent use of common drugs of abuse. The single screening question for unhealthy alcohol use was 67.6% sensitive (95% confidence interval [CI], 50.2-82.0%) and 64.7% specific (95% CI, 58.4-70.6%) for the detection of a drug use disorder. It was similarly insensitive for drug use detected by oral fluid testing and/or self-report. Although a patient with a drug use disorder has twice the odds of screening positive for unhealthy alcohol use compared to one without a drug use disorder, suggesting patients who screen positive for alcohol should be asked about drug use, a single screening question for unhealthy alcohol use was not sensitive or specific for the detection of other drug use or drug use disorders in a sample of primary care patients. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Toward antituberculosis drugs: in silico screening of synthetic compounds against Mycobacterium tuberculosisl,d-transpeptidase 2.

PubMed

Billones, Junie B; Carrillo, Maria Constancia O; Organo, Voltaire G; Macalino, Stephani Joy Y; Sy, Jamie Bernadette A; Emnacen, Inno A; Clavio, Nina Abigail B; Concepcion, Gisela P

2016-01-01

Mycobacterium tuberculosis (Mtb) the main causative agent of tuberculosis, is the main reason why this disease continues to be a global public health threat. It is therefore imperative to find a novel antitubercular drug target that is unique to the structural machinery or is essential to the growth and survival of the bacterium. One such target is the enzyme l,d-transpeptidase 2, also known as LdtMt2, a protein primarily responsible for the catalysis of 3→3 cross-linkages that make up the mycolyl-arabinogalactan-peptidoglycan complex of Mtb. In this study, structure-based pharmacophore screening, molecular docking, and in silico toxicity evaluations were employed in screening compounds from a database of synthetic compounds. Out of the 4.5 million database compounds, 18 structures were identified as high-scoring, high-binding hits with very satisfactory absorption, distribution, metabolism, excretion, and toxicity properties. Two out of the 18 compounds were further subjected to in vitro bioactivity assays, with one exhibiting a good inhibitory activity against the Mtb H37Ra strain.

Clinical decision support tools: performance of personal digital assistant versus online drug information databases.

PubMed

Clauson, Kevin A; Polen, Hyla H; Marsh, Wallace A

2007-12-01

To evaluate personal digital assistant (PDA) drug information databases used to support clinical decision-making, and to compare the performance of PDA databases with their online versions. Prospective evaluation with descriptive analysis. Five drug information databases available for PDAs and online were evaluated according to their scope (inclusion of correct answers), completeness (on a 3-point scale), and ease of use; 158 question-answer pairs across 15 weighted categories of drug information essential to health care professionals were used to evaluate these databases. An overall composite score integrating these three measures was then calculated. Scores for the PDA databases and for each PDA-online pair were compared. Among the PDA databases, composite rankings, from highest to lowest, were as follows: Lexi-Drugs, Clinical Pharmacology OnHand, Epocrates Rx Pro, mobileMicromedex (now called Thomson Clinical Xpert), and Epocrates Rx free version. When we compared database pairs, online databases that had greater scope than their PDA counterparts were Clinical Pharmacology (137 vs 100 answers, p<0.001), Micromedex (132 vs 96 answers, p<0.001), Lexi-Comp Online (131 vs 119 answers, p<0.001), and Epocrates Online Premium (103 vs 98 answers, p=0.001). Only Micromedex online was more complete than its PDA version (p=0.008). Regarding ease of use, the Lexi-Drugs PDA database was superior to Lexi-Comp Online (p<0.001); however, Epocrates Online Premium, Epocrates Online Free, and Micromedex online were easier to use than their PDA counterparts (p<0.001). In terms of composite scores, only the online versions of Clinical Pharmacology and Micromedex demonstrated superiority over their PDA versions (p>0.01). Online and PDA drug information databases assist practitioners in improving their clinical decision-making. Lexi-Drugs performed significantly better than all of the other PDA databases evaluated. No PDA database demonstrated superiority to its online counterpart

Detecting signals of drug-drug interactions in a spontaneous reports database.

PubMed

Thakrar, Bharat T; Grundschober, Sabine Borel; Doessegger, Lucette

2007-10-01

The spontaneous reports database is widely used for detecting signals of ADRs. We have extended the methodology to include the detection of signals of ADRs that are associated with drug-drug interactions (DDI). In particular, we have investigated two different statistical assumptions for detecting signals of DDI. Using the FDA's spontaneous reports database, we investigated two models, a multiplicative and an additive model, to detect signals of DDI. We applied the models to four known DDIs (methotrexate-diclofenac and bone marrow depression, simvastatin-ciclosporin and myopathy, ketoconazole-terfenadine and torsades de pointes, and cisapride-erythromycin and torsades de pointes) and to four drug-event combinations where there is currently no evidence of a DDI (fexofenadine-ketoconazole and torsades de pointes, methotrexade-rofecoxib and bone marrow depression, fluvastatin-ciclosporin and myopathy, and cisapride-azithromycine and torsade de pointes) and estimated the measure of interaction on the two scales. The additive model correctly identified all four known DDIs by giving a statistically significant (P < 0.05) positive measure of interaction. The multiplicative model identified the first two of the known DDIs as having a statistically significant or borderline significant (P < 0.1) positive measure of interaction term, gave a nonsignificant positive trend for the third interaction (P = 0.27), and a negative trend for the last interaction. Both models correctly identified the four known non interactions by estimating a negative measure of interaction. The spontaneous reports database is a valuable resource for detecting signals of DDIs. In particular, the additive model is more sensitive in detecting such signals. The multiplicative model may further help qualify the strength of the signal detected by the additive model.

Retrieving Online Information on Drugs: An Analysis of Four Databases.

ERIC Educational Resources Information Center

Lavengood, Kathryn A.

This study examines the indexing of drugs in the literature and compares actual drug indexing to stated indexing policies in selected databases. The goal is to aid health science information specialists, end-users, and/or non-subject experts to improve recall and comprehensiveness when searching for drug information by identifying the most useful…

Lack of cross-reactivity of Ambien (zolpidem) with drugs in standard urine drug screens.

PubMed

Piergies, A A; Sainati, S; Roth-Schechter, B

1997-04-01

To determine in healthy volunteers (men and women; 18 to 40 years old) the potential cross-reactivity of Ambien (zolpidem) and/or its metabolites with drugs that are screened by the Syva EMIT II and the Abbott ADx urine drug screens assays. Open-label, fixed-treatment sequence of 1 night each of treatment with zolpidem (10 mg) and temazepam (15 mg). Clinical Pharmacology Unit within a teaching hospital. Over a 24-hour period, presence or absence of positive results on the Syva EMIT II or the Abbott ADx urine drug assay system, each performed at two different laboratory assay sites. Following ingestion of zolpidem, no subject had any positive response in either laboratory to the Syva EMIT II or the Abbott ADx urine drug screen assays at 0, 4, 8, 12, and 24 hours postdose. During the same time period, all subjects had measurable zolpidem plasma concentrations at 1.5 and 8 hours postdose, with mean concentrations of 115.2 ng/mL and 30.1 ng/mL, respectively (in agreement with its half-life of 2.5 hours). The positive response rate at 10 hours after ingestion of Restoril (temazepam) among the four laboratory/assay combinations ranged from 36.8% to 73.7%, a range that is within the reported response rates for these tests. These data indicate that zolpidem will not cross-react in standard urine drug screens with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines.

The role of insurance claims databases in drug therapy outcomes research.

PubMed

Lewis, N J; Patwell, J T; Briesacher, B A

1993-11-01

The use of insurance claims databases in drug therapy outcomes research holds great promise as a cost-effective alternative to post-marketing clinical trials. Claims databases uniquely capture information about episodes of care across healthcare services and settings. They also facilitate the examination of drug therapy effects on cohorts of patients and specific patient subpopulations. However, there are limitations to the use of insurance claims databases including incomplete diagnostic and provider identification data. The characteristics of the population included in the insurance plan, the plan benefit design, and the variables of the database itself can influence the research results. Given the current concerns regarding the completeness of insurance claims databases, and the validity of their data, outcomes research usually requires original data to validate claims data or to obtain additional information. Improvements to claims databases such as standardisation of claims information reporting, addition of pertinent clinical and economic variables, and inclusion of information relative to patient severity of illness, quality of life, and satisfaction with provided care will enhance the benefit of such databases for outcomes research.

Human stem cells and drug screening: opportunities and challenges.

PubMed

Ebert, Allison D; Svendsen, Clive N

2010-05-01

High-throughput screening technologies are widely used in the early stages of drug discovery to rapidly evaluate the properties of thousands of compounds. However, they generally rely on testing compound libraries on highly proliferative immortalized or cancerous cell lines, which do not necessarily provide an accurate indication of the effects of compounds in normal human cells or the specific cell type under study. Recent advances in stem cell technology have the potential to allow production of a virtually limitless supply of normal human cells that can be differentiated into any specific cell type. Moreover, using induced pluripotent stem cell technology, they can also be generated from patients with specific disease traits, enabling more relevant modelling and drug screens. This article discusses the opportunities and challenges for the use of stem cells in drug screening with a focus on induced pluripotent stem cells.

DrugPath: a database for academic investigators to match oncology molecular targets with drugs in development.

PubMed

Shah, Eric D; Fisch, Brandon M A; Arceci, Robert J; Buckley, Jonathan D; Reaman, Gregory H; Sorensen, Poul H; Triche, Timothy J; Reynolds, C Patrick

2014-05-01

Academic laboratories are developing increasingly large amounts of data that describe the genomic landscape and gene expression patterns of various types of cancers. Such data can potentially identify novel oncology molecular targets in cancer types that may not be the primary focus of a drug sponsor's initial research for an investigational new drug. Obtaining preclinical data that point toward the potential for a given molecularly targeted agent, or a novel combination of agents requires knowledge of drugs currently in development in both the academic and commercial sectors. We have developed the DrugPath database ( http://www.drugpath.org ) as a comprehensive, free-of-charge resource for academic investigators to identify agents being developed in academics or industry that may act against molecular targets of interest. DrugPath data on molecular targets overlay the Michigan Molecular Interactions ( http://mimi.ncibi.org ) gene-gene interaction map to facilitate identification of related agents in the same pathway. The database catalogs 2,081 drug development programs representing 751 drug sponsors and 722 molecular and genetic targets. DrugPath should assist investigators in identifying and obtaining drugs acting on specific molecular targets for biological and preclinical therapeutic studies.

Synthetic Tumor Networks for Screening Drug Delivery Systems

PubMed Central

Prabhakarpandian, Balabhaskar; Shen, Ming-Che; Nichols, Joseph B.; Garson, Charles J.; Mills, Ivy R.; Matar, Majed M.; Fewell, Jason G.; Pant, Kapil

2015-01-01

Tumor drug delivery is a complex phenomenon affected by several elements in addition to drug or delivery vehicle’s physico-chemical properties. A key factor is tumor microvasculature with complex effects including convective transport, high interstitial pressure and enhanced vascular permeability due to the presence of “leaky vessels”. Current in vitro models of the tumor microenvironment for evaluating drug delivery are oversimplified and, as a result, show poor correlation with in vivo performance. In this study, we report on the development of a novel microfluidic platform that models the tumor microenvironment more accurately, with physiologically and morphologically realistic microvasculature including endothelial cell lined leaky capillary vessels along with 3D solid tumors. Endothelial cells and 3D spheroids of cervical tumor cells were co-cultured in the networks. Drug vehicle screening was demonstrated using GFP gene delivery by different formulations of nanopolymers. The synthetic tumor network was successful in predicting in vivo delivery efficiencies of the drug vehicles. The developed assay will have critical applications both in basic research, where it can be used to develop next generation delivery vehicles, and in drug discovery where it can be used to study drug transport and delivery efficacy in realistic tumor microenvironment, thereby enabling drug compound and/or delivery vehicle screening. PMID:25599856

Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions.

PubMed

Sedykh, Alexander; Fourches, Denis; Duan, Jianmin; Hucke, Oliver; Garneau, Michel; Zhu, Hao; Bonneau, Pierre; Tropsha, Alexander

2013-04-01

Membrane transporters mediate many biological effects of chemicals and play a major role in pharmacokinetics and drug resistance. The selection of viable drug candidates among biologically active compounds requires the assessment of their transporter interaction profiles. Using public sources, we have assembled and curated the largest, to our knowledge, human intestinal transporter database (>5,000 interaction entries for >3,700 molecules). This data was used to develop thoroughly validated classification Quantitative Structure-Activity Relationship (QSAR) models of transport and/or inhibition of several major transporters including MDR1, BCRP, MRP1-4, PEPT1, ASBT, OATP2B1, OCT1, and MCT1. QSAR models have been developed with advanced machine learning techniques such as Support Vector Machines, Random Forest, and k Nearest Neighbors using Dragon and MOE chemical descriptors. These models afforded high external prediction accuracies of 71-100% estimated by 5-fold external validation, and showed hit retrieval rates with up to 20-fold enrichment in the virtual screening of DrugBank compounds. The compendium of predictive QSAR models developed in this study can be used for virtual profiling of drug candidates and/or environmental agents with the optimal transporter profiles.

Bead-based screening in chemical biology and drug discovery.

PubMed

Komnatnyy, Vitaly V; Nielsen, Thomas E; Qvortrup, Katrine

2018-06-11

High-throughput screening is an important component of the drug discovery process. The screening of libraries containing hundreds of thousands of compounds requires assays amenable to miniaturisation and automization. Combinatorial chemistry holds a unique promise to deliver structurally diverse libraries for early drug discovery. Among the various library forms, the one-bead-one-compound (OBOC) library, where each bead carries many copies of a single compound, holds the greatest potential for the rapid identification of novel hits against emerging drug targets. However, this potential has not yet been fully realized due to a number of technical obstacles. In this feature article, we review the progress that has been made in bead-based library screening and its application to the discovery of bioactive compounds. We identify the key challenges of this approach and highlight key steps needed for making a greater impact in the field.

Diagnostic accuracy of a two-item screen for drug use developed from the alcohol, smoking and substance involvement screening test (ASSIST).

PubMed

Tiet, Quyen Q; Leyva, Yani; Moos, Rudolf H; Smith, Brandy

2016-07-01

The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) is a screening instrument to detect substance use in primary care (PC). To screen for illicit substances (excluding tobacco and alcohol), the ASSIST consists of 8-57 questions and requires complicated scoring. To improve the efficiency of screening of drug misuse in PC, this study constructed and validated a two-item screen for drug use from the ASSIST. Guided by previous reviews, the ASSIST was revised. Patients were recruited in VA primary care clinics (N=1283). Half of the sample was used to develop the ASSIST-Drug; the other half was used to validate it. The Mini International Neuropsychiatric Interview (MINI) and the Inventory of Drug Use Consequences were the criterion measures. A brief, two-item ASSIST-Drug was constructed. Based on the development sample, the ASSIST-Drug was 94.1% sensitive and 89.6% specific for drug use disorders. Based on the validation sample, it was 95.4% sensitive and 87.8% specific. The ASSIST-Drug also had comparable sensitivity and specificity to identify drug use negative consequences, as well as for diverse subgroups of patients in terms of gender, age, race/ethnicity, marital status, educational levels, and post traumatic stress disorder status. The ASSIST-Drug may be a useful screening tool for PC settings. It is reliable, brief, and easy to remember, administer and score. It is sensitive and specific for drug use disorders and drug use negative consequences, and the predictive properties are consistent across subgroup of patients. Published by Elsevier Ireland Ltd.

Drug and bioactive molecule screening based on a bioelectrical impedance cell culture platform

PubMed Central

Ramasamy, Sakthivel; Bennet, Devasier; Kim, Sanghyo

2014-01-01

This review will present a brief discussion on the recent advancements of bioelectrical impedance cell-based biosensors, especially the electric cell-substrate impedance sensing (ECIS) system for screening of various bioactive molecules. The different technical integrations of various chip types, working principles, measurement systems, and applications for drug targeting of molecules in cells are highlighted in this paper. Screening of bioactive molecules based on electric cell-substrate impedance sensing is a trial-and-error process toward the development of therapeutically active agents for drug discovery and therapeutics. In general, bioactive molecule screening can be used to identify active molecular targets for various diseases and toxicity at the cellular level with nanoscale resolution. In the innovation and screening of new drugs or bioactive molecules, the activeness, the efficacy of the compound, and safety in biological systems are the main concerns on which determination of drug candidates is based. Further, drug discovery and screening of compounds are often performed in cell-based test systems in order to reduce costs and save time. Moreover, this system can provide more relevant results in in vivo studies, as well as high-throughput drug screening for various diseases during the early stages of drug discovery. Recently, MEMS technologies and integration with image detection techniques have been employed successfully. These new technologies and their possible ongoing transformations are addressed. Select reports are outlined, and not all the work that has been performed in the field of drug screening and development is covered. PMID:25525360

[Use of urine drug screening in the emergency department of a paediatric hospital].

PubMed

Ferrer Bosch, Núria; Martínez Sánchez, Lidia; Trenchs Sainz de la Maza, Victoria; Velasco Rodríguez, Jesús; García González, Elsa; Luaces Cubells, Carles

2018-01-01

To describe the situations in which urine drug screening is used in a Paediatric Emergency Department (ED). An analysis is also made on its potential usefulness on whether it changes the patient management, and if the results are confirmed by using specific techniques. A retrospective study was conducted on patients under the age of 18 attended in the ED during 2014 and in whom urine drug screening was requested. Depending on the potential capacity of the screening result to change patient management, two groups were defined (potentially useful and not potentially useful). Urine drug screening was performed on a total of 161 patients. The screening was considered not to be potentially useful in 87 (54.0%). This was because the clinical history already explained the symptoms the patient had in 55 (34.1%) patients, in 29 (18.0%) because the patient was asymptomatic, and in 3 (1.9%) because the suspected drug was not detectable in the screening. The drug screening results changed the patient management in 5 (3.1%) cases. A toxic substance was detected in 44 (27.3%). Two out of the 44 that were positive (2.1%) were re-tested by specific techniques, and presence of the toxic substance was ruled out in both of them (false positives). Most of the drug screening tests are not justified, and it is very infrequent that they change patient management. It is very rare that the results are confirmed using more specific methods. Urine drug screening tests should be restricted to particular cases and if the result has legal implications, or if the patient denies using the drug, it should be followed by a specific toxicological study to provide a conclusive result. Copyright © 2016 Asociación Española de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

Screening the receptorome to discover the molecular targets for plant-derived psychoactive compounds: a novel approach for CNS drug discovery.

PubMed

Roth, Bryan L; Lopez, Estela; Beischel, Scott; Westkaemper, Richard B; Evans, Jon M

2004-05-01

Because psychoactive plants exert profound effects on human perception, emotion, and cognition, discovering the molecular mechanisms responsible for psychoactive plant actions will likely yield insights into the molecular underpinnings of human consciousness. Additionally, it is likely that elucidation of the molecular targets responsible for psychoactive drug actions will yield validated targets for CNS drug discovery. This review article focuses on an unbiased, discovery-based approach aimed at uncovering the molecular targets responsible for psychoactive drug actions wherein the main active ingredients of psychoactive plants are screened at the "receptorome" (that portion of the proteome encoding receptors). An overview of the receptorome is given and various in silico, public-domain resources are described. Newly developed tools for the in silico mining of data derived from the National Institute of Mental Health Psychoactive Drug Screening Program's (NIMH-PDSP) K(i) Database (K(i) DB) are described in detail. Additionally, three case studies aimed at discovering the molecular targets responsible for Hypericum perforatum, Salvia divinorum, and Ephedra sinica actions are presented. Finally, recommendations are made for future studies.

Virtual screening using the ligand ZINC database for novel lipoxygenase-3 inhibitors.

PubMed

Monika; Kour, Janmeet; Singh, Kulwinder

2013-01-01

The leukotrienes constitute a group of arachidonic acid-derived compounds with biologic activities suggesting important roles in inflammation and immediate hypersensitivity. Epidermis-type lipoxygenase-3 (ALOXE3), a distinct subclass within the multigene family of mammalian lipoxygenases, is a novel isoenzyme involved in the metabolism of leukotrienes and plays a very important role in skin barrier functions. Lipoxygenase selective inhibitors such as azelastine and zileuton are currently used to reduce inflammatory response. Nausea, pharyngolaryngeal pain, headache, nasal burning and somnolence are the most frequently reported adverse effects of these drugs. Therefore, there is still a need to develop more potent lipoxygenase inhibitors. In this paper, we report the screening of various compounds from the ZINC database (contains over 21 million compounds) using the Molegro Virtual Docker software against the ALOXE3 protein. Screening was performed using molecular constraints tool to filter compounds with physico-chemical properties similar to the 1N8Q bound ligand protocatechuic acid. The analysis resulted in 4319 Lipinski compliant hits which are docked and scored to identify structurally novel ligands that make similar interactions to those of known ligands or may have different interactions with other parts of the binding site. Our screening approach identified four molecules ZINC84299674; ZINC76643455; ZINC84299122 & ZINC75626957 with MolDock score of -128.901, -120.22, -116.873 & - 102.116 kcal/mol, respectively. Their energy scores were better than the 1N8Q bound co-crystallized ligand protocatechuic acid (with MolDock score of -77.225 kcal/mol). All the ligands were docked within the binding pocket forming interactions with amino acid residues.

Molecular scaffold analysis of natural products databases in the public domain.

PubMed

Yongye, Austin B; Waddell, Jacob; Medina-Franco, José L

2012-11-01

Natural products represent important sources of bioactive compounds in drug discovery efforts. In this work, we compiled five natural products databases available in the public domain and performed a comprehensive chemoinformatic analysis focused on the content and diversity of the scaffolds with an overview of the diversity based on molecular fingerprints. The natural products databases were compared with each other and with a set of molecules obtained from in-house combinatorial libraries, and with a general screening commercial library. It was found that publicly available natural products databases have different scaffold diversity. In contrast to the common concept that larger libraries have the largest scaffold diversity, the largest natural products collection analyzed in this work was not the most diverse. The general screening library showed, overall, the highest scaffold diversity. However, considering the most frequent scaffolds, the general reference library was the least diverse. In general, natural products databases in the public domain showed low molecule overlap. In addition to benzene and acyclic compounds, flavones, coumarins, and flavanones were identified as the most frequent molecular scaffolds across the different natural products collections. The results of this work have direct implications in the computational and experimental screening of natural product databases for drug discovery. © 2012 John Wiley & Sons A/S.

The Candidate Cancer Gene Database: a database of cancer driver genes from forward genetic screens in mice.

PubMed

Abbott, Kenneth L; Nyre, Erik T; Abrahante, Juan; Ho, Yen-Yi; Isaksson Vogel, Rachel; Starr, Timothy K

2015-01-01

Identification of cancer driver gene mutations is crucial for advancing cancer therapeutics. Due to the overwhelming number of passenger mutations in the human tumor genome, it is difficult to pinpoint causative driver genes. Using transposon mutagenesis in mice many laboratories have conducted forward genetic screens and identified thousands of candidate driver genes that are highly relevant to human cancer. Unfortunately, this information is difficult to access and utilize because it is scattered across multiple publications using different mouse genome builds and strength metrics. To improve access to these findings and facilitate meta-analyses, we developed the Candidate Cancer Gene Database (CCGD, http://ccgd-starrlab.oit.umn.edu/). The CCGD is a manually curated database containing a unified description of all identified candidate driver genes and the genomic location of transposon common insertion sites (CISs) from all currently published transposon-based screens. To demonstrate relevance to human cancer, we performed a modified gene set enrichment analysis using KEGG pathways and show that human cancer pathways are highly enriched in the database. We also used hierarchical clustering to identify pathways enriched in blood cancers compared to solid cancers. The CCGD is a novel resource available to scientists interested in the identification of genetic drivers of cancer. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Machine Learning-based Virtual Screening and Its Applications to Alzheimer's Drug Discovery: A Review.

PubMed

Carpenter, Kristy A; Huang, Xudong

2018-06-07

Virtual Screening (VS) has emerged as an important tool in the drug development process, as it conducts efficient in silico searches over millions of compounds, ultimately increasing yields of potential drug leads. As a subset of Artificial Intelligence (AI), Machine Learning (ML) is a powerful way of conducting VS for drug leads. ML for VS generally involves assembling a filtered training set of compounds, comprised of known actives and inactives. After training the model, it is validated and, if sufficiently accurate, used on previously unseen databases to screen for novel compounds with desired drug target binding activity. The study aims to review ML-based methods used for VS and applications to Alzheimer's disease (AD) drug discovery. To update the current knowledge on ML for VS, we review thorough backgrounds, explanations, and VS applications of the following ML techniques: Naïve Bayes (NB), k-Nearest Neighbors (kNN), Support Vector Machines (SVM), Random Forests (RF), and Artificial Neural Networks (ANN). All techniques have found success in VS, but the future of VS is likely to lean more heavily toward the use of neural networks - and more specifically, Convolutional Neural Networks (CNN), which are a subset of ANN that utilize convolution. We additionally conceptualize a work flow for conducting ML-based VS for potential therapeutics of for AD, a complex neurodegenerative disease with no known cure and prevention. This both serves as an example of how to apply the concepts introduced earlier in the review and as a potential workflow for future implementation. Different ML techniques are powerful tools for VS, and they have advantages and disadvantages albeit. ML-based VS can be applied to AD drug development. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A knowledge-based approach for identification of drugs against vivapain-2 protein of Plasmodium vivax through pharmacophore-based virtual screening with comparative modelling.

PubMed

Yadav, Manoj Kumar; Singh, Amisha; Swati, D

2014-08-01

Malaria is one of the most infectious diseases in the world. Plasmodium vivax, the pathogen causing endemic malaria in humans worldwide, is responsible for extensive disease morbidity. Due to the emergence of resistance to common anti-malarial drugs, there is a continuous need to develop a new class of drugs for this pathogen. P. vivax cysteine protease, also known as vivapain-2, plays an important role in haemoglobin hydrolysis and is considered essential for the survival of the parasite. The three-dimensional (3D) structure of vivapain-2 is not predicted experimentally, so its structure is modelled by using comparative modelling approach and further validated by Qualitative Model Energy Analysis (QMEAN) and RAMPAGE tools. The potential binding site of selected vivapain-2 structure has been detected by grid-based function prediction method. Drug targets and their respective drugs similar to vivapain-2 have been identified using three publicly available databases: STITCH 3.1, DrugBank and Therapeutic Target Database (TTD). The second approach of this work focuses on docking study of selected drug E-64 against vivapain-2 protein. Docking reveals crucial information about key residues (Asn281, Cys283, Val396 and Asp398) that are responsible for holding the ligand in the active site. The similarity-search criterion is used for the preparation of our in-house database of drugs, obtained from filtering the drugs from the DrugBank database. A five-point 3D pharmacophore model is generated for the docked complex of vivapain-2 with E-64. This study of 3D pharmacophore-based virtual screening results in identifying three new drugs, amongst which one is approved and the other two are experimentally proved. The ADMET properties of these drugs are found to be in the desired range. These drugs with novel scaffolds may act as potent drugs for treating malaria caused by P. vivax.

Updates on drug-target network; facilitating polypharmacology and data integration by growth of DrugBank database.

PubMed

Barneh, Farnaz; Jafari, Mohieddin; Mirzaie, Mehdi

2016-11-01

Network pharmacology elucidates the relationship between drugs and targets. As the identified targets for each drug increases, the corresponding drug-target network (DTN) evolves from solely reflection of the pharmaceutical industry trend to a portrait of polypharmacology. The aim of this study was to evaluate the potentials of DrugBank database in advancing systems pharmacology. We constructed and analyzed DTN from drugs and targets associations in the DrugBank 4.0 database. Our results showed that in bipartite DTN, increased ratio of identified targets for drugs augmented density and connectivity of drugs and targets and decreased modular structure. To clear up the details in the network structure, the DTNs were projected into two networks namely, drug similarity network (DSN) and target similarity network (TSN). In DSN, various classes of Food and Drug Administration-approved drugs with distinct therapeutic categories were linked together based on shared targets. Projected TSN also showed complexity because of promiscuity of the drugs. By including investigational drugs that are currently being tested in clinical trials, the networks manifested more connectivity and pictured the upcoming pharmacological space in the future years. Diverse biological processes and protein-protein interactions were manipulated by new drugs, which can extend possible target combinations. We conclude that network-based organization of DrugBank 4.0 data not only reveals the potential for repurposing of existing drugs, also allows generating novel predictions about drugs off-targets, drug-drug interactions and their side effects. Our results also encourage further effort for high-throughput identification of targets to build networks that can be integrated into disease networks. © The Author 2015. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Drug induced hepatotoxicity: data from the Serbian pharmacovigilance database.

PubMed

Petronijevic, Marija; Ilic, Katarina; Suzuki, Ayako

2011-04-01

The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified. Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting. Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%). Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals. Copyright © 2011 John Wiley & Sons, Ltd.

[Virtual screening of anti-angiogenesis flavonoids from Sophora flavescens].

PubMed

Chen, Xi-Xin; Liu, Yi; Huang, Rong; Zhao, Lin-Lin; Chen, Lei; Wang, Shu-Mei

2017-03-01

Angiogenesis is a dynamic, multi-step process. It is known that about 70 diseases are related to angiogenesis. Both the experimental and the literature reports showed that Sophora flavescens inhibit angiogenesis significantly, but the material basis and the mechanism of action have not been clear. In this study, molecular docking was used for screening of anti-angiogenesis flavonoids from the roots of S. flavescens. One handred and twenty-six flavonoids selected from S. flavescens were screened in the docking ligand database with six targets(VEGF-a,TEK,KDR,Flt1,FGFR1 and FGFR2) as the receptors. In addition, the small-molecule approved drugs of targets from DrugBank database were set as a reference with minimum score of each target's approved drugs as threshold. The LibDock module in Discovery Studio 2.5 (DS2.5) software was applied to screen the compounds. As a result, 37 compounds were screened out that their scores were higher than the minimum score of approved drugs as well as being in the top of 10%. At last the mechanism of flavonoids anti-angiogenesis was preliminarily revealed, which provided a new method for the development of angiogenesis inhibitor drugs. Copyright© by the Chinese Pharmaceutical Association.

Screening for drugs of abuse (II): Cannabinoids, lysergic acid diethylamide, buprenorphine, methadone, barbiturates, benzodiazepines and other drugs.

PubMed

Simpson, D; Braithwaite, R A; Jarvie, D R; Stewart, M J; Walker, S; Watson, I W; Widdop, B

1997-09-01

Requirements for the provision of an efficient and reliable service for drugs of abuse screening in urine have been summarized in Part I of this review. The requirements included rapid turn-around times, good communications between requesting clinicians and the laboratory, and participation in quality assessment schemes. In addition, the need for checking/confirmation of positive results obtained for preliminary screening methods was stressed. This aspect of the service has assumed even greater importance with widespread use of dip-stick technology and the increasing number of reasons for which drug screening is performed. Many of these additional uses of drug screening have possible serious legal implications, for example, screening school pupils, professional footballers, parents involved in child custody cases, persons applying for renewal of a driving licence after disqualification for a drug-related offence, doctors seeking re-registration after removal for drug abuse, and checking for compliance with terms of probation orders; as well as pre-employment screening and work-place testing. In many cases these requests will be received from a general practitioner or drug clinic with no indication of the reason for which testing has been requested. This also raises the serious problems of a chain of custody, provision of two samples, stability of samples, and secure and lengthy storage of samples in the laboratory-samples may be requested by legal authorities several months after the initial testing. The need for confirmation of positive results is now widely accepted but it may be equally important to confirm unexpected negative results. Failure to detect the presence of maintenance drugs may lead to the patient being discharged from a drug treatment clinic and, if attendance at the clinic is one of the terms of continued employment, to dismissal. It seems likely that increasing abuse of drugs and the efforts of regulatory authorities to control this, will lead to

Identification of novel tyrosine kinase inhibitors for drug resistant T315I mutant BCR-ABL: a virtual screening and molecular dynamics simulations study

NASA Astrophysics Data System (ADS)

Banavath, Hemanth Naick; Sharma, Om Prakash; Kumar, Muthuvel Suresh; Baskaran, R.

2014-11-01

BCR-ABL tyrosine kinase plays a major role in the pathogenesis of chronic myeloid leukemia (CML) and is a proven target for drug development. Currently available drugs in the market are effective against CML; however, side-effects and drug-resistant mutations in BCR-ABL limit their full potential. Using high throughput virtual screening approach, we have screened several small molecule databases and docked against wild-type and drug resistant T315I mutant BCR-ABL. Drugs that are currently available, such as imatinib and ponatinib, were also docked against BCR-ABL protein to set a cutoff value for our screening. Selected lead compounds were further evaluated for chemical reactivity employing density functional theory approach, all selected ligands shows HLG value > 0.09900 and the binding free energy between protein-ligand complex interactions obtained was rescored using MM-GBSA. The selected compounds showed least ΔG score -71.53 KJ/mol to maximum -126.71 KJ/mol in both wild type and drug resistant T315I mutant BCR-ABL. Following which, the stability of the docking complexes were evaluated by molecular dynamics simulation (MD) using GROMACS4.5.5. Results uncovered seven lead molecules, designated with Drug-Bank and PubChem ids as DB07107, DB06977, ST013616, DB04200, ST007180 ST019342, and DB01172, which shows docking scores higher than imatinib and ponatinib.

Stem cells: a model for screening, discovery and development of drugs.

PubMed

Kitambi, Satish Srinivas; Chandrasekar, Gayathri

2011-01-01

The identification of normal and cancerous stem cells and the recent advances made in isolation and culture of stem cells have rapidly gained attention in the field of drug discovery and regenerative medicine. The prospect of performing screens aimed at proliferation, directed differentiation, and toxicity and efficacy studies using stem cells offers a reliable platform for the drug discovery process. Advances made in the generation of induced pluripotent stem cells from normal or diseased tissue serves as a platform to perform drug screens aimed at developing cell-based therapies against conditions like Parkinson's disease and diabetes. This review discusses the application of stem cells and cancer stem cells in drug screening and their role in complementing, reducing, and replacing animal testing. In addition to this, target identification and major advances in the field of personalized medicine using induced pluripotent cells are also discussed.

Validity of data in the Danish Colorectal Cancer Screening Database

PubMed Central

Thomsen, Mette Kielsholm; Njor, Sisse Helle; Rasmussen, Morten; Linnemann, Dorte; Andersen, Berit; Baatrup, Gunnar; Friis-Hansen, Lennart Jan; Jørgensen, Jens Christian Riis; Mikkelsen, Ellen Margrethe

2017-01-01

Background In Denmark, a nationwide screening program for colorectal cancer was implemented in March 2014. Along with this, a clinical database for program monitoring and research purposes was established. Objective The aim of this study was to estimate the agreement and validity of diagnosis and procedure codes in the Danish Colorectal Cancer Screening Database (DCCSD). Methods All individuals with a positive immunochemical fecal occult blood test (iFOBT) result who were invited to screening in the first 3 months since program initiation were identified. From these, a sample of 150 individuals was selected using stratified random sampling by age, gender and region of residence. Data from the DCCSD were compared with data from hospital records, which were used as the reference. Agreement, sensitivity, specificity and positive and negative predictive values were estimated for categories of codes “clean colon”, “colonoscopy performed”, “overall completeness of colonoscopy”, “incomplete colonoscopy”, “polypectomy”, “tumor tissue left behind”, “number of polyps”, “lost polyps”, “risk group of polyps” and “colorectal cancer and polyps/benign tumor”. Results Hospital records were available for 136 individuals. Agreement was highest for “colorectal cancer” (97.1%) and lowest for “lost polyps” (88.2%). Sensitivity varied between moderate and high, with 60.0% for “incomplete colonoscopy” and 98.5% for “colonoscopy performed”. Specificity was 92.7% or above, except for the categories “colonoscopy performed” and “overall completeness of colonoscopy”, where the specificity was low; however, the estimates were imprecise. Conclusion A high level of agreement between categories of codes in DCCSD and hospital records indicates that DCCSD reflects the hospital records well. Further, the validity of the categories of codes varied from moderate to high. Thus, the DCCSD may be a valuable data source for future research on

Validity of data in the Danish Colorectal Cancer Screening Database.

PubMed

Thomsen, Mette Kielsholm; Njor, Sisse Helle; Rasmussen, Morten; Linnemann, Dorte; Andersen, Berit; Baatrup, Gunnar; Friis-Hansen, Lennart Jan; Jørgensen, Jens Christian Riis; Mikkelsen, Ellen Margrethe

2017-01-01

In Denmark, a nationwide screening program for colorectal cancer was implemented in March 2014. Along with this, a clinical database for program monitoring and research purposes was established. The aim of this study was to estimate the agreement and validity of diagnosis and procedure codes in the Danish Colorectal Cancer Screening Database (DCCSD). All individuals with a positive immunochemical fecal occult blood test (iFOBT) result who were invited to screening in the first 3 months since program initiation were identified. From these, a sample of 150 individuals was selected using stratified random sampling by age, gender and region of residence. Data from the DCCSD were compared with data from hospital records, which were used as the reference. Agreement, sensitivity, specificity and positive and negative predictive values were estimated for categories of codes "clean colon", "colonoscopy performed", "overall completeness of colonoscopy", "incomplete colonoscopy", "polypectomy", "tumor tissue left behind", "number of polyps", "lost polyps", "risk group of polyps" and "colorectal cancer and polyps/benign tumor". Hospital records were available for 136 individuals. Agreement was highest for "colorectal cancer" (97.1%) and lowest for "lost polyps" (88.2%). Sensitivity varied between moderate and high, with 60.0% for "incomplete colonoscopy" and 98.5% for "colonoscopy performed". Specificity was 92.7% or above, except for the categories "colonoscopy performed" and "overall completeness of colonoscopy", where the specificity was low; however, the estimates were imprecise. A high level of agreement between categories of codes in DCCSD and hospital records indicates that DCCSD reflects the hospital records well. Further, the validity of the categories of codes varied from moderate to high. Thus, the DCCSD may be a valuable data source for future research on colorectal cancer screening.

Identification of drug interactions in hospitals--computerized screening vs. bedside recording.

PubMed

Blix, H S; Viktil, K K; Moger, T A; Reikvam, A

2008-04-01

Managing drug interactions in hospitalized patients is important and challenging. The objective of the study was to compare two methods for identification of drug interactions (DDIs)--computerized screening and prospective bedside recording--with regard to capability of identifying DDIs. Patient characteristics were recorded for patients admitted to five hospitals. By bedside evaluation drug-related problems, including DDIs, were prospectively recorded by pharmacists and discussed in multidisciplinary teams. A computer screening programme was used to identify DDIs retrospectively--dividing DDIs into four classes: A, avoid; B, avoid/take precautions; C, take precautions; D, no action needed. Among 827 patients, computer screening identified DDIs in 544 patients (66%); 351 had DDIs introduced in hospital. The 1513 computer-identified DDIs had the following distribution: type A 78; type B 915; type C 38; type D 482. By bedside evaluation, 99 DDIs were identified in 73 patients (9%). The proportions of computer recorded DDIs which were also identified at the bedside were: 5%, 8%, 8%, 2% DDIs of types A, B, C and D respectively. In 10 patients, DDIs not registered by computer screening were identified by bedside evaluation. The drugs most frequently involved in DDIs, identified by computerized screening were acetylsalicylic acid, warfarin, furosemide and digitoxin compared with warfarin, simvastatin, theophylline and carbamazepine, by bedside evaluation. Despite an active prospective bedside search for DDIs, this approach identified less than one in 10 of the DDIs recorded by computer screening, including those regarded as hazardous. However, computer screening overestimates considerably when the objective is to identify clinically relevant DDIs.

A biomaterial screening approach reveals microenvironmental mechanisms of drug resistance.

PubMed

Schwartz, Alyssa D; Barney, Lauren E; Jansen, Lauren E; Nguyen, Thuy V; Hall, Christopher L; Meyer, Aaron S; Peyton, Shelly R

2017-12-11

Traditional drug screening methods lack features of the tumor microenvironment that contribute to resistance. Most studies examine cell response in a single biomaterial platform in depth, leaving a gap in understanding how extracellular signals such as stiffness, dimensionality, and cell-cell contacts act independently or are integrated within a cell to affect either drug sensitivity or resistance. This is critically important, as adaptive resistance is mediated, at least in part, by the extracellular matrix (ECM) of the tumor microenvironment. We developed an approach to screen drug responses in cells cultured on 2D and in 3D biomaterial environments to explore how key features of ECM mediate drug response. This approach uncovered that cells on 2D hydrogels and spheroids encapsulated in 3D hydrogels were less responsive to receptor tyrosine kinase (RTK)-targeting drugs sorafenib and lapatinib, but not cytotoxic drugs, compared to single cells in hydrogels and cells on plastic. We found that transcriptomic differences between these in vitro models and tumor xenografts did not reveal mechanisms of ECM-mediated resistance to sorafenib. However, a systems biology analysis of phospho-kinome data uncovered that variation in MEK phosphorylation was associated with RTK-targeted drug resistance. Using sorafenib as a model drug, we found that co-administration with a MEK inhibitor decreased ECM-mediated resistance in vitro and reduced in vivo tumor burden compared to sorafenib alone. In sum, we provide a novel strategy for identifying and overcoming ECM-mediated resistance mechanisms by performing drug screening, phospho-kinome analysis, and systems biology across multiple biomaterial environments.

Essential proteins and possible therapeutic targets of Wolbachia endosymbiont and development of FiloBase-a comprehensive drug target database for Lymphatic filariasis

NASA Astrophysics Data System (ADS)

Sharma, Om Prakash; Kumar, Muthuvel Suresh

2016-01-01

Lymphatic filariasis (Lf) is one of the oldest and most debilitating tropical diseases. Millions of people are suffering from this prevalent disease. It is estimated to infect over 120 million people in at least 80 nations of the world through the tropical and subtropical regions. More than one billion people are in danger of getting affected with this life-threatening disease. Several studies were suggested its emerging limitations and resistance towards the available drugs and therapeutic targets for Lf. Therefore, better medicine and drug targets are in demand. We took an initiative to identify the essential proteins of Wolbachia endosymbiont of Brugia malayi, which are indispensable for their survival and non-homologous to human host proteins. In this current study, we have used proteome subtractive approach to screen the possible therapeutic targets for wBm. In addition, numerous literatures were mined in the hunt for potential drug targets, drugs, epitopes, crystal structures, and expressed sequence tag (EST) sequences for filarial causing nematodes. Data obtained from our study were presented in a user friendly database named FiloBase. We hope that information stored in this database may be used for further research and drug development process against filariasis. URL: http://filobase.bicpu.edu.in.

Work-related injuries in a state trauma registry: relationship between industry and drug screening.

PubMed

Bunn, Terry L; Slavova, Svetla; Bernard, Andrew C

2014-08-01

Work-related injuries exert a great financial and economic burden on the US population. The study objectives were to identify the industries and occupations associated with worker injuries and to determine the predictors for injured worker drug screening in trauma centers. Work-related injury cases were selected using three criteria (expected payer source of workers' compensation, industry-related e-codes, and work-related indicator) from the Kentucky Trauma Registry data set for years 2008 to 2012. Descriptive analyses and multiple logistic regression were performed on the work-related injury cases. The "other services" and construction industry sectors accounted for the highest number of work-related cases. Drugs were detected in 55% of all drug-screened work-related trauma cases. Higher percentages of injured workers tested positive for drugs in the natural resources and mining, transportation and public utilities, and construction industries. In comparison, higher percentages of injured workers in the other services as well as transportation and public utilities industries were drug screened. Treatment at Level I trauma centers and Glasgow Coma Scale (GCS) scores indicating a coma or severe brain injury were both significant independent predictors for being screened for drugs; industry was not a significant predictor for being drug screened. The injured worker was more likely to be drug screened if the worker had a greater than mild injury, regardless of whether the worker was an interfacility transfer. These findings indicate that there may be elevated drug use or abuse in natural resources and mining, transportation and public utilities, as well as construction industry workers; improved identification of the specific drug types in positive drug screen results of injured workers is needed to better target prevention efforts. Epidemiologic study, level III.

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

NASA Astrophysics Data System (ADS)

Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, Mc.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C.

2017-04-01

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan.

A staged screening of registered drugs highlights remyelinating drug candidates for clinical trials

PubMed Central

Eleuteri, C.; Olla, S.; Veroni, C.; Umeton, R.; Mechelli, R.; Romano, S.; Buscarinu, MC.; Ferrari, F.; Calò, G.; Ristori, G.; Salvetti, M.; Agresti, C.

2017-01-01

There is no treatment for the myelin loss in multiple sclerosis, ultimately resulting in the axonal degeneration that leads to the progressive phase of the disease. We established a multi-tiered platform for the sequential screening of drugs that could be repurposed as remyelinating agents. We screened a library of 2,000 compounds (mainly Food and Drug Administration (FDA)-approved compounds and natural products) for cellular metabolic activity on mouse oligodendrocyte precursors (OPC), identifying 42 molecules with significant stimulating effects. We then characterized the effects of these compounds on OPC proliferation and differentiation in mouse glial cultures, and on myelination and remyelination in organotypic cultures. Three molecules, edaravone, 5-methyl-7-methoxyisoflavone and lovastatin, gave positive results in all screening tiers. We validated the results by retesting independent stocks of the compounds, analyzing their purity, and performing dose-response curves. To identify the chemical features that may be modified to enhance the compounds’ activity, we tested chemical analogs and identified, for edaravone, the functional groups that may be essential for its activity. Among the selected remyelinating candidates, edaravone appears to be of strong interest, also considering that this drug has been approved as a neuroprotective agent for acute ischemic stroke and amyotrophic lateral sclerosis in Japan. PMID:28387380

Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes

NASA Astrophysics Data System (ADS)

Kamstra, Rhiannon L.; Dadgar, Saedeh; Wigg, John; Chowdhury, Morshed A.; Phenix, Christopher P.; Floriano, Wely B.

2014-11-01

Our group has recently demonstrated that virtual screening is a useful technique for the identification of target-specific molecular probes. In this paper, we discuss some of our proof-of-concept results involving two biologically relevant target proteins, and report the development of a computational script to generate large databases of fluorescence-labelled compounds for computer-assisted molecular design. The virtual screening of a small library of 1,153 fluorescently-labelled compounds against two targets, and the experimental testing of selected hits reveal that this approach is efficient at identifying molecular probes, and that the screening of a labelled library is preferred over the screening of base compounds followed by conjugation of confirmed hits. The automated script for library generation explores the known reactivity of commercially available dyes, such as NHS-esters, to create large virtual databases of fluorescence-tagged small molecules that can be easily synthesized in a laboratory. A database of 14,862 compounds, each tagged with the ATTO680 fluorophore was generated with the automated script reported here. This library is available for downloading and it is suitable for virtual ligand screening aiming at the identification of target-specific fluorescent molecular probes.

Screening for substance abuse risk in cancer patients using the Opioid Risk Tool and urine drug screen.

PubMed

Barclay, Joshua S; Owens, Justine E; Blackhall, Leslie J

2014-07-01

The use of opioids for management of cancer-related pain has increased significantly and has been associated with a substantial rise in rates of substance abuse and diversion. There is a paucity of data not only on the prevalence of substance abuse in cancer patients, but also for issues of drug use and diversion in family caregivers. This study aimed to evaluate the frequency of risk factors for substance abuse and diversion, and abnormal urine drug screens in cancer patients receiving palliative care. A retrospective chart review was performed for patients with cancer who were seen in the University of Virginia Palliative Care Clinic during the month of September 2012. We evaluated Opioid Risk Tool variables and total scores, insurance status, and urine drug screen results. Of the 114 cancer patients seen in September 2012, the mean Opioid Risk Tool score was 3.79, with 43% of patients defined as medium to high risk. Age (16-45 years old, 23%) and a personal history of alcohol (23%) or illicit drugs (21%) were the most common risk factors identified. We obtained a urine drug screen on 40% of patients, noting abnormal findings in 45.65%. Opioids are an effective treatment for cancer-related pain, yet substantial risk for substance abuse exits in the cancer population. Screening tools, such as the Opioid Risk Tool, should be used as part of a complete patient assessment to balance risk with appropriate relief of suffering.

High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

PubMed Central

Mott, Bryan T.; Eastman, Richard T.; Guha, Rajarshi; Sherlach, Katy S.; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R.; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D.; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A.; Ferrer, Marc; Renslo, Adam R.; Inglese, James; Yuan, Jing; Roepe, Paul D.; Su, Xin-zhuan; Thomas, Craig J.

2015-01-01

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

Development of a consumer product ingredient database for chemical exposure screening and prioritization.

PubMed

Goldsmith, M-R; Grulke, C M; Brooks, R D; Transue, T R; Tan, Y M; Frame, A; Egeghy, P P; Edwards, R; Chang, D T; Tornero-Velez, R; Isaacs, K; Wang, A; Johnson, J; Holm, K; Reich, M; Mitchell, J; Vallero, D A; Phillips, L; Phillips, M; Wambaugh, J F; Judson, R S; Buckley, T J; Dary, C C

2014-03-01

Consumer products are a primary source of chemical exposures, yet little structured information is available on the chemical ingredients of these products and the concentrations at which ingredients are present. To address this data gap, we created a database of chemicals in consumer products using product Material Safety Data Sheets (MSDSs) publicly provided by a large retailer. The resulting database represents 1797 unique chemicals mapped to 8921 consumer products and a hierarchy of 353 consumer product "use categories" within a total of 15 top-level categories. We examine the utility of this database and discuss ways in which it will support (i) exposure screening and prioritization, (ii) generic or framework formulations for several indoor/consumer product exposure modeling initiatives, (iii) candidate chemical selection for monitoring near field exposure from proximal sources, and (iv) as activity tracers or ubiquitous exposure sources using "chemical space" map analyses. Chemicals present at high concentrations and across multiple consumer products and use categories that hold high exposure potential are identified. Our database is publicly available to serve regulators, retailers, manufacturers, and the public for predictive screening of chemicals in new and existing consumer products on the basis of exposure and risk. Published by Elsevier Ltd.

Structure-based virtual screening and characterization of a novel IL-6 antagonistic compound from synthetic compound database.

PubMed

Wang, Jing; Qiao, Chunxia; Xiao, He; Lin, Zhou; Li, Yan; Zhang, Jiyan; Shen, Beifen; Fu, Tinghuan; Feng, Jiannan

2016-01-01

According to the three-dimensional (3D) complex structure of (hIL-6⋅hIL-6R⋅gp 130) 2 and the binding orientation of hIL-6, three compounds with high affinity to hIL-6R and bioactivity to block hIL-6 in vitro were screened theoretically from the chemical databases, including 3D-Available Chemicals Directory (ACD) and MDL Drug Data Report (MDDR), by means of the computer-guided virtual screening method. Using distance geometry, molecular modeling and molecular dynamics trajectory analysis methods, the binding mode and binding energy of the three compounds were evaluated theoretically. Enzyme-linked immunosorbent assay analysis demonstrated that all the three compounds could block IL-6 binding to IL-6R specifically. However, only compound 1 could effectively antagonize the function of hIL-6 and inhibit the proliferation of XG-7 cells in a dose-dependent manner, whereas it showed no cytotoxicity to SP2/0 or L929 cells. These data demonstrated that the compound 1 could be a promising candidate of hIL-6 antagonist.

Diagnostic accuracy of a two-item Drug Abuse Screening Test (DAST-2).

PubMed

Tiet, Quyen Q; Leyva, Yani E; Moos, Rudolf H; Smith, Brandy

2017-11-01

Drug use is prevalent and costly to society, but individuals with drug use disorders (DUDs) are under-diagnosed and under-treated, particularly in primary care (PC) settings. Drug screening instruments have been developed to identify patients with DUDs and facilitate treatment. The Drug Abuse Screening Test (DAST) is one of the most well-known drug screening instruments. However, similar to many such instruments, it is too long for routine use in busy PC settings. This study developed and validated a briefer and more practical DAST for busy PC settings. We recruited 1300 PC patients in two Department of Veterans Affairs (VA) clinics. Participants responded to a structured diagnostic interview. We randomly selected half of the sample to develop and the other half to validate the new instrument. We employed signal detection techniques to select the best DAST items to identify DUDs (based on the MINI) and negative consequences of drug use (measured by the Inventory of Drug Use Consequences). Performance indicators were calculated. The two-item DAST (DAST-2) was 97% sensitive and 91% specific for DUDs in the development sample and 95% sensitive and 89% specific in the validation sample. It was highly sensitive and specific for DUD and negative consequences of drug use in subgroups of patients, including gender, age, race/ethnicity, marital status, educational level, and posttraumatic stress disorder status. The DAST-2 is an appropriate drug screening instrument for routine use in PC settings in the VA and may be applicable in broader range of PC clinics. Published by Elsevier Ltd.

Building a medical image processing algorithm verification database

NASA Astrophysics Data System (ADS)

Brown, C. Wayne

2000-06-01

The design of a database containing head Computed Tomography (CT) studies is presented, along with a justification for the database's composition. The database will be used to validate software algorithms that screen normal head CT studies from studies that contain pathology. The database is designed to have the following major properties: (1) a size sufficient for statistical viability, (2) inclusion of both normal (no pathology) and abnormal scans, (3) inclusion of scans due to equipment malfunction, technologist error, and uncooperative patients, (4) inclusion of data sets from multiple scanner manufacturers, (5) inclusion of data sets from different gender and age groups, and (6) three independent diagnosis of each data set. Designed correctly, the database will provide a partial basis for FDA (United States Food and Drug Administration) approval of image processing algorithms for clinical use. Our goal for the database is the proof of viability of screening head CT's for normal anatomy using computer algorithms. To put this work into context, a classification scheme for 'computer aided diagnosis' systems is proposed.

Application of the ToxMiner Database: Network Analysis ...

EPA Pesticide Factsheets

The US EPA ToxCast program is using in vitro HTS (High-Throughput Screening) methods to profile and model bioactivity of environmental chemicals. The main goals of the ToxCast program are to generate predictive signatures of toxicity, and ultimately provide rapid and cost-effective alternatives to animal testing. The chemicals selected for Phase I are composed largely by a diverse set of pesticide active ingredients, which had sufficient supporting in vivo data included as part of their registration process with the EPA. Other miscellaneous chemicals of environmental concern were also included. Application of HTS to environmental toxicants is a novel approach to predictive toxicology and health risk assessment, and differs from what is required for drug efficacy screening in that biochemical interaction of environmental chemicals are sometimes weaker than that seen with drugs and their intended targets. Additionally, the chemical space covered by environmental chemicals is much broader compared to that of pharmaceuticals. The ToxMiner database has been created and added to the EPA’s ACToR (Aggregated Computational Toxicology Resource) chemical database. One purpose of the ToxMiner database is to link biological, metabolic, and cellular pathway data to genes and in vitro assay data for the initial subset of chemicals screened in the ToxCast Phase I HTS assays. Also included in ToxMiner is human disease information, which correlates with ToxCast assays that ta

Computational databases, pathway and cheminformatics tools for tuberculosis drug discovery

PubMed Central

Ekins, Sean; Freundlich, Joel S.; Choi, Inhee; Sarker, Malabika; Talcott, Carolyn

2010-01-01

We are witnessing the growing menace of both increasing cases of drug-sensitive and drug-resistant Mycobacterium tuberculosis strains and the challenge to produce the first new tuberculosis (TB) drug in well over 40 years. The TB community, having invested in extensive high-throughput screening efforts, is faced with the question of how to optimally leverage this data in order to move from a hit to a lead to a clinical candidate and potentially a new drug. Complementing this approach, yet conducted on a much smaller scale, cheminformatic techniques have been leveraged and are herein reviewed. We suggest these computational approaches should be more optimally integrated in a workflow with experimental approaches to accelerate TB drug discovery. PMID:21129975

Database for High Throughput Screening Hits (dHITS): a simple tool to retrieve gene specific phenotypes from systematic screens done in yeast.

PubMed

Chuartzman, Silvia G; Schuldiner, Maya

2018-03-25

In the last decade several collections of Saccharomyces cerevisiae yeast strains have been created. In these collections every gene is modified in a similar manner such as by a deletion or the addition of a protein tag. Such libraries have enabled a diversity of systematic screens, giving rise to large amounts of information regarding gene functions. However, often papers describing such screens focus on a single gene or a small set of genes and all other loci affecting the phenotype of choice ('hits') are only mentioned in tables that are provided as supplementary material and are often hard to retrieve or search. To help unify and make such data accessible, we have created a Database of High Throughput Screening Hits (dHITS). The dHITS database enables information to be obtained about screens in which genes of interest were found as well as the other genes that came up in that screen - all in a readily accessible and downloadable format. The ability to query large lists of genes at the same time provides a platform to easily analyse hits obtained from transcriptional analyses or other screens. We hope that this platform will serve as a tool to facilitate investigation of protein functions to the yeast community. © 2018 The Authors Yeast Published by John Wiley & Sons Ltd.

Screening for mental illness: the merger of eugenics and the drug industry.

PubMed

Sharav, Vera Hassner

2005-01-01

The implementation of a recommendation by the President's New Freedom Commission (NFC) to screen the entire United States population--children first--for presumed, undetected, mental illness is an ill-conceived policy destined for disastrous consequences. The "pseudoscientific" methods used to screen for mental and behavioral abnormalities are a legacy from the discredited ideology of eugenics. Both eugenics and psychiatry suffer from a common philosophical fallacy that undermines the validity of their theories and prescriptions. Both are wed to a faith-based ideological assumption that mental and behavioral manifestations are biologically determined, and are, therefore, ameliorated by biological interventions. NFC promoted the Texas Medication Algorithm Project (TMAP) as a "model" medication treatment plan. The impact of TMAP is evident in the skyrocketing increase in psychotropic drug prescriptions for children and adults, and in the disproportionate expenditure for psychotropic drugs. The New Freedom Commission's screening for mental illness initiative is, therefore, but the first step toward prescribing drugs. The escalating expenditure for psychotropic drugs since TMAP leaves little doubt about who the beneficiaries of TMAP are. Screening for mental illness will increase their use.

Complete genome-wide screening and subtractive genomic approach revealed new virulence factors, potential drug targets against bio-war pathogen Brucella melitensis 16M

PubMed Central

Pradeepkiran, Jangampalli Adi; Sainath, Sri Bhashyam; Kumar, Konidala Kranthi; Bhaskar, Matcha

2015-01-01

Brucella melitensis 16M is a Gram-negative coccobacillus that infects both animals and humans. It causes a disease known as brucellosis, which is characterized by acute febrile illness in humans and causes abortions in livestock. To prevent and control brucellosis, identification of putative drug targets is crucial. The present study aimed to identify drug targets in B. melitensis 16M by using a subtractive genomic approach. We used available database repositories (Database of Essential Genes, Kyoto Encyclopedia of Genes and Genomes Automatic Annotation Server, and Kyoto Encyclopedia of Genes and Genomes) to identify putative genes that are nonhomologous to humans and essential for pathogen B. melitensis 16M. The results revealed that among 3 Mb genome size of pathogen, 53 putative characterized and 13 uncharacterized hypothetical genes were identified; further, from Basic Local Alignment Search Tool protein analysis, one hypothetical protein showed a close resemblance (50%) to Silicibacter pomeroyi DUF1285 family protein (2RE3). A further homology model of the target was constructed using MODELLER 9.12 and optimized through variable target function method by molecular dynamics optimization with simulating annealing. The stereochemical quality of the restrained model was evaluated by PROCHECK, VERIFY-3D, ERRAT, and WHATIF servers. Furthermore, structure-based virtual screening was carried out against the predicted active site of the respective protein using the glycerol structural analogs from the PubChem database. We identified five best inhibitors with strong affinities, stable interactions, and also with reliable drug-like properties. Hence, these leads might be used as the most effective inhibitors of modeled protein. The outcome of the present work of virtual screening of putative gene targets might facilitate design of potential drugs for better treatment against brucellosis. PMID:25834405

Generation of human pluripotent stem cell-derived hepatocyte-like cells for drug toxicity screening.

PubMed

Takayama, Kazuo; Mizuguchi, Hiroyuki

2017-02-01

Because drug-induced liver injury is one of the main reasons for drug development failures, it is important to perform drug toxicity screening in the early phase of pharmaceutical development. Currently, primary human hepatocytes are most widely used for the prediction of drug-induced liver injury. However, the sources of primary human hepatocytes are limited, making it difficult to supply the abundant quantities required for large-scale drug toxicity screening. Therefore, there is an urgent need for a novel unlimited, efficient, inexpensive, and predictive model which can be applied for large-scale drug toxicity screening. Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells are able to replicate indefinitely and differentiate into most of the body's cell types, including hepatocytes. It is expected that hepatocyte-like cells generated from human ES/iPS cells (human ES/iPS-HLCs) will be a useful tool for drug toxicity screening. To apply human ES/iPS-HLCs to various applications including drug toxicity screening, homogenous and functional HLCs must be differentiated from human ES/iPS cells. In this review, we will introduce the current status of hepatocyte differentiation technology from human ES/iPS cells and a novel method to predict drug-induced liver injury using human ES/iPS-HLCs. Copyright © 2016 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Online drug databases: a new method to assess and compare inclusion of clinically relevant information.

PubMed

Silva, Cristina; Fresco, Paula; Monteiro, Joaquim; Rama, Ana Cristina Ribeiro

2013-08-01

Evidence-Based Practice requires health care decisions to be based on the best available evidence. The model "Information Mastery" proposes that clinicians should use sources of information that have previously evaluated relevance and validity, provided at the point of care. Drug databases (DB) allow easy and fast access to information and have the benefit of more frequent content updates. Relevant information, in the context of drug therapy, is that which supports safe and effective use of medicines. Accordingly, the European Guideline on the Summary of Product Characteristics (EG-SmPC) was used as a standard to evaluate the inclusion of relevant information contents in DB. To develop and test a method to evaluate relevancy of DB contents, by assessing the inclusion of information items deemed relevant for effective and safe drug use. Hierarchical organisation and selection of the principles defined in the EGSmPC; definition of criteria to assess inclusion of selected information items; creation of a categorisation and quantification system that allows score calculation; calculation of relative differences (RD) of scores for comparison with an "ideal" database, defined as the one that achieves the best quantification possible for each of the information items; pilot test on a sample of 9 drug databases, using 10 drugs frequently associated in literature with morbidity-mortality and also being widely consumed in Portugal. Main outcome measure Calculate individual and global scores for clinically relevant information items of drug monographs in databases, using the categorisation and quantification system created. A--Method development: selection of sections, subsections, relevant information items and corresponding requisites; system to categorise and quantify their inclusion; score and RD calculation procedure. B--Pilot test: calculated scores for the 9 databases; globally, all databases evaluated significantly differed from the "ideal" database; some DB performed

ChemBank: a small-molecule screening and cheminformatics resource database.

PubMed

Seiler, Kathleen Petri; George, Gregory A; Happ, Mary Pat; Bodycombe, Nicole E; Carrinski, Hyman A; Norton, Stephanie; Brudz, Steve; Sullivan, John P; Muhlich, Jeremy; Serrano, Martin; Ferraiolo, Paul; Tolliday, Nicola J; Schreiber, Stuart L; Clemons, Paul A

2008-01-01

ChemBank (http://chembank.broad.harvard.edu/) is a public, web-based informatics environment developed through a collaboration between the Chemical Biology Program and Platform at the Broad Institute of Harvard and MIT. This knowledge environment includes freely available data derived from small molecules and small-molecule screens and resources for studying these data. ChemBank is unique among small-molecule databases in its dedication to the storage of raw screening data, its rigorous definition of screening experiments in terms of statistical hypothesis testing, and its metadata-based organization of screening experiments into projects involving collections of related assays. ChemBank stores an increasingly varied set of measurements derived from cells and other biological assay systems treated with small molecules. Analysis tools are available and are continuously being developed that allow the relationships between small molecules, cell measurements, and cell states to be studied. Currently, ChemBank stores information on hundreds of thousands of small molecules and hundreds of biomedically relevant assays that have been performed at the Broad Institute by collaborators from the worldwide research community. The goal of ChemBank is to provide life scientists unfettered access to biomedically relevant data and tools heretofore available primarily in the private sector.

Urine drug screens: Considerations for the psychiatric pharmacist

PubMed Central

Hale, Genevieve M.; Ross, Clint

2016-01-01

Introduction: Proper psychiatric evaluation of patients necessitates that the clinician be vigilant in ruling out secondary causes of symptoms, such as substance-induced symptoms. Immunoassay-type urine drug screens (UDSs) offer clinicians rapid drug screen results, ease of use, and inexpensive cost. Unfortunately, these screens are not without their limitations. This review aims to outline the nuances and limitations of immunoassay UDSs and to provide the clinician with information that facilitates more accurate interpretation of UDS results. Specifically, false positive results associated with psychiatric medications and the availability and methods for acquisition of commercialized UDS masking agents will be reviewed. Methods: A literature review was conducted to identify false positive UDSs associated with psychiatric medications. References for each article identified were also reviewed. Additionally, a Google® search was conducted to identify commercially available preparations used to mask UDS results and the methods of acquisition of these products. Results: A total of 14 articles were identified using PubMed. No articles for mood stabilizing agents were identified. Entering the phrase how to pass a drug test into Google® search yielded about 12.6 million results, and select references were reviewed based on relevance and user reviews. Discussion: Several psychiatric medications are documented as potential sources of false positive UDSs. Additionally, several agents are available for consumer purchase that may result in false negative UDSs. The clinician must be vigilant in interpreting immunoassay UDS results and should utilize more advanced forms of testing as clinically appropriate.

Parallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification.

PubMed

Deans, Richard M; Morgens, David W; Ökesli, Ayşe; Pillay, Sirika; Horlbeck, Max A; Kampmann, Martin; Gilbert, Luke A; Li, Amy; Mateo, Roberto; Smith, Mark; Glenn, Jeffrey S; Carette, Jan E; Khosla, Chaitan; Bassik, Michael C

2016-05-01

Broad-spectrum antiviral drugs targeting host processes could potentially treat a wide range of viruses while reducing the likelihood of emergent resistance. Despite great promise as therapeutics, such drugs remain largely elusive. Here we used parallel genome-wide high-coverage short hairpin RNA (shRNA) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens to identify the cellular target and mechanism of action of GSK983, a potent broad-spectrum antiviral with unexplained cytotoxicity. We found that GSK983 blocked cell proliferation and dengue virus replication by inhibiting the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH). Guided by mechanistic insights from both genomic screens, we found that exogenous deoxycytidine markedly reduced GSK983 cytotoxicity but not antiviral activity, providing an attractive new approach to improve the therapeutic window of DHODH inhibitors against RNA viruses. Our results highlight the distinct advantages and limitations of each screening method for identifying drug targets, and demonstrate the utility of parallel knockdown and knockout screens for comprehensive probing of drug activity.

LigandBox: A database for 3D structures of chemical compounds

PubMed Central

Kawabata, Takeshi; Sugihara, Yusuke; Fukunishi, Yoshifumi; Nakamura, Haruki

2013-01-01

A database for the 3D structures of available compounds is essential for the virtual screening by molecular docking. We have developed the LigandBox database (http://ligandbox.protein.osaka-u.ac.jp/ligandbox/) containing four million available compounds, collected from the catalogues of 37 commercial suppliers, and approved drugs and biochemical compounds taken from KEGG_DRUG, KEGG_COMPOUND and PDB databases. Each chemical compound in the database has several 3D conformers with hydrogen atoms and atomic charges, which are ready to be docked into receptors using docking programs. The 3D conformations were generated using our molecular simulation program package, myPresto. Various physical properties, such as aqueous solubility (LogS) and carcinogenicity have also been calculated to characterize the ADME-Tox properties of the compounds. The Web database provides two services for compound searches: a property/chemical ID search and a chemical structure search. The chemical structure search is performed by a descriptor search and a maximum common substructure (MCS) search combination, using our program kcombu. By specifying a query chemical structure, users can find similar compounds among the millions of compounds in the database within a few minutes. Our database is expected to assist a wide range of researchers, in the fields of medical science, chemical biology, and biochemistry, who are seeking to discover active chemical compounds by the virtual screening. PMID:27493549

LigandBox: A database for 3D structures of chemical compounds.

PubMed

Kawabata, Takeshi; Sugihara, Yusuke; Fukunishi, Yoshifumi; Nakamura, Haruki

2013-01-01

A database for the 3D structures of available compounds is essential for the virtual screening by molecular docking. We have developed the LigandBox database (http://ligandbox.protein.osaka-u.ac.jp/ligandbox/) containing four million available compounds, collected from the catalogues of 37 commercial suppliers, and approved drugs and biochemical compounds taken from KEGG_DRUG, KEGG_COMPOUND and PDB databases. Each chemical compound in the database has several 3D conformers with hydrogen atoms and atomic charges, which are ready to be docked into receptors using docking programs. The 3D conformations were generated using our molecular simulation program package, myPresto. Various physical properties, such as aqueous solubility (LogS) and carcinogenicity have also been calculated to characterize the ADME-Tox properties of the compounds. The Web database provides two services for compound searches: a property/chemical ID search and a chemical structure search. The chemical structure search is performed by a descriptor search and a maximum common substructure (MCS) search combination, using our program kcombu. By specifying a query chemical structure, users can find similar compounds among the millions of compounds in the database within a few minutes. Our database is expected to assist a wide range of researchers, in the fields of medical science, chemical biology, and biochemistry, who are seeking to discover active chemical compounds by the virtual screening.

Focused use of drug screening in overdose patients increases impact on management.

PubMed

Erdmann, Andreas; Werner, Dominique; Hugli, Olivier; Yersin, Bertrand

2015-01-01

Drug poisoning is a common cause for attendance in the emergency department. Several toxicology centres suggest performing urinary drug screens, even though they rarely influence patient management. Measuring the impact on patient management, in a University Emergency Department with approximately 40 000 admissions annually, of a rapid urinary drug screening test using specifically focused indications. Drug screening was restricted to patients having a first psychotic episode or cases demonstrating respiratory failure, coma, seizures, a sympathomimetic toxidrome, severe opiate overdose necessitating naloxone, hypotension, ventricular arrhythmia, acquired long QT or QRS >100 ms, and high-degree heart block. Retrospective analysis of Triage® TOX drug screen tests performed between September 2009 and November 2011, and between January 2013 and March 2014. A total of 262 patients were included, mean age 35 ± 14.6 (standard deviation) years, 63% men; 29% poisoning with alcohol, and 2.3% deaths. Indications for testing were as follows: 34% were first psychotic episodes; 20% had acute respiratory failure; 16% coma; 8% seizures; 8% sympathomimetic toxidromes; 7% severe opioid toxidromes; 4% hypotension; 3% ventricular arrhythmias or acquired long QT intervals on electrocardiogram. A total of 78% of the tests were positive (median two substances, maximum five). The test resulted in drug-specific therapy in 6.1%, drug specific diagnostic tests in 13.3 %, prolonged monitoring in 10.7% of methadone-positive tests, and psychiatric admission in 4.2%. Overall, 34.3% tests influenced patient management. In contrast to previous studies showing modest effects of toxicological testing, restricted use of rapid urinary drug testing increases the impact on management of suspected overdose patients in the ED.

DGIdb 3.0: a redesign and expansion of the drug-gene interaction database.

PubMed

Cotto, Kelsy C; Wagner, Alex H; Feng, Yang-Yang; Kiwala, Susanna; Coffman, Adam C; Spies, Gregory; Wollam, Alex; Spies, Nicholas C; Griffith, Obi L; Griffith, Malachi

2018-01-04

The drug-gene interaction database (DGIdb, www.dgidb.org) consolidates, organizes and presents drug-gene interactions and gene druggability information from papers, databases and web resources. DGIdb normalizes content from 30 disparate sources and allows for user-friendly advanced browsing, searching and filtering for ease of access through an intuitive web user interface, application programming interface (API) and public cloud-based server image. DGIdb v3.0 represents a major update of the database. Nine of the previously included 24 sources were updated. Six new resources were added, bringing the total number of sources to 30. These updates and additions of sources have cumulatively resulted in 56 309 interaction claims. This has also substantially expanded the comprehensive catalogue of druggable genes and anti-neoplastic drug-gene interactions included in the DGIdb. Along with these content updates, v3.0 has received a major overhaul of its codebase, including an updated user interface, preset interaction search filters, consolidation of interaction information into interaction groups, greatly improved search response times and upgrading the underlying web application framework. In addition, the expanded API features new endpoints which allow users to extract more detailed information about queried drugs, genes and drug-gene interactions, including listings of PubMed IDs, interaction type and other interaction metadata.

Application of the ToxMiner Database: Network Analysis of ...

EPA Pesticide Factsheets

The US EPA ToxCast program is using in vitro HTS (High-Throughput Screening) methods to profile and model bioactivity of environmental chemicals. The main goals of the ToxCast program are to generate predictive signatures of toxicity, and ultimately provide rapid and cost-effective alternatives to animal testing. The chemicals selected for Phase I are composed largely by a diverse set of pesticide active ingredients, which had sufficient supporting in vivo data included as part of their registration process with the EPA. Other miscellaneous chemicals of environmental concern were also included. Application of HTS to environmental toxicants is a novel approach to predictive toxicology and health risk assessment, and differs from what is required for drug efficacy screening in that biochemical interaction of environmental chemicals are sometimes weaker than that seen with drugs and their intended targets. Additionally, the chemical space covered by environmental chemicals is much broader compared to that of pharmaceuticals. The ToxMiner database has been created and added to the EPA’s ACToR (Aggregated Computational Toxicology Resource) chemical database. One purpose of the ToxMiner database is to link biological, metabolic and cellular pathway data to genes and in vitro assay data for the initial subset of chemicals screened in the ToxCast Phase I HTS assays. Also included in ToxMiner is human disease information, which correlates with ToxCast assays that tar

A Fully Automated High-Throughput Flow Cytometry Screening System Enabling Phenotypic Drug Discovery.

PubMed

Joslin, John; Gilligan, James; Anderson, Paul; Garcia, Catherine; Sharif, Orzala; Hampton, Janice; Cohen, Steven; King, Miranda; Zhou, Bin; Jiang, Shumei; Trussell, Christopher; Dunn, Robert; Fathman, John W; Snead, Jennifer L; Boitano, Anthony E; Nguyen, Tommy; Conner, Michael; Cooke, Mike; Harris, Jennifer; Ainscow, Ed; Zhou, Yingyao; Shaw, Chris; Sipes, Dan; Mainquist, James; Lesley, Scott

2018-05-01

The goal of high-throughput screening is to enable screening of compound libraries in an automated manner to identify quality starting points for optimization. This often involves screening a large diversity of compounds in an assay that preserves a connection to the disease pathology. Phenotypic screening is a powerful tool for drug identification, in that assays can be run without prior understanding of the target and with primary cells that closely mimic the therapeutic setting. Advanced automation and high-content imaging have enabled many complex assays, but these are still relatively slow and low throughput. To address this limitation, we have developed an automated workflow that is dedicated to processing complex phenotypic assays for flow cytometry. The system can achieve a throughput of 50,000 wells per day, resulting in a fully automated platform that enables robust phenotypic drug discovery. Over the past 5 years, this screening system has been used for a variety of drug discovery programs, across many disease areas, with many molecules advancing quickly into preclinical development and into the clinic. This report will highlight a diversity of approaches that automated flow cytometry has enabled for phenotypic drug discovery.

Engineering three-dimensional cardiac microtissues for potential drug screening applications.

PubMed

Wang, L; Huang, G; Sha, B; Wang, S; Han, Y L; Wu, J; Li, Y; Du, Y; Lu, T J; Xu, F

2014-01-01

Heart disease is one of the major global health issues. Despite rapid advances in cardiac tissue engineering, limited successful strategies have been achieved to cure cardiovascular diseases. This situation is mainly due to poor understanding of the mechanism of diverse heart diseases and unavailability of effective in vitro heart tissue models for cardiovascular drug screening. With the development of microengineering technologies, three-dimensional (3D) cardiac microtissue (CMT) models, mimicking 3D architectural microenvironment of native heart tissues, have been developed. The engineered 3D CMT models hold greater potential to be used for assessing effective drugs candidates than traditional two-dimensional cardiomyocyte culture models. This review discusses the development of 3D CMT models and highlights their potential applications for high-throughput screening of cardiovascular drug candidates.

Screening pharmaceuticals for possible carcinogenic effects: initial positive results for drugs not previously screened

PubMed Central

Friedman, Gary D.; Udaltsova, Natalia; Chan, James; Quesenberry, Charles P; Habel, Laurel A.

2010-01-01

Objective We screened commonly used prescription drugs for possible carcinogenic effects. Methods In a large health care program we identified 105 commonly used drugs, not previously screened. Recipients were followed for up to 12½ years for incident cancer. Nested case-control analyses of 55 cancer sites and all combined included up to ten matched controls per case, with lag of at least two years between drug dispensing and cancer. Positive associations entailed a relative risk (RR) of 1.50, with p≤ 0.01 and higher risk for three or more, than for one prescription. Evaluation included further analyses, searches of the literature, and clinical judgment. Results There were 101 associations of interest for 61 drugs. Sixty-six associations were judged to have involved substantial confounding. We found evidence that of the remaining 35, the following associations may not be due to chance: sulindac with gallbladder cancer and leukemia, hyoscyamine with non-Hodgkin lymphoma, nortriptyline with esophageal and hepatic cancer, oxazepam with lung cancer, both fluoxetine and paroxetine with testicular cancer, hydrochlorothiazide with renal and lip cancer, and nifedipine with lip cancer. Conclusions These preliminary findings suggest that further studies are indicated regarding sulindac, hyoscyamine, nortriptyline, oxazepam, fluoxetine, paroxetine, hydrochlorothiazide and nifedipine. PMID:19582585

Validation of the Drug Abuse Screening Test (DAST-10): A study on illicit drug use among Chinese pregnant women.

PubMed

Lam, Lap Po; Leung, Wing Cheong; Ip, Patrick; Chow, Chun Bong; Chan, Mei Fung; Ng, Judy Wai Ying; Sing, Chu; Lam, Ying Hoo; Mak, Wing Lai Tony; Chow, Kam Ming; Chin, Robert Kien Howe

2015-06-19

We assessed the Chinese version of the Drug Abuse Screening Test (DAST-10) for identifying illicit drug use during pregnancy among Chinese population. Chinese pregnant women attending their first antenatal visit or their first unbooked visit to the maternity ward were recruited during a 4-month study period in 2011. The participants completed self-administered questionnaires on demographic information, a single question on illicit drug use during pregnancy and the DAST-10. Urine samples screened positive by the urine Point-of-Care Test were confirmed by gas chromatography-mass spectrometry. DAST-10 performance was compared with three different gold standards: urinalysis, self-reported drug use, and evidence of drug use by urinalysis or self-report. 1214 Chinese pregnant women participated in the study and 1085 complete DAST-10 forms were collected. Women who had used illicit drugs had significantly different DAST-10 scores than those who had not. The sensitivity of DAST-10 for identify illicit drug use in pregnant women ranged from 79.2% to 33.3% and specificity ranged from 67.7% to 99.7% using cut-off scores from ≥ 1 to ≥ 3. The ~ 80% sensitivity of DAST-10 using a cut-off score of ≥ 1 should be sufficient for screening of illicit drug use in Chinese pregnant women, but validation tests for drug use are needed.

IDAAPM: integrated database of ADMET and adverse effects of predictive modeling based on FDA approved drug data.

PubMed

Legehar, Ashenafi; Xhaard, Henri; Ghemtio, Leo

2016-01-01

The disposition of a pharmaceutical compound within an organism, i.e. its Absorption, Distribution, Metabolism, Excretion, Toxicity (ADMET) properties and adverse effects, critically affects late stage failure of drug candidates and has led to the withdrawal of approved drugs. Computational methods are effective approaches to reduce the number of safety issues by analyzing possible links between chemical structures and ADMET or adverse effects, but this is limited by the size, quality, and heterogeneity of the data available from individual sources. Thus, large, clean and integrated databases of approved drug data, associated with fast and efficient predictive tools are desirable early in the drug discovery process. We have built a relational database (IDAAPM) to integrate available approved drug data such as drug approval information, ADMET and adverse effects, chemical structures and molecular descriptors, targets, bioactivity and related references. The database has been coupled with a searchable web interface and modern data analytics platform (KNIME) to allow data access, data transformation, initial analysis and further predictive modeling. Data were extracted from FDA resources and supplemented from other publicly available databases. Currently, the database contains information regarding about 19,226 FDA approval applications for 31,815 products (small molecules and biologics) with their approval history, 2505 active ingredients, together with as many ADMET properties, 1629 molecular structures, 2.5 million adverse effects and 36,963 experimental drug-target bioactivity data. IDAAPM is a unique resource that, in a single relational database, provides detailed information on FDA approved drugs including their ADMET properties and adverse effects, the corresponding targets with bioactivity data, coupled with a data analytics platform. It can be used to perform basic to complex drug-target ADMET or adverse effects analysis and predictive modeling. IDAAPM is

Exploiting PubChem for Virtual Screening

PubMed Central

Xie, Xiang-Qun

2011-01-01

Importance of the field PubChem is a public molecular information repository, a scientific showcase of the NIH Roadmap Initiative. The PubChem database holds over 27 million records of unique chemical structures of compounds (CID) derived from nearly 70 million substance depositions (SID), and contains more than 449,000 bioassay records with over thousands of in vitro biochemical and cell-based screening bioassays established, with targeting more than 7000 proteins and genes linking to over 1.8 million of substances. Areas covered in this review This review builds on recent PubChem-related computational chemistry research reported by other authors while providing readers with an overview of the PubChem database, focusing on its increasing role in cheminformatics, virtual screening and toxicity prediction modeling. What the reader will gain These publicly available datasets in PubChem provide great opportunities for scientists to perform cheminformatics and virtual screening research for computer-aided drug design. However, the high volume and complexity of the datasets, in particular the bioassay-associated false positives/negatives and highly imbalanced datasets in PubChem, also creates major challenges. Several approaches regarding the modeling of PubChem datasets and development of virtual screening models for bioactivity and toxicity predictions are also reviewed. Take home message Novel data-mining cheminformatics tools and virtual screening algorithms are being developed and used to retrieve, annotate and analyze the large-scale and highly complex PubChem biological screening data for drug design. PMID:21691435

A new retrospective, multi-evidence veterinary drug screening method using drift tube ion mobility mass spectrometry.

PubMed

Xu, Zhenzhen; Li, Jianzhong; Chen, Ailiang; Ma, Xin; Yang, Shuming

2018-05-03

The retrospectivity (the ability to retrospect to a previously unknown compound in raw data) is very meaningful for food safety and risk assessment when facing new emerging drugs. Accurate mass and retention time based screening may lead false positive and false negative results so new retrospective, reliable platform is desirable. Different concentration levels of standards with and without matrix were analyzed using ion mobility (IM)-quadrupole-time-of-flight (Q-TOF) for collecting retrospective accurate mass, retention time, drift time and tandem MS evidence for identification in a single experiment. The isomer separation ability of IM and the four-dimensional (4D) feature abundance quantification abilities were evaluated for veterinary drugs for the first time. The sensitivity of the IM-Q-TOF workflow was obviously higher than that of the traditional database searching algorithm [find by formula (FbF) function] for Q-TOF. In addition, the IM-Q-TOF workflow contained most of the results from FbF and removed the false positive results. Some isomers were separated by IM and the 4D feature abundance quantitation removed interference with similar accurate mass and showed good linearity. A new retrospective, multi-evidence platform was built for veterinary drug screening in a single experiment. The sensitivity was significantly improved and the data can be used for quantification. The platform showed its potential to be used for food safety and risk assessment. This article is protected by copyright. All rights reserved.

A comprehensive review of the psychometric properties of the Drug Abuse Screening Test.

PubMed

Yudko, Errol; Lozhkina, Olga; Fouts, Adriana

2007-03-01

This article reviews the reliability and the validity of the (10-, 20-, and 28-item) Drug Abuse Screening Test (DAST). The reliability and the validity of the adolescent version of the DAST are also reviewed. An extensive literature review was conducted using the Medline and Psychinfo databases from the years 1982 to 2005. All articles that addressed the reliability and the validity of the DAST were examined. Publications in which the DAST was used as a screening tool but had no data on its psychometric properties were not included. Descriptive information about each version of the test, as well as discussion of the empirical literature that has explored measures of the reliability and the validity of the DAST, has been included. The DAST tended to have moderate to high levels of test-retest, interitem, and item-total reliabilities. The DAST also tended to have moderate to high levels of validity, sensitivity, and specificity. In general, all versions of the DAST yield satisfactory measures of reliability and validity for use as clinical or research tools. Furthermore, these tests are easy to administer and have been used in a variety of populations.

Role of Chemical Reactivity and Transition State Modeling for Virtual Screening.

PubMed

Karthikeyan, Muthukumarasamy; Vyas, Renu; Tambe, Sanjeev S; Radhamohan, Deepthi; Kulkarni, Bhaskar D

2015-01-01

Every drug discovery research program involves synthesis of a novel and potential drug molecule utilizing atom efficient, economical and environment friendly synthetic strategies. The current work focuses on the role of the reactivity based fingerprints of compounds as filters for virtual screening using a tool ChemScore. A reactant-like (RLS) and a product- like (PLS) score can be predicted for a given compound using the binary fingerprints derived from the numerous known organic reactions which capture the molecule-molecule interactions in the form of addition, substitution, rearrangement, elimination and isomerization reactions. The reaction fingerprints were applied to large databases in biology and chemistry, namely ChEMBL, KEGG, HMDB, DSSTox, and the Drug Bank database. A large network of 1113 synthetic reactions was constructed to visualize and ascertain the reactant product mappings in the chemical reaction space. The cumulative reaction fingerprints were computed for 4000 molecules belonging to 29 therapeutic classes of compounds, and these were found capable of discriminating between the cognition disorder related and anti-allergy compounds with reasonable accuracy of 75% and AUC 0.8. In this study, the transition state based fingerprints were also developed and used effectively for virtual screening in drug related databases. The methodology presented here provides an efficient handle for the rapid scoring of molecular libraries for virtual screening.

[Chemical databases and virtual screening].

PubMed

Rognan, Didier; Bonnet, Pascal

2014-12-01

A prerequisite to any virtual screening is the definition of compound libraries to be screened. As we describe here, various sources are available. The selection of the proper library is usually project-dependent but at least as important as the screening method itself. This review details the main compound libraries that are available for virtual screening and guide the reader to the best possible selection according to its needs. © 2014 médecine/sciences – Inserm.

A high-sensitivity ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) method for screening synthetic cannabinoids and other drugs of abuse in urine.

PubMed

Sundström, Mira; Pelander, Anna; Angerer, Verena; Hutter, Melanie; Kneisel, Stefan; Ojanperä, Ilkka

2013-10-01

The continuing emergence of designer drugs imposes high demands on the scope and sensitivity of toxicological drug screening procedures. An ultra-high performance liquid chromatography/high-resolution time-of-flight mass spectrometry (UHPLC-HR-TOFMS) method was developed for screening and simultaneous confirmation of both designer drugs and other drugs of abuse in urine samples in a single run. The method covered selected synthetic cannabinoids and cathinones, amphetamines, natural cannabinoids, opioids, cocaine and other important drugs of abuse, together with their main urinary metabolites. The database consisted of 277 compounds with molecular formula and exact monoisotopic mass; retention time was included for 192 compounds, and primary and secondary qualifier ion exact mass for 191 and 95 compounds, respectively. Following a solid-phase extraction, separation was performed by UHPLC and mass analysis by HR-TOFMS. MS, and broad-band collision-induced dissociation data were acquired at m/z range 50-700. Compound identification was based on a reverse database search with acceptance criteria for retention time, precursor ion mass accuracy, isotopic pattern and abundance of qualifier ions. Mass resolving power in spiked urine samples was on average FWHM 23,500 and mass accuracy 0.3 mDa. The mean and median cut-off concentrations determined for 75 compounds were 4.2 and 1 ng/mL, respectively. The range of cut-off concentrations for synthetic cannabinoids was 0.2-60 ng/mL and for cathinones 0.7-15 ng/mL. The method proved to combine high sensitivity and a wide scope in a manner not previously reported in drugs of abuse screening. The method's feasibility was demonstrated with 50 authentic urine samples.

Drug-Associated Acute Kidney Injury Identified in the United States Food and Drug Administration Adverse Event Reporting System Database.

PubMed

Welch, Hanna K; Kellum, John A; Kane-Gill, Sandra L

2018-06-08

Acute kidney injury (AKI) is a common condition associated with both short-term and long-term consequences including dialysis, chronic kidney disease, and mortality. Although the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database is a powerful tool to examine drug-associated events, to our knowledge, no study has analyzed this database to identify the most common drugs reported with AKI. The objective of this study was to analyze AKI reports and associated medications in the FAERS database. Retrospective pharmacovigilance disproportionality analysis. FAERS database. We queried the FAERS database for reports of AKI from 2004 quarter 1 through 2015 quarter 3. Extracted drugs were assessed using published references and categorized as known, possible, or new potential nephrotoxins. The reporting odds ratio (ROR), a measure of reporting disproportionality, was calculated for the 20 most frequently reported drugs in each category. We retrieved 7,241,385 adverse event reports, of which 193,996 (2.7%) included a report of AKI. Of the AKI reports, 16.5% were known nephrotoxins, 18.6% were possible nephrotoxins, and 64.8% were new potential nephrotoxins. Among the most commonly reported drugs, those with the highest AKI ROR were aprotinin (7,614 reports; ROR 115.70, 95% confidence interval [CI] 110.63-121.01), sodium phosphate (1,687 reports; ROR 55.81, 95% CI 51.78-60.17), furosemide (1,743 reports; ROR 12.61, 95% CI 11.94-13.32), vancomycin (1,270 reports, ROR 12.19, 95% CI 11.45-12.99), and metformin (4,701 reports; ROR 10.65, 95% CI 10.31-11.00). The combined RORs for the 20 most frequently reported drugs with each nephrotoxin classification were 3.71 (95% CI 3.66-3.76) for known nephrotoxins, 2.09 (95% CI 2.06-2.12) for possible nephrotoxins, and 1.55 (95% CI 1.53-1.57) for new potential nephrotoxins. AKI was a common reason for adverse event reporting in the FAERS. Most AKI reports were generated for medications not recognized

An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs.

PubMed

Kim, Wooseong; Hendricks, Gabriel Lambert; Lee, Kiho; Mylonakis, Eleftherios

2017-06-01

The emergence of antibiotic-resistant and -tolerant bacteria is a major threat to human health. Although efforts for drug discovery are ongoing, conventional bacteria-centered screening strategies have thus far failed to yield new classes of effective antibiotics. Therefore, new paradigms for discovering novel antibiotics are of critical importance. Caenorhabditis elegans, a model organism used for in vivo, offers a promising solution for identification of anti-infective compounds. Areas covered: This review examines the advantages of C. elegans-based high-throughput screening over conventional, bacteria-centered in vitro screens. It discusses major anti-infective compounds identified from large-scale C. elegans-based screens and presents the first clinically-approved drugs, then known bioactive compounds, and finally novel small molecules. Expert opinion: There are clear advantages of using a C. elegans-infection based screening method. A C. elegans-based screen produces an enriched pool of non-toxic, efficacious, potential anti-infectives, covering: conventional antimicrobial agents, immunomodulators, and anti-virulence agents. Although C. elegans-based screens do not denote the mode of action of hit compounds, this can be elucidated in secondary studies by comparing the results to target-based screens, or conducting subsequent target-based screens, including the genetic knock-down of host or bacterial genes.

Screening_mgmt: a Python module for managing screening data.

PubMed

Helfenstein, Andreas; Tammela, Päivi

2015-02-01

High-throughput screening is an established technique in drug discovery and, as such, has also found its way into academia. High-throughput screening generates a considerable amount of data, which is why specific software is used for its analysis and management. The commercially available software packages are often beyond the financial limits of small-scale academic laboratories and, furthermore, lack the flexibility to fulfill certain user-specific requirements. We have developed a Python module, screening_mgmt, which is a lightweight tool for flexible data retrieval, analysis, and storage for different screening assays in one central database. The module reads custom-made analysis scripts and plotting instructions, and it offers a graphical user interface to import, modify, and display the data in a uniform manner. During the test phase, we used this module for the management of 10,000 data points of various origins. It has provided a practical, user-friendly tool for sharing and exchanging information between researchers. © 2014 Society for Laboratory Automation and Screening.

Similarity-based modeling in large-scale prediction of drug-drug interactions.

PubMed

Vilar, Santiago; Uriarte, Eugenio; Santana, Lourdes; Lorberbaum, Tal; Hripcsak, George; Friedman, Carol; Tatonetti, Nicholas P

2014-09-01

Drug-drug interactions (DDIs) are a major cause of adverse drug effects and a public health concern, as they increase hospital care expenses and reduce patients' quality of life. DDI detection is, therefore, an important objective in patient safety, one whose pursuit affects drug development and pharmacovigilance. In this article, we describe a protocol applicable on a large scale to predict novel DDIs based on similarity of drug interaction candidates to drugs involved in established DDIs. The method integrates a reference standard database of known DDIs with drug similarity information extracted from different sources, such as 2D and 3D molecular structure, interaction profile, target and side-effect similarities. The method is interpretable in that it generates drug interaction candidates that are traceable to pharmacological or clinical effects. We describe a protocol with applications in patient safety and preclinical toxicity screening. The time frame to implement this protocol is 5-7 h, with additional time potentially necessary, depending on the complexity of the reference standard DDI database and the similarity measures implemented.

Drug screening of cancer cell lines and human primary tumors using droplet microfluidics.

PubMed

Wong, Ada Hang-Heng; Li, Haoran; Jia, Yanwei; Mak, Pui-In; Martins, Rui Paulo da Silva; Liu, Yan; Vong, Chi Man; Wong, Hang Cheong; Wong, Pak Kin; Wang, Haitao; Sun, Heng; Deng, Chu-Xia

2017-08-22

Precision Medicine in Oncology requires tailoring of therapeutic strategies to individual cancer patients. Due to the limited quantity of tumor samples, this proves to be difficult, especially for early stage cancer patients whose tumors are small. In this study, we exploited a 2.4 × 2.4 centimeters polydimethylsiloxane (PDMS) based microfluidic chip which employed droplet microfluidics to conduct drug screens against suspended and adherent cancer cell lines, as well as cells dissociated from primary tumor of human patients. Single cells were dispersed in aqueous droplets and imaged within 24 hours of drug treatment to assess cell viability by ethidium homodimer 1 staining. Our results showed that 5 conditions could be screened for every 80,000 cells in one channel on our chip under current circumstances. Additionally, screening conditions have been adapted to both suspended and adherent cancer cells, giving versatility to potentially all types of cancers. Hence, this study provides a powerful tool for rapid, low-input drug screening of primary cancers within 24 hours after tumor resection from cancer patients. This paves the way for further technological advancement to cutting down sample size and increasing drug screening throughput in advent to personalized cancer therapy.

Microengineering methods for cell-based microarrays and high-throughput drug-screening applications.

PubMed

Xu, Feng; Wu, JinHui; Wang, ShuQi; Durmus, Naside Gozde; Gurkan, Umut Atakan; Demirci, Utkan

2011-09-01

Screening for effective therapeutic agents from millions of drug candidates is costly, time consuming, and often faces concerns due to the extensive use of animals. To improve cost effectiveness, and to minimize animal testing in pharmaceutical research, in vitro monolayer cell microarrays with multiwell plate assays have been developed. Integration of cell microarrays with microfluidic systems has facilitated automated and controlled component loading, significantly reducing the consumption of the candidate compounds and the target cells. Even though these methods significantly increased the throughput compared to conventional in vitro testing systems and in vivo animal models, the cost associated with these platforms remains prohibitively high. Besides, there is a need for three-dimensional (3D) cell-based drug-screening models which can mimic the in vivo microenvironment and the functionality of the native tissues. Here, we present the state-of-the-art microengineering approaches that can be used to develop 3D cell-based drug-screening assays. We highlight the 3D in vitro cell culture systems with live cell-based arrays, microfluidic cell culture systems, and their application to high-throughput drug screening. We conclude that among the emerging microengineering approaches, bioprinting holds great potential to provide repeatable 3D cell-based constructs with high temporal, spatial control and versatility.

Challenges for Detecting Valproic Acid in a Nontargeted Urine Drug Screening Method.

PubMed

Pope, Jeffrey D; Black, Marion J; Drummer, Olaf H; Schneider, Hans G

2017-08-01

Valproic acid (VPA) is a widely prescribed medicine, and acute toxicity is possible. As such, it should be included in any nontargeted urine drug screening method. In many published liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS) methods, VPA is usually measured using a pseudo-multiple reaction monitoring (MRM) transition. We investigate a simple ultra-high-performance liquid chromatography-quadrupole time-of-flight (QTof) approach to detect the presence of VPA with more confidence. Three commercially sourced VPA metabolites were characterized and added to a nontargeted high-resolution MS urine drug screening method. All analyses were performed on a Waters Xevo G2-XS LC-QTof in negative electrospray ionization mode. The mass detector was operated in MS mode, and data were processed with UNIFI software. Sixty-eight patient urine samples, which were previously identified by a well-established gas chromatography-MS method as containing VPA, were analyzed on the Waters Xevo G2-XS LC-QTof, to validate this approach. VPA metabolite standards were characterized, and their detection data were added to the broad drug screening library. VPA metabolites were readily detectable in the urine of patients taking VPA. The inclusion of characterized VPA metabolites provides a simple and reliable method enabling the detection of VPA in nontargeted urine drug screening.

Microengineering Methods for Cell Based Microarrays and High-Throughput Drug Screening Applications

PubMed Central

Xu, Feng; Wu, JinHui; Wang, ShuQi; Durmus, Naside Gozde; Gurkan, Umut Atakan; Demirci, Utkan

2011-01-01

Screening for effective therapeutic agents from millions of drug candidates is costly, time-consuming and often face ethical concerns due to extensive use of animals. To improve cost-effectiveness, and to minimize animal testing in pharmaceutical research, in vitro monolayer cell microarrays with multiwell plate assays have been developed. Integration of cell microarrays with microfluidic systems have facilitated automated and controlled component loading, significantly reducing the consumption of the candidate compounds and the target cells. Even though these methods significantly increased the throughput compared to conventional in vitro testing systems and in vivo animal models, the cost associated with these platforms remains prohibitively high. Besides, there is a need for three-dimensional (3D) cell based drug-screening models, which can mimic the in vivo microenvironment and the functionality of the native tissues. Here, we present the state-of-the-art microengineering approaches that can be used to develop 3D cell based drug screening assays. We highlight the 3D in vitro cell culture systems with live cell-based arrays, microfluidic cell culture systems, and their application to high-throughput drug screening. We conclude that among the emerging microengineering approaches, bioprinting holds a great potential to provide repeatable 3D cell based constructs with high temporal, spatial control and versatility. PMID:21725152

Timing of specimen collection is crucial in urine screening of drug dependent mothers and newborns.

PubMed

Halstead, A C; Godolphin, W; Lockitch, G; Segal, S

1988-01-01

We compared results of urine drug analysis with clinical data and history to test the usefulness of peripartum drug screening and to establish guidelines for optimal testing. Urine from 28 mothers and 52 babies was analysed. Drugs not suspected by history were found in 10 mothers and six babies. Results assisted in the management of neonatal withdrawal in three babies. Drugs suspected by history were not found in 11/22 mothers and 23/35 babies. About half of these results were associated with delayed urine collection. In 12/28 mothers, drugs administered in hospital could have confused interpretation of screen results. We conclude that urine drug screening without strict protocols for specimen collection is of limited usefulness for management of drug abuse in pregnancy and neonatal drug withdrawal. We favour testing of maternal urine obtained before drugs are administered in hospital. Neonatal urine, if used, should be collected in the first day of life.

Standardisation of the FAERS database: a systematic approach to manually recoding drug name variants.

PubMed

Wong, Carmen K; Ho, Samuel S; Saini, Bandana; Hibbs, David E; Fois, Romano A

2015-07-01

The US Food and Drug Administration Adverse Event Reporting System (FAERS), one of the world's largest spontaneous reporting systems, is difficult to use because of report duplication and a lack of standardisation in the recording of drug names. Unresolved data quality issues may distort statistical analyses, rendering the results difficult to interpret when detecting and monitoring adverse effects of pharmaceutical products. The aim of this study was to develop and implement a data cleaning protocol to identify and resolve drug nomenclature issues. The key 'data treatment' plan involved standardising drug names held in the FAERS database. Four million five hundred and six thousand five hundred and seventy-seven. Individual Safety Reports submitted to the FAERS between 1 January 2003 and 31 August 2012 were included for this study. OpenRefine was used to standardise drug name variants in the database such that they were consistent with international non-proprietary nomenclature defined by the World Health Organisation Anatomical Therapeutic Chemical classification. Drug variants where generic constituents could not be confidently determined, undecipherable drug names and non-medicinal products were retained verbatim. After the standardisation process, more than 16 611 916 drug entries were cleaned to their relevant international non-proprietary name. The cleaned drug table comprised 71 858 drug name variants and includes both standardised and original terms. Ninety-nine per cent of drug names was standardised using this method. The millions of reports enclosed in the FAERS contain valuable information that is of interest to pharmacovigilance, toxicology and post-marketing surveillance researchers. With the standardisation of the drug nomenclature, the database can be better utilised by research groups around the world. Copyright © 2015 John Wiley & Sons, Ltd.

Screening of cardiovascular risk factors in patients with schizophrenia and patients treated with antipsychotic drugs: are we equally exhaustive as with the general population?

PubMed

Castillo-Sánchez, Miguel; Fàbregas-Escurriola, Mireia; Bergè-Baquero, Daniel; Fernández-SanMartín, MªIsabel; Goday-Arno, Albert

2017-01-01

Many studies have previously shown increased cardiovascular risk factors related to schizophrenia independently from the use of antipsychotic drugs. However, a poorer effort in clinical detection and management of cardiovascular risk in patients with severe mental illness could also explain these results. To test this hypothesis, we analyzed the differences in screening and incidence of cardiovascular risk factors between schizophrenia, non-schizophrenic patients on treatment with antipsychotic drugs (NS-TAD) and the general population. Data from adult subjects assessed by high-quality register general practitioners from 2006 to 2011 were extracted from the Catalonian SIDIAP database. The schizophrenia, NS-TAD, and control groups were compared in terms of measurements and incidence of diabetes, dyslipidemia, obesity, hypertension, and smoking. A total of 4911 patients in the schizophrenia group, 4157 in NS-TAD group, and 98644 in the control group were included. Schizophrenia patients were screened for dyslipidemia and diabetes more frequently than the control group, while for obesity or hypertension, they were screened equal to controls. Also, as compared to the control group, the NS-TAD group was more frequently screened for obesity with no differences in dyslipidemia and diabetes and less frequently for hypertension. Smoking was less frequently screened in both study groups. The incidence of all risk factors studied in both study groups was higher than or equal to the control group, except for hypertension, which had lower incidence. The lack of screening of risk factors does not appear decisive in the increased cardiovascular risk of patients diagnosed with schizophrenia seen in primary care. Studies evaluating the possible under diagnosis of the risk factors are required. Schizophrenia (SZ); Treatment with antipsychotic drugs (TAD); Cardiovascular risk factor/s (CVRF); Without schizophrenia but on therapy with antipsychotic drugs (NS-TAD); Defined Daily Dose

An optimal user-interface for EPIMS database conversions and SSQ 25002 EEE parts screening

NASA Technical Reports Server (NTRS)

Watson, John C.

1996-01-01

The Electrical, Electronic, and Electromechanical (EEE) Parts Information Management System (EPIMS) database was selected by the International Space Station Parts Control Board for providing parts information to NASA managers and contractors. Parts data is transferred to the EPIMS database by converting parts list data to the EP1MS Data Exchange File Format. In general, parts list information received from contractors and suppliers does not convert directly into the EPIMS Data Exchange File Format. Often parts lists use different variable and record field assignments. Many of the EPES variables are not defined in the parts lists received. The objective of this work was to develop an automated system for translating parts lists into the EPIMS Data Exchange File Format for upload into the EPIMS database. Once EEE parts information has been transferred to the EPIMS database it is necessary to screen parts data in accordance with the provisions of the SSQ 25002 Supplemental List of Qualified Electrical, Electronic, and Electromechanical Parts, Manufacturers, and Laboratories (QEPM&L). The SSQ 2S002 standards are used to identify parts which satisfy the requirements for spacecraft applications. An additional objective for this work was to develop an automated system which would screen EEE parts information against the SSQ 2S002 to inform managers of the qualification status of parts used in spacecraft applications. The EPIMS Database Conversion and SSQ 25002 User Interfaces are designed to interface through the World-Wide-Web(WWW)/Internet to provide accessibility by NASA managers and contractors.

A multilayer microdevice for cell-based high-throughput drug screening

NASA Astrophysics Data System (ADS)

Liu, Chong; Wang, Lei; Xu, Zheng; Li, Jingmin; Ding, Xiping; Wang, Qi; Chunyu, Li

2012-06-01

A multilayer polydimethylsiloxane microdevice for cell-based high-throughput drug screening is described in this paper. This established microdevice was based on a modularization method and it integrated a drug/medium concentration gradient generator (CGG), pneumatic microvalves and a cell culture microchamber array. The CGG was able to generate five steps of linear concentrations with the same outlet flow rate. The medium/drug flowed through CGG and then into the pear-shaped cell culture microchambers vertically. This vertical perfusion mode was used to reduce the impact of the shear stress on the physiology of cells induced by the fluid flow in the microchambers. Pear-shaped microchambers with two arrays of miropillars at each outlet were adopted in this microdevice, which were beneficial to cell distribution. The chemotherapeutics Cisplatin (DDP)-induced Cisplatin-resistant cell line A549/DDP apoptotic experiments were performed well on this platform. The results showed that this novel microdevice could not only provide well-defined and stable conditions for cell culture, but was also useful for cell-based high-throughput drug screening with less reagents and time consumption.

Antimalarial drug discovery: screening of Brazilian medicinal plants and purified compounds.

PubMed

Krettli, Antoniana Ursine

2009-02-01

Malaria is the most important parasitic disease and its control depends on specific chemotherapy, now complicated by Plasmodium falciparum that has become resistant to most commonly available antimalarials. Treatment of the disease requires quinine or drug combinations of artemisinin derivatives and other antimalarials. Further drug resistance is expected. New active compounds need to be discovered. To find new antimalarials from medicinal and randomly collected plants, crude extracts are screened against P. falciparum in cultures and in malaria animal models, following bioassays of purified fractions, and cytotoxicity tests. For antimalarial research, screening medicinal plants is more efficient than screening randomly chosen plants. Biomonitored fractionation allows selection of new active molecules identified as potential antimalarials in multidisciplinary projects in Brazil; no new molecule is available for human testing. The advantages of projects based on ethnopharmacology are discussed.

An ion channel library for drug discovery and safety screening on automated platforms.

PubMed

Wible, Barbara A; Kuryshev, Yuri A; Smith, Stephen S; Liu, Zhiqi; Brown, Arthur M

2008-12-01

Ion channels represent the third largest class of targets in drug discovery after G-protein coupled receptors and kinases. In spite of this ranking, ion channels continue to be under exploited as drug targets compared with the other two groups for several reasons. First, with 400 ion channel genes and an even greater number of functional channels due to mixing and matching of individual subunits, a systematic collection of ion channel-expressing cell lines for drug discovery and safety screening has not been available. Second, the lack of high-throughput functional assays for ion channels has limited their use as drug targets. Now that automated electrophysiology has come of age and provided the technology to assay ion channels at medium to high throughput, we have addressed the need for a library of ion channel cell lines by constructing the Ion Channel Panel (ChanTest Corp., Cleveland, OH). From 400 ion channel genes, a collection of 82 of the most relevant human ion channels for drug discovery, safety, and human disease has been assembled.Each channel has been stably overexpressed in human embryonic kidney 293 or Chinese hamster ovary cells. Cell lines have been selected and validated on automated electrophysiology systems to facilitate cost-effective screening for safe and selective compounds at earlier stages in the drug development process. The screening and validation processes as well as the relative advantages of different screening platforms are discussed.

[Survey of Literature on the Development of an Evidence Database for Hospital-prepared Drugs in Japan].

PubMed

Momo, Kenji

2018-01-01

　Hospital-prepared drugs (HP), known as In'Naiseizai in Japan, are custom-prepared formulations which offer medical professionals an alternative administration pathway by changing the formulation of existing drugs according to a patients' needs. Preparing the HP is one of several roles of pharmacists in providing personalized medicine at hospitals in Japan. In 2012, the Japanese Society of Hospital Pharmacists provided guidelines for the appropriate use of "Hospital-prepared drugs". The following information was included in this guide: 1) documentation of the proper procedures, materials, prescription practices, etc., 2) required approval from the institutional review board of each HP on the risk-based classifications, and 3) to assess the stability, efficacy, and safety of each HP. However, several problems persist for pharmacists trying to prepare or use HP appropriately; the most common is insufficient manpower to both assess and prepare these drugs during routine hospital work. To resolve this problem, we are developing an evidence database for HP based on surveys of the current literature. This database has been developed for 109 drugs to date. Data-driven assessment of the stability of HP showed that 52 out of 109 drugs examined (47.7%). Notably, only 6 of the 109 HP (5.5%) in the database had all three characteristics of "stability", "safety", and "efficacy". In conclusion, the application of this database will save manpower hours for hospital pharmacists in the preparation of HP. In the near future, we will make this database available to the wider medical community via the web or through literature.

Privacy-preserving search for chemical compound databases.

PubMed

Shimizu, Kana; Nuida, Koji; Arai, Hiromi; Mitsunari, Shigeo; Attrapadung, Nuttapong; Hamada, Michiaki; Tsuda, Koji; Hirokawa, Takatsugu; Sakuma, Jun; Hanaoka, Goichiro; Asai, Kiyoshi

2015-01-01

Searching for similar compounds in a database is the most important process for in-silico drug screening. Since a query compound is an important starting point for the new drug, a query holder, who is afraid of the query being monitored by the database server, usually downloads all the records in the database and uses them in a closed network. However, a serious dilemma arises when the database holder also wants to output no information except for the search results, and such a dilemma prevents the use of many important data resources. In order to overcome this dilemma, we developed a novel cryptographic protocol that enables database searching while keeping both the query holder's privacy and database holder's privacy. Generally, the application of cryptographic techniques to practical problems is difficult because versatile techniques are computationally expensive while computationally inexpensive techniques can perform only trivial computation tasks. In this study, our protocol is successfully built only from an additive-homomorphic cryptosystem, which allows only addition performed on encrypted values but is computationally efficient compared with versatile techniques such as general purpose multi-party computation. In an experiment searching ChEMBL, which consists of more than 1,200,000 compounds, the proposed method was 36,900 times faster in CPU time and 12,000 times as efficient in communication size compared with general purpose multi-party computation. We proposed a novel privacy-preserving protocol for searching chemical compound databases. The proposed method, easily scaling for large-scale databases, may help to accelerate drug discovery research by making full use of unused but valuable data that includes sensitive information.

Privacy-preserving search for chemical compound databases

PubMed Central

2015-01-01

Background Searching for similar compounds in a database is the most important process for in-silico drug screening. Since a query compound is an important starting point for the new drug, a query holder, who is afraid of the query being monitored by the database server, usually downloads all the records in the database and uses them in a closed network. However, a serious dilemma arises when the database holder also wants to output no information except for the search results, and such a dilemma prevents the use of many important data resources. Results In order to overcome this dilemma, we developed a novel cryptographic protocol that enables database searching while keeping both the query holder's privacy and database holder's privacy. Generally, the application of cryptographic techniques to practical problems is difficult because versatile techniques are computationally expensive while computationally inexpensive techniques can perform only trivial computation tasks. In this study, our protocol is successfully built only from an additive-homomorphic cryptosystem, which allows only addition performed on encrypted values but is computationally efficient compared with versatile techniques such as general purpose multi-party computation. In an experiment searching ChEMBL, which consists of more than 1,200,000 compounds, the proposed method was 36,900 times faster in CPU time and 12,000 times as efficient in communication size compared with general purpose multi-party computation. Conclusion We proposed a novel privacy-preserving protocol for searching chemical compound databases. The proposed method, easily scaling for large-scale databases, may help to accelerate drug discovery research by making full use of unused but valuable data that includes sensitive information. PMID:26678650

Coupling computer-interpretable guidelines with a drug-database through a web-based system – The PRESGUID project

PubMed Central

Dufour, Jean-Charles; Fieschi, Dominique; Fieschi, Marius

2004-01-01

Background Clinical Practice Guidelines (CPGs) available today are not extensively used due to lack of proper integration into clinical settings, knowledge-related information resources, and lack of decision support at the point of care in a particular clinical context. Objective The PRESGUID project (PREScription and GUIDelines) aims to improve the assistance provided by guidelines. The project proposes an online service enabling physicians to consult computerized CPGs linked to drug databases for easier integration into the healthcare process. Methods Computable CPGs are structured as decision trees and coded in XML format. Recommendations related to drug classes are tagged with ATC codes. We use a mapping module to enhance computerized guidelines coupling with a drug database, which contains detailed information about each usable specific medication. In this way, therapeutic recommendations are backed up with current and up-to-date information from the database. Results Two authoritative CPGs, originally diffused as static textual documents, have been implemented to validate the computerization process and to illustrate the usefulness of the resulting automated CPGs and their coupling with a drug database. We discuss the advantages of this approach for practitioners and the implications for both guideline developers and drug database providers. Other CPGs will be implemented and evaluated in real conditions by clinicians working in different health institutions. PMID:15053828

Using Hierarchical Virtual Screening To Combat Drug Resistance of the HIV-1 Protease.

PubMed

Li, Nan; Ainsworth, Richard I; Ding, Bo; Hou, Tingjun; Wang, Wei

2015-07-27

Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of highly active anti-retroviral therapy (HAART) that block the catalytic site of HIV protease, thus preventing maturation of the HIV virion. However, with two decades of PI prescriptions in clinical practice, drug-resistant HIV mutants have now been found for all of the PI drugs. Therefore, the continuous development of new PI drugs is crucial both to combat the existing drug-resistant HIV strains and to provide treatments for future patients. Here we purpose an HIV PI drug design strategy to select candidate PIs with binding energy distributions dominated by interactions with conserved protease residues in both wild-type and various drug-resistant mutants. On the basis of this strategy, we have constructed a virtual screening pipeline including combinatorial library construction, combinatorial docking, MM/GBSA-based rescoring, and reranking on the basis of the binding energy distribution. We have tested our strategy on lopinavir by modifying its two functional groups. From an initial 751 689 candidate molecules, 18 candidate inhibitors were selected using the pipeline for experimental validation. IC50 measurements and drug resistance predictions successfully identified two ligands with both HIV protease inhibitor activity and an improved drug resistance profile on 2382 HIV mutants. This study provides a proof of concept for the integration of MM/GBSA energy analysis and drug resistance information at the stage of virtual screening and sheds light on future HIV drug design and the use of virtual screening to combat drug resistance.

Miniature short hairpin RNA screens to characterize antiproliferative drugs.

PubMed

Kittanakom, Saranya; Arnoldo, Anthony; Brown, Kevin R; Wallace, Iain; Kunavisarut, Tada; Torti, Dax; Heisler, Lawrence E; Surendra, Anuradha; Moffat, Jason; Giaever, Guri; Nislow, Corey

2013-08-07

The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields "hits" that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes. In one scenario, drug perturbation could, for example, improperly activate a protein that normally inhibits a particular kinase. In other cases, additional, lower affinity targets can be inhibited as in the example of inhibition of c-Kit observed in Bcr-Abl-positive cells treated with Gleevec. Drug transport and metabolism also play an important role in the way any chemicals act within the cells. Finally, RNAi per se can also affect cell fitness by more general off-target effects, e.g., via the modulation of apoptosis or DNA damage repair. Regardless of the root cause of these unwanted effects, understanding the scope of a drug's activity and polypharmacology is essential for better understanding its mechanism(s) of action, and such information can guide development of improved therapies. We describe a rapid, cost-effective approach to characterize primary and secondary effects of small-molecules by using small-scale libraries of virally integrated short hairpin RNAs. We demonstrate this principle using a "minipool" composed of shRNAs that target the genes encoding the reported protein targets of approved drugs. Among the 28 known reported drug-target pairs, we successfully identify 40% of the targets described in the literature and uncover several unanticipated drug-target interactions based on drug-induced synthetic lethality. We provide a detailed protocol for performing such screens and for

Affective and behavioral dysfunction under antiepileptic drugs in epilepsy: Development of a new drug-sensitive screening tool.

PubMed

Mertens, Lea Julia; Witt, Juri-Alexander; Helmstaedter, Christoph

2018-06-01

Behavioral problems and psychiatric symptoms are common in patients with epilepsy and have a multifactorial origin, including adverse effects of antiepileptic drugs (AEDs). In order to develop a screening tool for behavioral AED effects, the aim of this study was to identify behavioral problems and symptoms particularly sensitive to AED drug load and the presence/absence of AEDs with known negative psychotropic profiles. Four hundred ninety-four patients with epilepsy were evaluated who had been assessed with three self-report questionnaires on mood, personality, and behavior (Beck Depression Inventory, BDI; Neurological Disorders Depression Inventory for Epilepsy extended, NDDI-E; and Fragebogen zur Persönlichkeit bei zerebralen Erkrankungen, FPZ). Drug-sensitive items were determined via correlation analyses and entered into an exploratory factor analysis for scale construction. The resulting scales were then analyzed as a function of drug treatment. Analyses revealed 30 items, which could be allocated to six behavioral domains: Emotional Lability, Depression, Aggression/Irritability, Psychosis & Suicidality, Risk- & Sensation-seeking, and Somatization. Subsequent analysis showed significant effects of the number of AEDs on behavior, as in Emotional Lability (F=2.54, p=.029), Aggression/Irritability (F=2.29, p=.046), Psychosis & Suicidality (F=2.98, p=.012), and Somatization (F=2.39, p=.038). Affective and behavioral difficulties were more prominent in those patients taking AEDs with supposedly negative psychotropic profiles. These effects were largely domain-unspecific and primarily manifested in polytherapy. Drug-sensitive behavioral domains and items were identified which qualify for a self-report screening tool. The tool indicates impairments with a higher drug load and when administering AEDs with negative psychotropic profiles. The next steps require normalization in healthy subjects and the clinical validation of the newly developed screening tool Psy

MLViS: A Web Tool for Machine Learning-Based Virtual Screening in Early-Phase of Drug Discovery and Development

PubMed Central

Korkmaz, Selcuk; Zararsiz, Gokmen; Goksuluk, Dincer

2015-01-01

Virtual screening is an important step in early-phase of drug discovery process. Since there are thousands of compounds, this step should be both fast and effective in order to distinguish drug-like and nondrug-like molecules. Statistical machine learning methods are widely used in drug discovery studies for classification purpose. Here, we aim to develop a new tool, which can classify molecules as drug-like and nondrug-like based on various machine learning methods, including discriminant, tree-based, kernel-based, ensemble and other algorithms. To construct this tool, first, performances of twenty-three different machine learning algorithms are compared by ten different measures, then, ten best performing algorithms have been selected based on principal component and hierarchical cluster analysis results. Besides classification, this application has also ability to create heat map and dendrogram for visual inspection of the molecules through hierarchical cluster analysis. Moreover, users can connect the PubChem database to download molecular information and to create two-dimensional structures of compounds. This application is freely available through www.biosoft.hacettepe.edu.tr/MLViS/. PMID:25928885

Discovery of novel human acrosin inhibitors by virtual screening

NASA Astrophysics Data System (ADS)

Liu, Xuefei; Dong, Guoqiang; Zhang, Jue; Qi, Jingjing; Zheng, Canhui; Zhou, Youjun; Zhu, Ju; Sheng, Chunquan; Lü, Jiaguo

2011-10-01

Human acrosin is an attractive target for the discovery of male contraceptive drugs. For the first time, structure-based drug design was applied to discover structurally diverse human acrosin inhibitors. A parallel virtual screening strategy in combination with pharmacophore-based and docking-based techniques was used to screen the SPECS database. From 16 compounds selected by virtual screening, a total of 10 compounds were found to be human acrosin inhibitors. Compound 2 was found to be the most potent hit (IC50 = 14 μM) and its binding mode was investigated by molecular dynamics simulations. The hit interacted with human acrosin mainly through hydrophobic and hydrogen-bonding interactions, which provided a good starting structure for further optimization studies.

Importance of Urinary Drug Screening in the Multiple Sleep Latency Test and Maintenance of Wakefulness Test.

PubMed

Anniss, Angela M; Young, Alan; O'Driscoll, Denise M

2016-12-15

Multiple sleep latency testing (MSLT) and the maintenance of wakefulness test (MWT) are gold-standard objective tests of daytime sleepiness and alertness; however, there is marked variability in their interpretation and practice. This study aimed to determine the incidence of positive drug screens and their influence on MSLT, MWT, and polysomnographic variables. All patients attending Eastern Health Sleep Laboratory for MSLT or MWT over a 21-mo period were included in the study. Urinary drug screening for amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, methadone, and opiates was performed following overnight polysomnography (PSG). Demographics and PSG variables were compared. Of 69 studies, MSLT (43) and MWT (26), 16% of patients had positive urinary drug screening (7 MSLT; 4 MWT). Drugs detected included amphetamines, cannabinoids, opiates, and benzodiazepines. No patient self-reported use of these medications prior to testing. No demographic, MSLT or MWT PSG data or overnight PSG data showed any statistical differences between positive and negative drug screen groups. Of seven MSLT patients testing positive for drug use, one met criteria for the diagnosis of narcolepsy and five for idiopathic hypersomnia. On MWT, three of the four drug-positive patients had a history of a motor vehicle accident and two patients were occupational drivers. These findings indicate drug use is present in patients attending for daytime testing of objective sleepiness and wakefulness. These data support routine urinary drug screening in all patients undergoing MSLT or MWT studies to ensure accurate interpretation in the context of illicit and prescription drug use. © 2016 American Academy of Sleep Medicine

DrugBank: a knowledgebase for drugs, drug actions and drug targets

PubMed Central

Wishart, David S.; Knox, Craig; Guo, An Chi; Cheng, Dean; Shrivastava, Savita; Tzur, Dan; Gautam, Bijaya; Hassanali, Murtaza

2008-01-01

DrugBank is a richly annotated resource that combines detailed drug data with comprehensive drug target and drug action information. Since its first release in 2006, DrugBank has been widely used to facilitate in silico drug target discovery, drug design, drug docking or screening, drug metabolism prediction, drug interaction prediction and general pharmaceutical education. The latest version of DrugBank (release 2.0) has been expanded significantly over the previous release. With ∼4900 drug entries, it now contains 60% more FDA-approved small molecule and biotech drugs including 10% more ‘experimental’ drugs. Significantly, more protein target data has also been added to the database, with the latest version of DrugBank containing three times as many non-redundant protein or drug target sequences as before (1565 versus 524). Each DrugCard entry now contains more than 100 data fields with half of the information being devoted to drug/chemical data and the other half devoted to pharmacological, pharmacogenomic and molecular biological data. A number of new data fields, including food–drug interactions, drug–drug interactions and experimental ADME data have been added in response to numerous user requests. DrugBank has also significantly improved the power and simplicity of its structure query and text query searches. DrugBank is available at http://www.drugbank.ca PMID:18048412

The QDREC web server: determining dose-response characteristics of complex macroparasites in phenotypic drug screens.

PubMed

Asarnow, Daniel; Rojo-Arreola, Liliana; Suzuki, Brian M; Caffrey, Conor R; Singh, Rahul

2015-05-01

Neglected tropical diseases (NTDs) caused by helminths constitute some of the most common infections of the world's poorest people. The etiological agents are complex and recalcitrant to standard techniques of molecular biology. Drug screening against helminths has often been phenotypic and typically involves manual description of drug effect and efficacy. A key challenge is to develop automated, quantitative approaches to drug screening against helminth diseases. The quantal dose-response calculator (QDREC) constitutes a significant step in this direction. It can be used to automatically determine quantitative dose-response characteristics and half-maximal effective concentration (EC50) values using image-based readouts from phenotypic screens, thereby allowing rigorous comparisons of the efficacies of drug compounds. QDREC has been developed and validated in the context of drug screening for schistosomiasis, one of the most important NTDs. However, it is equally applicable to general phenotypic screening involving helminths and other complex parasites. QDREC is publically available at: http://haddock4.sfsu.edu/qdrec2/. Source code and datasets are at: http://tintin.sfsu.edu/projects/phenotypicAssays.html. rahul@sfsu.edu. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Screening for Drug Abuse Among College Students: Modification of the Michigan Alcoholism Screening Test

ERIC Educational Resources Information Center

Cannell, M. Barry; Favazza, Armando R.

1978-01-01

Modified version of the Michigan Alcoholism Screening Test was anonymously given to 245 college students on two Midwestern university campuses. Cutoff score for suspected drug abuse was set at five points. The percent of students scoring five or more points was 25 and 22 from campuses A and B respectively. (Author)

FlyRNAi.org—the database of the Drosophila RNAi screening center and transgenic RNAi project: 2017 update

PubMed Central

Hu, Yanhui; Comjean, Aram; Roesel, Charles; Vinayagam, Arunachalam; Flockhart, Ian; Zirin, Jonathan; Perkins, Lizabeth; Perrimon, Norbert; Mohr, Stephanie E.

2017-01-01

The FlyRNAi database of the Drosophila RNAi Screening Center (DRSC) and Transgenic RNAi Project (TRiP) at Harvard Medical School and associated DRSC/TRiP Functional Genomics Resources website (http://fgr.hms.harvard.edu) serve as a reagent production tracking system, screen data repository, and portal to the community. Through this portal, we make available protocols, online tools, and other resources useful to researchers at all stages of high-throughput functional genomics screening, from assay design and reagent identification to data analysis and interpretation. In this update, we describe recent changes and additions to our website, database and suite of online tools. Recent changes reflect a shift in our focus from a single technology (RNAi) and model species (Drosophila) to the application of additional technologies (e.g. CRISPR) and support of integrated, cross-species approaches to uncovering gene function using functional genomics and other approaches. PMID:27924039

Incorporating Virtual Reactions into a Logic-based Ligand-based Virtual Screening Method to Discover New Leads

PubMed Central

Reynolds, Christopher R; Muggleton, Stephen H; Sternberg, Michael J E

2015-01-01

The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21×1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs. PMID:26583052

Contaminant screening of wastewater with HPLC-IM-qTOF-MS and LC+LC-IM-qTOF-MS using a CCS database.

PubMed

Stephan, Susanne; Hippler, Joerg; Köhler, Timo; Deeb, Ahmad A; Schmidt, Torsten C; Schmitz, Oliver J

2016-09-01

Non-target analysis has become an important tool in the field of water analysis since a broad variety of pollutants from different sources are released to the water cycle. For identification of compounds in such complex samples, liquid chromatography coupled to high resolution mass spectrometry are often used. The introduction of ion mobility spectrometry provides an additional separation dimension and allows determining collision cross sections (CCS) of the analytes as a further physicochemical constant supporting the identification. A CCS database with more than 500 standard substances including drug-like compounds and pesticides was used for CCS data base search in this work. A non-target analysis of a wastewater sample was initially performed with high performance liquid chromatography (HPLC) coupled to an ion mobility-quadrupole-time of flight mass spectrometer (IM-qTOF-MS). A database search including exact mass (±5 ppm) and CCS (±1 %) delivered 22 different compounds. Furthermore, the same sample was analyzed with a two-dimensional LC method, called LC+LC, developed in our group for the coupling to IM-qTOF-MS. This four dimensional separation platform revealed 53 different compounds, identified over exact mass and CCS, in the examined wastewater sample. It is demonstrated that the CCS database can also help to distinguish between isobaric structures exemplified for cyclophosphamide and ifosfamide. Graphical Abstract Scheme of sample analysis and database screening.

High-throughput screening with nanoimprinting 3D culture for efficient drug development by mimicking the tumor environment.

PubMed

Yoshii, Yukie; Furukawa, Takako; Waki, Atsuo; Okuyama, Hiroaki; Inoue, Masahiro; Itoh, Manabu; Zhang, Ming-Rong; Wakizaka, Hidekatsu; Sogawa, Chizuru; Kiyono, Yasushi; Yoshii, Hiroshi; Fujibayashi, Yasuhisa; Saga, Tsuneo

2015-05-01

Anti-cancer drug development typically utilizes high-throughput screening with two-dimensional (2D) cell culture. However, 2D culture induces cellular characteristics different from tumors in vivo, resulting in inefficient drug development. Here, we report an innovative high-throughput screening system using nanoimprinting 3D culture to simulate in vivo conditions, thereby facilitating efficient drug development. We demonstrated that cell line-based nanoimprinting 3D screening can more efficiently select drugs that effectively inhibit cancer growth in vivo as compared to 2D culture. Metabolic responses after treatment were assessed using positron emission tomography (PET) probes, and revealed similar characteristics between the 3D spheroids and in vivo tumors. Further, we developed an advanced method to adopt cancer cells from patient tumor tissues for high-throughput drug screening with nanoimprinting 3D culture, which we termed Cancer tissue-Originated Uniformed Spheroid Assay (COUSA). This system identified drugs that were effective in xenografts of the original patient tumors. Nanoimprinting 3D spheroids showed low permeability and formation of hypoxic regions inside, similar to in vivo tumors. Collectively, the nanoimprinting 3D culture provides easy-handling high-throughput drug screening system, which allows for efficient drug development by mimicking the tumor environment. The COUSA system could be a useful platform for drug development with patient cancer cells. Copyright © 2015 Elsevier Ltd. All rights reserved.

Healthcare Databases for Drug Safety Research: Data Validity Assessment Remains Crucial.

PubMed

Rawson, Nigel S B; D'Arcy, Carl

2018-04-30

Administrative healthcare utilization databases are frequently used either individually or as a component of aggregated data for evaluating drug safety issues without taking into account their known deficiencies. All too often insufficient evidence is provided about their validity for the purposes for which they are used. The assessment of data validity is a key constituent that should be included in drug safety research studies and should take a broad multifaceted approach that encompasses both diagnostic and drug exposure data. Drug safety researchers need to continue advancing their knowledge of the data resources they use and to ensure that they and the users of their research understand the limitations of the data that are the foundation on which their research is built. Fundamental issues regarding data validity should be addressed in each use of administrative data for drug safety research.

76 FR 53912 - FDA's Public Database of Products With Orphan-Drug Designation: Replacing Non-Informative Code...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-30

...] FDA's Public Database of Products With Orphan-Drug Designation: Replacing Non-Informative Code Names... replaced non- informative code names with descriptive identifiers on its public database of products that... on our public database with non-informative code names. After careful consideration of this matter...

Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation

PubMed Central

Rotem, Asaf; Janzer, Andreas; Izar, Benjamin; Ji, Zhe; Doench, John G.; Garraway, Levi A.; Struhl, Kevin

2015-01-01

Colony formation in soft agar is the gold-standard assay for cellular transformation in vitro, but it is unsuited for high-throughput screening. Here, we describe an assay for cellular transformation that involves growth in low attachment (GILA) conditions and is strongly correlated with the soft-agar assay. Using GILA, we describe high-throughput screens for drugs and genes that selectively inhibit or increase transformation, but not proliferation. Such molecules are unlikely to be found through conventional drug screening, and they include kinase inhibitors and drugs for noncancer diseases. In addition to known oncogenes, the genetic screen identifies genes that contribute to cellular transformation. Lastly, we demonstrate the ability of Food and Drug Administration-approved noncancer drugs to selectively kill ovarian cancer cells derived from patients with chemotherapy-resistant disease, suggesting this approach may provide useful information for personalized cancer treatment. PMID:25902495

Alternative to the soft-agar assay that permits high-throughput drug and genetic screens for cellular transformation.

PubMed

Rotem, Asaf; Janzer, Andreas; Izar, Benjamin; Ji, Zhe; Doench, John G; Garraway, Levi A; Struhl, Kevin

2015-05-05

Colony formation in soft agar is the gold-standard assay for cellular transformation in vitro, but it is unsuited for high-throughput screening. Here, we describe an assay for cellular transformation that involves growth in low attachment (GILA) conditions and is strongly correlated with the soft-agar assay. Using GILA, we describe high-throughput screens for drugs and genes that selectively inhibit or increase transformation, but not proliferation. Such molecules are unlikely to be found through conventional drug screening, and they include kinase inhibitors and drugs for noncancer diseases. In addition to known oncogenes, the genetic screen identifies genes that contribute to cellular transformation. Lastly, we demonstrate the ability of Food and Drug Administration-approved noncancer drugs to selectively kill ovarian cancer cells derived from patients with chemotherapy-resistant disease, suggesting this approach may provide useful information for personalized cancer treatment.

FilTer BaSe: A web accessible chemical database for small compound libraries.

PubMed

Kolte, Baban S; Londhe, Sanjay R; Solanki, Bhushan R; Gacche, Rajesh N; Meshram, Rohan J

2018-03-01

Finding novel chemical agents for targeting disease associated drug targets often requires screening of large number of new chemical libraries. In silico methods are generally implemented at initial stages for virtual screening. Filtering of such compound libraries on physicochemical and substructure ground is done to ensure elimination of compounds with undesired chemical properties. Filtering procedure, is redundant, time consuming and requires efficient bioinformatics/computer manpower along with high end software involving huge capital investment that forms a major obstacle in drug discovery projects in academic setup. We present an open source resource, FilTer BaSe- a chemoinformatics platform (http://bioinfo.net.in/filterbase/) that host fully filtered, ready to use compound libraries with workable size. The resource also hosts a database that enables efficient searching the chemical space of around 348,000 compounds on the basis of physicochemical and substructure properties. Ready to use compound libraries and database presented here is expected to aid a helping hand for new drug developers and medicinal chemists. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation of Electronic Healthcare Databases for Post-Marketing Drug Safety Surveillance and Pharmacoepidemiology in China.

PubMed

Yang, Yu; Zhou, Xiaofeng; Gao, Shuangqing; Lin, Hongbo; Xie, Yanming; Feng, Yuji; Huang, Kui; Zhan, Siyan

2018-01-01

Electronic healthcare databases (EHDs) are used increasingly for post-marketing drug safety surveillance and pharmacoepidemiology in Europe and North America. However, few studies have examined the potential of these data sources in China. Three major types of EHDs in China (i.e., a regional community-based database, a national claims database, and an electronic medical records [EMR] database) were selected for evaluation. Forty core variables were derived based on the US Mini-Sentinel (MS) Common Data Model (CDM) as well as the data features in China that would be desirable to support drug safety surveillance. An email survey of these core variables and eight general questions as well as follow-up inquiries on additional variables was conducted. These 40 core variables across the three EHDs and all variables in each EHD along with those in the US MS CDM and Observational Medical Outcomes Partnership (OMOP) CDM were compared for availability and labeled based on specific standards. All of the EHDs' custodians confirmed their willingness to share their databases with academic institutions after appropriate approval was obtained. The regional community-based database contained 1.19 million people in 2015 with 85% of core variables. Resampled annually nationwide, the national claims database included 5.4 million people in 2014 with 55% of core variables, and the EMR database included 3 million inpatients from 60 hospitals in 2015 with 80% of core variables. Compared with MS CDM or OMOP CDM, the proportion of variables across the three EHDs available or able to be transformed/derived from the original sources are 24-83% or 45-73%, respectively. These EHDs provide potential value to post-marketing drug safety surveillance and pharmacoepidemiology in China. Future research is warranted to assess the quality and completeness of these EHDs or additional data sources in China.

Assessing the Effects of Non-steroidal Anti-inflammatory Drugs on Antihypertensive Drug Therapy Using Post-Marketing Surveillance Database

PubMed Central

Ishiguro, Chieko; Fujita, Toshiharu; Omori, Takashi; Fujii, Yosuke; Mayama, Takeshi; Sato, Tosiya

2008-01-01

Background Antihypertensive and non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat many common diseases. However, it has been suspected that interactions between these drugs exist. Here, we assessed the interactions between non-selective NSAIDs and several classes of antihypertensive drugs. Methods The study design was a cohort study using “The Antihypertensive Drug Database,” which is a collection of data accumulated from Drug Use Investigations. Subjects newly starting antihypertensive drug therapy were identified in the database. We compared the “User” group, who were co-administered NSAIDs, with the “Non-user” group, who were not. The outcome measure was the change in systolic blood pressure from the baseline after 2 months of treatment. We estimated the non-adjusted and adjusted differences in the change in systolic blood pressure between the “User” and “Non-user” groups. Results Data were collected for a total of 1,204 subjects, of whom 364 were prescribed beta blockers, 60 were prescribed diuretics, 628 were prescribed angiotensin-converting enzyme inhibitors, and 152 were prescribed calcium channel blockers. The adjusted difference in the change in systolic blood pressure between the User (n = 301) and Non-user (n = 903) groups was 2.88 mmHg (95% confidence interval: 0.89, 4.87); thus, systolic blood pressure in the Non-User group decreased further from the baseline than that in the User group. In subjects administered beta blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers, the corresponding differences were 0.37 mmHg (-3.24, 3.98), 6.11 mmHg (-3.16, 15.37), 3.85 mmHg (1.16, 6.66), and 3.50 mmHg (-2.03, 9.02). Conclusion The effectiveness of antihypertensive drugs was attenuated by the co-administration of NSAIDs. The differences in the effects of NSAIDs varied with different classes of antihypertensive drugs. PMID:18469490

Assessing the effects of non-steroidal anti-inflammatory drugs on antihypertensive drug therapy using post-marketing surveillance database.

PubMed

Ishiguro, Chieko; Fujita, Toshiharu; Omori, Takashi; Fujii, Yosuke; Mayama, Takeshi; Sato, Tosiya

2008-01-01

Antihypertensive and non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat many common diseases. However, it has been suspected that interactions between these drugs exist. Here, we assessed the interactions between non-selective NSAIDs and several classes of antihypertensive drugs. The study design was a cohort study using "The Antihypertensive Drug Database," which is a collection of data accumulated from Drug Use Investigations. Subjects newly starting antihypertensive drug therapy were identified in the database. We compared the "User" group, who were co-administered NSAIDs, with the "Non-user" group, who were not. The outcome measure was the change in systolic blood pressure from the baseline after 2 months of treatment. We estimated the non-adjusted and adjusted differences in the change in systolic blood pressure between the "User" and "Non-user" groups. Data were collected for a total of 1,204 subjects, of whom 364 were prescribed beta blockers, 60 were prescribed diuretics, 628 were prescribed angiotensin-converting enzyme inhibitors, and 152 were prescribed calcium channel blockers. The adjusted difference in the change in systolic blood pressure between the User (n = 301) and Non-user (n = 903) groups was 2.88 mmHg (95% confidence interval: 0.89, 4.87); thus, systolic blood pressure in the Non-User group decreased further from the baseline than that in the User group. In subjects administered beta blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium channel blockers, the corresponding differences were 0.37 mmHg (-3.24, 3.98), 6.11 mmHg (-3.16, 15.37), 3.85 mmHg (1.16, 6.66), and 3.50 mmHg (-2.03, 9.02). The effectiveness of antihypertensive drugs was attenuated by the co-administration of NSAIDs. The differences in the effects of NSAIDs varied with different classes of antihypertensive drugs.

Large-scale annotation of small-molecule libraries using public databases.

PubMed

Zhou, Yingyao; Zhou, Bin; Chen, Kaisheng; Yan, S Frank; King, Frederick J; Jiang, Shumei; Winzeler, Elizabeth A

2007-01-01

While many large publicly accessible databases provide excellent annotation for biological macromolecules, the same is not true for small chemical compounds. Commercial data sources also fail to encompass an annotation interface for large numbers of compounds and tend to be cost prohibitive to be widely available to biomedical researchers. Therefore, using annotation information for the selection of lead compounds from a modern day high-throughput screening (HTS) campaign presently occurs only under a very limited scale. The recent rapid expansion of the NIH PubChem database provides an opportunity to link existing biological databases with compound catalogs and provides relevant information that potentially could improve the information garnered from large-scale screening efforts. Using the 2.5 million compound collection at the Genomics Institute of the Novartis Research Foundation (GNF) as a model, we determined that approximately 4% of the library contained compounds with potential annotation in such databases as PubChem and the World Drug Index (WDI) as well as related databases such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) and ChemIDplus. Furthermore, the exact structure match analysis showed 32% of GNF compounds can be linked to third party databases via PubChem. We also showed annotations such as MeSH (medical subject headings) terms can be applied to in-house HTS databases in identifying signature biological inhibition profiles of interest as well as expediting the assay validation process. The automated annotation of thousands of screening hits in batch is becoming feasible and has the potential to play an essential role in the hit-to-lead decision making process.

Phenotypic Screening Approaches to Develop Aurora Kinase Inhibitors: Drug Discovery Perspectives.

PubMed

Marugán, Carlos; Torres, Raquel; Lallena, María José

2015-01-01

Targeting mitotic regulators as a strategy to fight cancer implies the development of drugs against key proteins, such as Aurora-A and -B. Current drugs, which target mitosis through a general mechanism of action (stabilization/destabilization of microtubules), have several side effects (neutropenia, alopecia, and emesis). Pharmaceutical companies aim at avoiding these unwanted effects by generating improved and selective drugs that increase the quality of life of the patients. However, the development of these drugs is an ambitious task that involves testing thousands of compounds through biochemical and cell-based assays. In addition, molecules usually target complex biological processes, involving several proteins and different molecular pathways, further emphasizing the need for high-throughput screening techniques and multiplexing technologies in order to identify drugs with the desired phenotype. We will briefly describe two multiplexing technologies [high-content imaging (HCI) and flow cytometry] and two key processes for drug discovery research (assay development and validation) following our own published industry quality standards. We will further focus on HCI as a useful tool for phenotypic screening and will provide a concrete example of HCI assay to detect Aurora-A or -B selective inhibitors discriminating the off-target effects related to the inhibition of other cell cycle or non-cell cycle key regulators. Finally, we will describe other assays that can help to characterize the in vitro pharmacology of the inhibitors.

FERN Ethnomedicinal Plant Database: Exploring Fern Ethnomedicinal Plants Knowledge for Computational Drug Discovery.

PubMed

Thakar, Sambhaji B; Ghorpade, Pradnya N; Kale, Manisha V; Sonawane, Kailas D

2015-01-01

Fern plants are known for their ethnomedicinal applications. Huge amount of fern medicinal plants information is scattered in the form of text. Hence, database development would be an appropriate endeavor to cope with the situation. So by looking at the importance of medicinally useful fern plants, we developed a web based database which contains information about several group of ferns, their medicinal uses, chemical constituents as well as protein/enzyme sequences isolated from different fern plants. Fern ethnomedicinal plant database is an all-embracing, content management web-based database system, used to retrieve collection of factual knowledge related to the ethnomedicinal fern species. Most of the protein/enzyme sequences have been extracted from NCBI Protein sequence database. The fern species, family name, identification, taxonomy ID from NCBI, geographical occurrence, trial for, plant parts used, ethnomedicinal importance, morphological characteristics, collected from various scientific literatures and journals available in the text form. NCBI's BLAST, InterPro, phylogeny, Clustal W web source has also been provided for the future comparative studies. So users can get information related to fern plants and their medicinal applications at one place. This Fern ethnomedicinal plant database includes information of 100 fern medicinal species. This web based database would be an advantageous to derive information specifically for computational drug discovery, botanists or botanical interested persons, pharmacologists, researchers, biochemists, plant biotechnologists, ayurvedic practitioners, doctors/pharmacists, traditional medicinal users, farmers, agricultural students and teachers from universities as well as colleges and finally fern plant lovers. This effort would be useful to provide essential knowledge for the users about the adventitious applications for drug discovery, applications, conservation of fern species around the world and finally to create

A choice-based screening method for compulsive drug users in rats.

PubMed

Lenoir, Magalie; Augier, Eric; Vouillac, Caroline; Ahmed, Serge H

2013-07-01

We describe a protocol for screening compulsive drug users among cocaine self-administering rats, the most frequently used animal model in addiction research. Rats are first trained on several alternating days to self-administer either cocaine (i.v.) or saccharin-sweetened water (by mouth)--a potent, albeit nonessential, nondrug reward. Then rats are allowed to choose between the two rewards over several days until the preference stabilizes. Most rats choose to stop using cocaine and pursue the alternative reward. Only a minority of Wistar strain rats (generally 15%) persist in taking the drug, regardless of the severity of past cocaine use and even when made hungry and offered the possibility to relieve their physiological need. Persistence of cocaine use in the face of a high-stakes choice is a core defining feature of compulsion. This choice-based screening method for compulsive drug users is easy to implement, has several important applications, and compares well with other methods in the field. 2013 by John Wiley & Sons, Inc.

Miniature Short Hairpin RNA Screens to Characterize Antiproliferative Drugs

PubMed Central

Kittanakom, Saranya; Arnoldo, Anthony; Brown, Kevin R.; Wallace, Iain; Kunavisarut, Tada; Torti, Dax; Heisler, Lawrence E.; Surendra, Anuradha; Moffat, Jason; Giaever, Guri; Nislow, Corey

2013-01-01

The application of new proteomics and genomics technologies support a view in which few drugs act solely by inhibiting a single cellular target. Indeed, drug activity is modulated by complex, often incompletely understood cellular mechanisms. Therefore, efforts to decipher mode of action through genetic perturbation such as RNAi typically yields “hits” that fall into several categories. Of particular interest to the present study, we aimed to characterize secondary activities of drugs on cells. Inhibiting a known target can result in clinically relevant synthetic phenotypes. In one scenario, drug perturbation could, for example, improperly activate a protein that normally inhibits a particular kinase. In other cases, additional, lower affinity targets can be inhibited as in the example of inhibition of c-Kit observed in Bcr-Abl−positive cells treated with Gleevec. Drug transport and metabolism also play an important role in the way any chemicals act within the cells. Finally, RNAi per se can also affect cell fitness by more general off-target effects, e.g., via the modulation of apoptosis or DNA damage repair. Regardless of the root cause of these unwanted effects, understanding the scope of a drug’s activity and polypharmacology is essential for better understanding its mechanism(s) of action, and such information can guide development of improved therapies. We describe a rapid, cost-effective approach to characterize primary and secondary effects of small-molecules by using small-scale libraries of virally integrated short hairpin RNAs. We demonstrate this principle using a “minipool” composed of shRNAs that target the genes encoding the reported protein targets of approved drugs. Among the 28 known reported drug−target pairs, we successfully identify 40% of the targets described in the literature and uncover several unanticipated drug−target interactions based on drug-induced synthetic lethality. We provide a detailed protocol for performing such

The development of high-content screening (HCS) technology and its importance to drug discovery.

PubMed

Fraietta, Ivan; Gasparri, Fabio

2016-01-01

High-content screening (HCS) was introduced about twenty years ago as a promising analytical approach to facilitate some critical aspects of drug discovery. Its application has spread progressively within the pharmaceutical industry and academia to the point that it today represents a fundamental tool in supporting drug discovery and development. Here, the authors review some of significant progress in the HCS field in terms of biological models and assay readouts. They highlight the importance of high-content screening in drug discovery, as testified by its numerous applications in a variety of therapeutic areas: oncology, infective diseases, cardiovascular and neurodegenerative diseases. They also dissect the role of HCS technology in different phases of the drug discovery pipeline: target identification, primary compound screening, secondary assays, mechanism of action studies and in vitro toxicology. Recent advances in cellular assay technologies, such as the introduction of three-dimensional (3D) cultures, induced pluripotent stem cells (iPSCs) and genome editing technologies (e.g., CRISPR/Cas9), have tremendously expanded the potential of high-content assays to contribute to the drug discovery process. Increasingly predictive cellular models and readouts, together with the development of more sophisticated and affordable HCS readers, will further consolidate the role of HCS technology in drug discovery.

Chloroplast 2010: A Database for Large-Scale Phenotypic Screening of Arabidopsis Mutants1[W][OA

PubMed Central

Lu, Yan; Savage, Linda J.; Larson, Matthew D.; Wilkerson, Curtis G.; Last, Robert L.

2011-01-01

Large-scale phenotypic screening presents challenges and opportunities not encountered in typical forward or reverse genetics projects. We describe a modular database and laboratory information management system that was implemented in support of the Chloroplast 2010 Project, an Arabidopsis (Arabidopsis thaliana) reverse genetics phenotypic screen of more than 5,000 mutants (http://bioinfo.bch.msu.edu/2010_LIMS; www.plastid.msu.edu). The software and laboratory work environment were designed to minimize operator error and detect systematic process errors. The database uses Ruby on Rails and Flash technologies to present complex quantitative and qualitative data and pedigree information in a flexible user interface. Examples are presented where the database was used to find opportunities for process changes that improved data quality. We also describe the use of the data-analysis tools to discover mutants defective in enzymes of leucine catabolism (heteromeric mitochondrial 3-methylcrotonyl-coenzyme A carboxylase [At1g03090 and At4g34030] and putative hydroxymethylglutaryl-coenzyme A lyase [At2g26800]) based upon a syndrome of pleiotropic seed amino acid phenotypes that resembles previously described isovaleryl coenzyme A dehydrogenase (At3g45300) mutants. In vitro assay results support the computational annotation of At2g26800 as hydroxymethylglutaryl-coenzyme A lyase. PMID:21224340

[Drug using risks screening in primary care patients using the ASSIST test: Cross sectional study].

PubMed

López-Rodríguez, Juan A; Rigabert, Alina; Gómez Llano, M Nieves; Rubio, Gabriel

2018-03-15

The aim of this study is to estimate risky-drug use patterns of consumption of primary care patients. Multicentric descriptive cross-sectional study. five primary health care centers of the South of Madrid. all patients between 16-100 year-old consulting with their family physician. Spanish-validated World Health Organization ASSIST test was use to screen risky drug use in primary care. Total points scored at the test were obtained. A sum of 441 screening test were collected. Mean age was 51,3 years and 51.6% of patients presented a moderate-severe risky drug use out of the nine drugs tested. The more frequent drug use screened were tobacco (41.7%) followed by alcohol (15.4%), hypnotics (13.7%) and cannabis (5.7%). Differences were found between genders in the patterns: men had higher risky drug uses compared to women regarding alcohol and cannabis. Women had higher sedatives/hypnotics consumption prevalence. A 16% of patients presented with polyconsumption drug use patterns. There is risk derived from drug misuse in primary care for tobacco, alcohol, hypnotics and cannabis as detected by the ASSIST test. There is a higher rate of hypnotics than expected. Copyright © 2018 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.

AIDSinfo Drug Database

MedlinePlus

... HIV/AIDS-related drugs for that condition. OK Filters Approval: What's this? FDA-Approved Investigational Class: What's ... Encephalitis Tuberculosis Varicella-Zoster Virus Diseases Update Loading... Filter by approval status, drug class, and condition Browse ...

Construction of a database for published phase II/III drug intervention clinical trials for the period 2009-2014 comprising 2,326 records, 90 disease categories, and 939 drug entities.

PubMed

Jeong, Sohyun; Han, Nayoung; Choi, Boyoon; Sohn, Minji; Song, Yun-Kyoung; Chung, Myeon-Woo; Na, Han-Sung; Ji, Eunhee; Kim, Hyunah; Rhew, Ki Yon; Kim, Therasa; Kim, In-Wha; Oh, Jung Mi

2016-06-01

To construct a database of published clinical drug trials suitable for use 1) as a research tool in accessing clinical trial information and 2) in evidence-based decision-making by regulatory professionals, clinical research investigators, and medical practitioners. Comprehensive information obtained from a search of design elements and results of clinical trials in peer reviewed journals using PubMed (http://www.ncbi.nlm.ih.gov/pubmed). The methodology to develop a structured database was devised by a panel composed of experts in medical, pharmaceutical, information technology, and members of Ministry of Food and Drug Safety (MFDS) using a step by step approach. A double-sided system consisting of user mode and manager mode served as the framework for the database; elements of interest from each trial were entered via secure manager mode enabling the input information to be accessed in a user-friendly manner (user mode). Information regarding methodology used and results of drug treatment were extracted as detail elements of each data set and then inputted into the web-based database system. Comprehensive information comprising 2,326 clinical trial records, 90 disease states, and 939 drugs entities and concerning study objectives, background, methods used, results, and conclusion could be extracted from published information on phase II/III drug intervention clinical trials appearing in SCI journals within the last 10 years. The extracted data was successfully assembled into a clinical drug trial database with easy access suitable for use as a research tool. The clinically most important therapeutic categories, i.e., cancer, cardiovascular, respiratory, neurological, metabolic, urogenital, gastrointestinal, psychological, and infectious diseases were covered by the database. Names of test and control drugs, details on primary and secondary outcomes and indexed keywords could also be retrieved and built into the database. The construction used in the database

SuperNatural: a searchable database of available natural compounds

PubMed Central

Dunkel, Mathias; Fullbeck, Melanie; Neumann, Stefanie; Preissner, Robert

2006-01-01

Although tremendous effort has been put into synthetic libraries, most drugs on the market are still natural compounds or derivatives thereof. There are encyclopaedias of natural compounds, but the availability of these compounds is often unclear and catalogues from numerous suppliers have to be checked. To overcome these problems we have compiled a database of ∼50 000 natural compounds from different suppliers. To enable efficient identification of the desired compounds, we have implemented substructure searches with typical templates. Starting points for in silico screenings are about 2500 well-known and classified natural compounds from a compendium that we have added. Possible medical applications can be ascertained via automatic searches for similar drugs in a free conformational drug database containing WHO indications. Furthermore, we have computed about three million conformers, which are deployed to account for the flexibilities of the compounds when the 3D superposition algorithm that we have developed is used. The SuperNatural Database is publicly available at . Viewing requires the free Chime-plugin from MDL (Chime) or Java2 Runtime Environment (MView), which is also necessary for using Marvin application for chemical drawing. PMID:16381957

SuperNatural: a searchable database of available natural compounds.

PubMed

Dunkel, Mathias; Fullbeck, Melanie; Neumann, Stefanie; Preissner, Robert

2006-01-01

Although tremendous effort has been put into synthetic libraries, most drugs on the market are still natural compounds or derivatives thereof. There are encyclopaedias of natural compounds, but the availability of these compounds is often unclear and catalogues from numerous suppliers have to be checked. To overcome these problems we have compiled a database of approximately 50,000 natural compounds from different suppliers. To enable efficient identification of the desired compounds, we have implemented substructure searches with typical templates. Starting points for in silico screenings are about 2500 well-known and classified natural compounds from a compendium that we have added. Possible medical applications can be ascertained via automatic searches for similar drugs in a free conformational drug database containing WHO indications. Furthermore, we have computed about three million conformers, which are deployed to account for the flexibilities of the compounds when the 3D superposition algorithm that we have developed is used. The SuperNatural Database is publicly available at http://bioinformatics.charite.de/supernatural. Viewing requires the free Chime-plugin from MDL (Chime) or Java2 Runtime Environment (MView), which is also necessary for using Marvin application for chemical drawing.

Application of the stochastic tunneling method to high throughput database screening

NASA Astrophysics Data System (ADS)

Merlitz, H.; Burghardt, B.; Wenzel, W.

2003-03-01

The stochastic tunneling technique is applied to screen a database of chemical compounds to the active site of dihydrofolate reductase for lead candidates in the receptor-ligand docking problem. Using an atomistic force field we consider the ligand's internal rotational degrees of freedom. It is shown that the natural ligand (methotrexate) scores best among 10 000 randomly chosen compounds. We analyze the top scoring compounds to identify hot-spots of the receptor. We mutate the amino acids that are responsible for the hot-spots of the receptor and verify that its specificity is lost upon modification.

PubChem BioAssay: A Decade's Development toward Open High-Throughput Screening Data Sharing.

PubMed

Wang, Yanli; Cheng, Tiejun; Bryant, Stephen H

2017-07-01

High-throughput screening (HTS) is now routinely conducted for drug discovery by both pharmaceutical companies and screening centers at academic institutions and universities. Rapid advance in assay development, robot automation, and computer technology has led to the generation of terabytes of data in screening laboratories. Despite the technology development toward HTS productivity, fewer efforts were devoted to HTS data integration and sharing. As a result, the huge amount of HTS data was rarely made available to the public. To fill this gap, the PubChem BioAssay database ( https://www.ncbi.nlm.nih.gov/pcassay/ ) was set up in 2004 to provide open access to the screening results tested on chemicals and RNAi reagents. With more than 10 years' development and contributions from the community, PubChem has now become the largest public repository for chemical structures and biological data, which provides an information platform to worldwide researchers supporting drug development, medicinal chemistry study, and chemical biology research. This work presents a review of the HTS data content in the PubChem BioAssay database and the progress of data deposition to stimulate knowledge discovery and data sharing. It also provides a description of the database's data standard and basic utilities facilitating information access and use for new users.

Discovery of novel drug targets and their functions using phenotypic screening of natural products.

PubMed

Chang, Junghwa; Kwon, Ho Jeong

2016-03-01

Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

Cardiac Arrhythmia: In vivo screening in the zebrafish to overcome complexity in drug discovery.

PubMed

Macrae, Calum A

2010-07-01

IMPORTANCE OF THE FIELD: Cardiac arrhythmias remain a major challenge for modern drug discovery. Clinical events are paroxysmal, often rare and may be asymptomatic until a highly morbid complication. Target selection is often based on limited information and though highly specific agents are identified in screening, the final efficacy is often compromised by unanticipated systemic responses, a narrow therapeutic index and substantial toxicities. AREAS COVERED IN THIS REVIEW: Our understanding of complexity of arrhythmogenesis has grown dramatically over the last two decades, and the range of potential disease mechanisms now includes pathways previously thought only tangentially involved in arrhythmia. This review surveys the literature on arrhythmia mechanisms from 1965 to the present day, outlines the complex biology underlying potentially each and every rhythm disturbance, and highlights the problems for rational target identification. The rationale for in vivo screening is described and the utility of the zebrafish for this approach and for complementary work in functional genomics is discussed. Current limitations of the model in this setting and the need for careful validation in new disease areas are also described. WHAT THE READER WILL GAIN: An overview of the complex mechanisms underlying most clinical arrhythmias, and insight into the limits of ion channel conductances as drug targets. An introduction to the zebrafish as a model organism, in particular for cardiovascular biology. Potential approaches to overcoming the hurdles to drug discovery in the face of complex biology including in vivo screening of zebrafish genetic disease models. TAKE HOME MESSAGE: In vivo screening in faithful disease models allows the effects of drugs on integrative physiology and disease biology to be captured during the screening process, in a manner agnostic to potential drug target or targets. This systematic strategy bypasses current gaps in our understanding of disease

Incomplete evidence: the inadequacy of databases in tracing published adverse drug reactions in clinical trials

PubMed Central

Derry, Sheena; Kong Loke, Yoon; Aronson, Jeffrey K

2001-01-01

Background We would expect information on adverse drug reactions in randomised clinical trials to be easily retrievable from specific searches of electronic databases. However, complete retrieval of such information may not be straightforward, for two reasons. First, not all clinical drug trials provide data on the frequency of adverse effects. Secondly, not all electronic records of trials include terms in the abstract or indexing fields that enable us to select those with adverse effects data. We have determined how often automated search methods, using indexing terms and/or textwords in the title or abstract, would fail to retrieve trials with adverse effects data. Methods We used a sample set of 107 trials known to report frequencies of adverse drug effects, and measured the proportion that (i) were not assigned the appropriate adverse effects indexing terms in the electronic databases, and (ii) did not contain identifiable adverse effects textwords in the title or abstract. Results Of the 81 trials with records on both MEDLINE and EMBASE, 25 were not indexed for adverse effects in either database. Twenty-six trials were indexed in one database but not the other. Only 66 of the 107 trials reporting adverse effects data mentioned this in the abstract or title of the paper. Simultaneous use of textword and indexing terms retrieved only 82/107 (77%) papers. Conclusions Specific search strategies based on adverse effects textwords and indexing terms will fail to identify nearly a quarter of trials that report on the rate of drug adverse effects. PMID:11591220

Multiple target drug cocktail design for attacking the core network markers of four cancers using ligand-based and structure-based virtual screening methods

PubMed Central

2015-01-01

Background Computer-aided drug design has a long history of being applied to discover new molecules to treat various cancers, but it has always been focused on single targets. The development of systems biology has let scientists reveal more hidden mechanisms of cancers, but attempts to apply systems biology to cancer therapies remain at preliminary stages. Our lab has successfully developed various systems biology models for several cancers. Based on these achievements, we present the first attempt to combine multiple-target therapy with systems biology. Methods In our previous study, we identified 28 significant proteins--i.e., common core network markers--of four types of cancers as house-keeping proteins of these cancers. In this study, we ranked these proteins by summing their carcinogenesis relevance values (CRVs) across the four cancers, and then performed docking and pharmacophore modeling to do virtual screening on the NCI database for anti-cancer drugs. We also performed pathway analysis on these proteins using Panther and MetaCore to reveal more mechanisms of these cancer house-keeping proteins. Results We designed several approaches to discover targets for multiple-target cocktail therapies. In the first one, we identified the top 20 drugs for each of the 28 cancer house-keeping proteins, and analyzed the docking pose to further understand the interaction mechanisms of these drugs. After screening for duplicates, we found that 13 of these drugs could target 11 proteins simultaneously. In the second approach, we chose the top 5 proteins with the highest summed CRVs and used them as the drug targets. We built a pharmacophore and applied it to do virtual screening against the Life-Chemical library for anti-cancer drugs. Based on these results, wet-lab bio-scientists could freely investigate combinations of these drugs for multiple-target therapy for cancers, in contrast to the traditional single target therapy. Conclusions Combination of systems biology

Screening mutations in drug-resistant Mycobacterium tuberculosis strains in Yunnan, China.

PubMed

Li, Daoqun; Song, Yuzhu; Zhang, Cheng-Lin; Li, Xiaofei; Xia, Xueshan; Zhang, A-Mei

Drug-resistant tuberculosis (DR-TB), especially multidrug-resistant tuberculosis (MDR-TB), is a serious medical and societal problem in China. The purpose of this study was to evaluate the mutation characteristics of drug-resistant Mycobacterium tuberculosis (M. tuberculosis) isolates in Yunnan, China. Drug susceptibility testing (DST) was performed in 523 clinical M. tuberculosis isolates. Six drug resistance genes (katG, inhA, rpoB, rpsL, embB, and pncA) were selected to screen for mutations. In total, 54 clinical M. tuberculosis strains were identified as drug-resistant by DST, including 18 single drug-resistant (SDR) strains and 36 multidrug-resistant (MDR) strains. Twenty-four types of mutations in five genes (excluding the inhA gene) were screened in forty-one strains. Six novel mutations were identified in this study, including three missense mutations (p.S302R in katG, p.D78G in embB, and p.M1I in pncA), two frameshift mutations (408 ins A and 538-580 del in pncA), and one mutation in a control region (-6 C>T located upstream of rpsL). The mutation frequencies in the hotspot mutation regions in the katG, rpoB, rpsL, embB, and pncA genes were 92.5%, 44.4%, 54.2%, 52.6%, and 37.5%, respectively. The mutation spectra and frequencies seemed somewhat unique in the Yunnan DR-TB strains. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: a structure-based drug designing approach.

PubMed

Kesharwani, Rajesh Kumar; Singh, Durg Vijay; Misra, Krishna

2013-01-01

Cysteine proteases (falcipains), a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64) and leupeptin respectively were retrieved from protein data bank (PDB) and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in case of falcipain-III, 15 designed leupeptin analogues having

A Drug Discovery Partnership for Personalized Breast Cancer Therapy

DTIC Science & Technology

2015-09-01

antagonists) and then virtually screen the USDA Phytochemical, Chinese Herbal Medicine , and the FDA Marketed Drug Databases for new estrogens. Task 1...and antagonists that are in the registered pharmaceuticals and herbal medicine databases. The 29 analogs obtained have been characterized for...Marleesa Bastian, Technician at Xavier University (Sridhar lab and is now pursuing graduation at Meharry Medical College school of Medicine , Tennessee

Evaluation of thromboembolic events in cancer patients receiving bevacizumab according to the Japanese Adverse Drug Event Report database.

PubMed

Matsumura, Chikako; Chisaki, Yugo; Sakimoto, Satoko; Sakae, Honoka; Yano, Yoshitaka

2018-01-01

Purpose We aimed to examine the risk factors, time of onset, incidence rates, and outcomes of thromboembolic events induced by bevacizumab in patients with cancer using the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceuticals and Medical Devices Agency. Methods Adverse event data recorded in the JADER database between January 2004 and January 2015 were used. After screening the data using the generic drug name bevacizumab, patient data were classified into two groups by age and five groups by cancer type. The histories of disorders were also categorized. Arterial thromboembolic event and venous thromboembolic event were classified as "favorable" or "unfavorable" outcomes. Results In total, 6076 patients were reported to have developed adverse events during the sample period, of which 233 and 453 developed arterial thromboembolic event and venous thromboembolic event, respectively. Logistic analysis suggested that the presence of cancer was a significant risk factor for both arterial thromboembolic event and venous thromboembolic event. Age (≥70 years), histories of either hypertension or diabetes mellitus were also risk factors for arterial thromboembolic event. Median cumulative times of onset for arterial thromboembolic event and venous thromboembolic event were 60 and 80 days, respectively, and were not significantly different by the log-rank test. By the chi-square test, the rate of unfavorable outcomes was found to be higher after developing arterial thromboembolic event than after venous thromboembolic event. Conclusion Thromboembolism is a leading cause of mortality in patients with cancer. Patients should be monitored for the symptoms of thromboembolic events right from the initial stages of bevacizumab treatment.

NMR screening in fragment-based drug design: a practical guide.

PubMed

Kim, Hai-Young; Wyss, Daniel F

2015-01-01

Fragment-based drug design (FBDD) comprises both fragment-based screening (FBS) to find hits and elaboration of these hits to lead compounds. Typical fragment hits have lower molecular weight (<300-350 Da) and lower initial potency but higher ligand efficiency when compared to those from high-throughput screening. NMR spectroscopy has been widely used for FBDD since it identifies and localizes the binding site of weakly interacting hits on the target protein. Here we describe ligand-based NMR methods for hit identification from fragment libraries and for functional cross-validation of primary hits.

Drug Repurposing Screening Identifies Novel Compounds That Effectively Inhibit Toxoplasma gondii Growth

PubMed Central

Dittmar, Ashley J.; Drozda, Allison A.

2016-01-01

ABSTRACT The urgent need to develop new antimicrobial therapies has spawned the development of repurposing screens in which well-studied drugs and other types of compounds are tested for potential off-label uses. As a proof-of-principle screen to identify compounds effective against Toxoplasma gondii, we screened a collection of 1,120 compounds for the ability to significantly reduce Toxoplasma replication. A total of 94 compounds blocked parasite replication with 50% inhibitory concentrations of <5 µM. A significant number of these compounds are established inhibitors of dopamine or estrogen signaling. Follow-up experiments with the dopamine receptor inhibitor pimozide revealed that the drug impacted both parasite invasion and replication but did so independently of inhibition of dopamine or other neurotransmitter receptor signaling. Tamoxifen, which is an established inhibitor of the estrogen receptor, also reduced parasite invasion and replication. Even though Toxoplasma can activate the estrogen receptor, tamoxifen inhibits parasite growth independently of this transcription factor. Tamoxifen is also a potent inducer of autophagy, and we find that the drug stimulates recruitment of the autophagy marker light chain 3-green fluorescent protein onto the membrane of the vacuolar compartment in which the parasite resides and replicates. In contrast to other antiparasitic drugs, including pimozide, tamoxifen treatment of infected cells leads to a time-dependent elimination of intracellular parasites. Taken together, these data suggest that tamoxifen restricts Toxoplasma growth by inducing xenophagy or autophagic destruction of this obligate intracellular parasite. IMPORTANCE There is an urgent need to develop new therapies to treat microbial infections, and the repurposing of well-characterized compounds is emerging as one approach to achieving this goal. Using the protozoan parasite Toxoplasma gondii, we screened a library of 1,120 compounds and identified several

Drug screening in medical examiner casework by high-resolution mass spectrometry (UPLC-MSE-TOF).

PubMed

Rosano, Thomas G; Wood, Michelle; Ihenetu, Kenneth; Swift, Thomas A

2013-10-01

Postmortem drug findings yield important analytical evidence in medical examiner casework, and chromatography coupled with nominal mass spectrometry (MS) serves as the predominant general unknown screening approach. We report screening by ultra performance liquid chromatography (UPLC) coupled with hybrid quadrupole time-of-flight mass spectrometer (MS(E)-TOF), with comparison to previously validated nominal mass UPLC-MS and UPLC-MS-MS methods. UPLC-MS(E)-TOF screening for over 950 toxicologically relevant drugs and metabolites was performed in a full-spectrum (m/z 50-1,000) mode using an MS(E) acquisition of both molecular and fragment ion data at low (6 eV) and ramped (10-40 eV) collision energies. Mass error averaged 1.27 ppm for a large panel of reference drugs and metabolites. The limit of detection by UPLC-MS(E)-TOF ranges from 0.5 to 100 ng/mL and compares closely with UPLC-MS-MS. The influence of column recovery and matrix effect on the limit of detection was demonstrated with ion suppression by matrix components correlating closely with early and late eluting reference analytes. Drug and metabolite findings by UPLC-MS(E)-TOF were compared with UPLC-MS and UPLC-MS-MS analyses of postmortem blood in 300 medical examiner cases. Positive findings by all methods totaled 1,528, with a detection rate of 57% by UPLC-MS, 72% by UPLC-MS-MS and 80% by combined UPLC-MS and UPLC-MS-MS screening. Compared with nominal mass screening methods, UPLC-MS(E)-TOF screening resulted in a 99% detection rate and, in addition, offered the potential for the detection of nontargeted analytes via high-resolution acquisition of molecular and fragment ion data.

Virtual screening of a milk peptide database for the identification of food-derived antimicrobial peptides.

PubMed

Liu, Yufang; Eichler, Jutta; Pischetsrieder, Monika

2015-11-01

Milk provides a wide range of bioactive substances, such as antimicrobial peptides and proteins. Our study aimed to identify novel antimicrobial peptides naturally present in milk. The components of an endogenous bovine milk peptide database were virtually screened for charge, amphipathy, and predicted secondary structure. Thus, 23 of 248 screened peptides were identified as candidates for antimicrobial effects. After commercial synthesis, their antimicrobial activities were determined against Escherichia coli NEB5α, E. coli ATCC25922, and Bacillus subtilis ATCC6051. In the tested concentration range (<2 mM), bacteriostatic activity of 14 peptides was detected including nine peptides inhibiting both Gram-positive and Gram-negative bacteria. The most effective fragment was TKLTEEEKNRLNFLKKISQRYQKFΑLPQYLK corresponding to αS2 -casein151-181 , with minimum inhibitory concentration (MIC) of 4.0 μM against B. subtilis ATCC6051, and minimum inhibitory concentrations of 16.2 μM against both E. coli strains. Circular dichroism spectroscopy revealed conformational changes of most active peptides in a membrane-mimic environment, transitioning from an unordered to α-helical structure. Screening of food peptide databases by prediction tools is an efficient method to identify novel antimicrobial food-derived peptides. Milk-derived antimicrobial peptides may have potential use as functional food ingredients and help to understand the molecular mechanisms of anti-infective milk effects. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library

PubMed Central

Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G.; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10–20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library.

PubMed

Feng, Jie; Shi, Wanliang; Zhang, Shuo; Sullivan, David; Auwaerter, Paul G; Zhang, Ying

2016-01-01

Although currently recommended antibiotics for Lyme disease such as doxycycline or amoxicillin cure the majority of the patients, about 10-20% of patients treated for Lyme disease may experience lingering symptoms including fatigue, pain, or joint and muscle aches. Under experimental stress conditions such as starvation or antibiotic exposure, Borrelia burgdorferi can develop round body forms, which are a type of persister bacteria that appear resistant in vitro to customary first-line antibiotics for Lyme disease. To identify more effective drugs with activity against the round body form of B. burgdorferi, we established a round body persister model induced by exposure to amoxicillin (50 μg/ml) and then screened the Food and Drug Administration drug library consisting of 1581 drug compounds and also 22 drug combinations using the SYBR Green I/propidium iodide viability assay. We identified 23 drug candidates that have higher activity against the round bodies of B. burgdorferi than either amoxicillin or doxycycline. Eleven individual drugs scored better than metronidazole and tinidazole which have been previously described to be active against round bodies. In this amoxicillin-induced round body model, some drug candidates such as daptomycin and clofazimine also displayed enhanced activity which was similar to a previous screen against stationary phase B. burgdorferi persisters not exposure to amoxicillin. Additional candidate drugs active against round bodies identified include artemisinin, ciprofloxacin, nifuroxime, fosfomycin, chlortetracycline, sulfacetamide, sulfamethoxypyridazine and sulfathiozole. Two triple drug combinations had the highest activity against amoxicillin-induced round bodies and stationary phase B. burgdorferi persisters: artemisinin/cefoperazone/doxycycline and sulfachlorpyridazine/daptomycin/doxycycline. These findings confirm and extend previous findings that certain drug combinations have superior activity against B. burgdorferi

Evaluation of the on-site immunoassay drug-screening device Triage-TOX in routine forensic autopsy.

PubMed

Tominaga, Mariko; Michiue, Tomomi; Maeda, Hitoshi

2015-11-01

Instrumental identification of drugs with quantification is essential in forensic toxicology, while on-site immunoassay urinalysis drug-screening devices conveniently provide preliminary information when adequately used. However, suitable or sufficient urine specimens are not always available. The present study evaluated the efficacy of a new on-site immunoassay drug-screening device Triage-TOX (Alere Inc., San Diego, CA, USA), which has recently been developed to provide objective data on the one-step automated processor, using 51 urine and 19 pericardial fluid samples from 66 forensic autopsy cases, compared with Triage-Drug of Abuse (DOA) and Monitect-9. For benzodiazepines, the positive predictive value and specificity of Triage-TOX were higher than those of Triage-DOA; however, sensitivity was higher with Monitect-9, despite frequent false-positives. The results for the other drugs with the three devices also included a few false-negatives and false-positives. These observations indicate the applicability of Triage-TOX in preliminary drug screening using urine or alternative materials in routine forensic autopsy, when a possible false-negative is considered, especially for benzodiazepines, providing objective information; however, the combined use of another device such as Monitect-9 can help minimize misinterpretation prior to instrumental analysis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

[Drugs in pregnancy: study in the EFEMERIS database (2004 to 2008)].

PubMed

Hurault-Delarue, C; Lacroix, I; Vidal, S; Montastruc, J-L; Damase-Michel, C

2011-10-01

To analyze the evolution of drug prescriptions during pregnancy from 2004 to 2008 in Haute-Garonne (France) and the impact of recommendations concerning drugs in pregnancy sent by French health authorities (AFSSAPS) and French college of gynaecologists and obstetricians to health professionals during the period. This descriptive study of reimbursed drug prescriptions during pregnancy concerns women included in the EFEMERIS database who have given birth from July 1st, 2004 to June 30th, 2008. The health insurance service records of Haute-Garonne were used. Taking into account 2 subsequent delistings of drugs for reimbursement during the period, we observed a significant increase of reimbursed drug prescriptions dispensed to pregnant women (8.7 different substances for women who have given birth in 2004 and 9.4 in 2008). Vitamins, immunserums, immunoglobulins and homeopathy prescriptions have especially increased. Paracetamol, iron, folic acid and phloroglucinol were the most prescribed drugs during all the periods. Since 2004, EFEMERIS represents a monitoring centre for the prescription of reimbursed drugs to pregnant women. This analysis allowed to exhibit trends in prescription patterns. Most of the alerts or recommendations had a positive but limited impact. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

NC-TEST: noncontact thermal emissions screening technique for drug and alcohol detection

NASA Astrophysics Data System (ADS)

Prokoski, Francine J.

1997-01-01

Drug abuse is highly correlated with criminal behavior. The typical drug-using criminal commits hundreds of crimes per year. The crime rate cannot be significantly reduced without a reduction in the percentage of the population abusing drugs and alcohol. Accurate and timely estimation of that percentage is important for policy decisions concerning crime control, public health measures, allocation of intervention resources for prevention and treatment, projections of criminal justice needs, and the evaluation of policy effectiveness. Such estimation is particularly difficult because self reporting is unreliable; and physical testing has to date required blood or urine analysis which is expensive and invasive, with the result that too few people are tested. MIKOS Ltd. has developed a non-contact, passive technique with the potential for automatic, real- time screening for drug and alcohol use. The system utilizes thermal radiation which is spontaneously and continuously emitted by the human body. Facial thermal patterns and changes in patterns are correlated with standardized effects of specific drugs and alcohol. A portable system incorporating the collection and analysis technique can be used episodically to collect data for estimating drug and alcohol use by general unknown populations such as crowds at airports, or it can be used for repetitive routine screening of specific known groups such as airline pilots, military personnel, school children, or persons on probation or parole.

The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs.

PubMed

Marek, Gerard J; Day, Mark; Hudzik, Thomas J

2016-03-01

Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

NALDB: nucleic acid ligand database for small molecules targeting nucleic acid.

PubMed

Kumar Mishra, Subodh; Kumar, Amit

2016-01-01

Nucleic acid ligand database (NALDB) is a unique database that provides detailed information about the experimental data of small molecules that were reported to target several types of nucleic acid structures. NALDB is the first ligand database that contains ligand information for all type of nucleic acid. NALDB contains more than 3500 ligand entries with detailed pharmacokinetic and pharmacodynamic information such as target name, target sequence, ligand 2D/3D structure, SMILES, molecular formula, molecular weight, net-formal charge, AlogP, number of rings, number of hydrogen bond donor and acceptor, potential energy along with their Ki, Kd, IC50 values. All these details at single platform would be helpful for the development and betterment of novel ligands targeting nucleic acids that could serve as a potential target in different diseases including cancers and neurological disorders. With maximum 255 conformers for each ligand entry, our database is a multi-conformer database and can facilitate the virtual screening process. NALDB provides powerful web-based search tools that make database searching efficient and simplified using option for text as well as for structure query. NALDB also provides multi-dimensional advanced search tool which can screen the database molecules on the basis of molecular properties of ligand provided by database users. A 3D structure visualization tool has also been included for 3D structure representation of ligands. NALDB offers an inclusive pharmacological information and the structurally flexible set of small molecules with their three-dimensional conformers that can accelerate the virtual screening and other modeling processes and eventually complement the nucleic acid-based drug discovery research. NALDB can be routinely updated and freely available on bsbe.iiti.ac.in/bsbe/naldb/HOME.php. Database URL: http://bsbe.iiti.ac.in/bsbe/naldb/HOME.php. © The Author(s) 2016. Published by Oxford University Press.

NALDB: nucleic acid ligand database for small molecules targeting nucleic acid

PubMed Central

Kumar Mishra, Subodh; Kumar, Amit

2016-01-01

Nucleic acid ligand database (NALDB) is a unique database that provides detailed information about the experimental data of small molecules that were reported to target several types of nucleic acid structures. NALDB is the first ligand database that contains ligand information for all type of nucleic acid. NALDB contains more than 3500 ligand entries with detailed pharmacokinetic and pharmacodynamic information such as target name, target sequence, ligand 2D/3D structure, SMILES, molecular formula, molecular weight, net-formal charge, AlogP, number of rings, number of hydrogen bond donor and acceptor, potential energy along with their Ki, Kd, IC50 values. All these details at single platform would be helpful for the development and betterment of novel ligands targeting nucleic acids that could serve as a potential target in different diseases including cancers and neurological disorders. With maximum 255 conformers for each ligand entry, our database is a multi-conformer database and can facilitate the virtual screening process. NALDB provides powerful web-based search tools that make database searching efficient and simplified using option for text as well as for structure query. NALDB also provides multi-dimensional advanced search tool which can screen the database molecules on the basis of molecular properties of ligand provided by database users. A 3D structure visualization tool has also been included for 3D structure representation of ligands. NALDB offers an inclusive pharmacological information and the structurally flexible set of small molecules with their three-dimensional conformers that can accelerate the virtual screening and other modeling processes and eventually complement the nucleic acid-based drug discovery research. NALDB can be routinely updated and freely available on bsbe.iiti.ac.in/bsbe/naldb/HOME.php. Database URL: http://bsbe.iiti.ac.in/bsbe/naldb/HOME.php PMID:26896846

A Drug Discovery Partnership for Personalized Breast Cancer Therapy

DTIC Science & Technology

2014-09-01

agonists or antagonists) and then virtually screen the USDA Phytochemical, Chinese Herbal Medicine , and the FDA Marketed Drug Databases for new estrogens...the basis for potent ER agonists and antagonists that are in the registered pharmaceuticals and herbal medicine databases. The 29 analogs obtained...Tropical Medicine , “LINEs and SINEs differ in their retrotransposition requirements and cellular interactions” 6- Monday November 18, 2013, Dr. Anup

In vitro screening of 50 highly prescribed drugs for thiol adduct formation--comparison of potential for drug-induced toxicity and extent of adduct formation.

PubMed

Gan, Jinping; Ruan, Qian; He, Bing; Zhu, Mingshe; Shyu, Wen C; Humphreys, W Griffith

2009-04-01

Reactive metabolite formation has been associated with drug-induced liver, skin, and hematopoietic toxicity of many drugs that has resulted in serious clinical toxicity, leading to clinical development failure, black box warnings, or, in some cases, withdrawal from the market. In vitro and in vivo screening for reactive metabolite formation has been proposed and widely adopted in the pharmaceutical industry with the aim of minimizing the property and thus the risk of drug-induced toxicity (DIT). One of the most common screening methods is in vitro thiol trapping of reactive metabolites. Although it is well-documented that many hepatotoxins form thiol adducts, there is no literature describing the adduct formation potential of safer drugs that are widely used. The objective of this study was to quantitatively assess the thiol adduct formation potential of 50 drugs (10 associated with DIT and 40 not associated) and document apparent differences in adduct formation between toxic and safer drugs. Dansyl glutathione was used as a trapping agent to aid the quantitation of adducts following in vitro incubation of drugs with human liver microsomes in the presence and absence of NADPH. Metabolic turnover of these drugs was also monitored by LC/UV. Overall, 15 out of the 50 drugs screened formed detectable levels of thiol adducts. There were general trends toward more positive findings in the DIT group vs the non-DIT group. These trends became more marked when the relative amount of thiol adducts was taken into account and improved further when dose and total daily reactive metabolite burdens were considered. In conclusion, there appears to be a general trend between the extent of thiol adduct formation and the potential for DIT, which would support the preclinical measurement and minimization of the property through screening of thiol adduct formation as part of an overall discovery optimization paradigm.

Virtual screening methods as tools for drug lead discovery from large chemical libraries.

PubMed

Ma, X H; Zhu, F; Liu, X; Shi, Z; Zhang, J X; Yang, S Y; Wei, Y Q; Chen, Y Z

2012-01-01

Virtual screening methods have been developed and explored as useful tools for searching drug lead compounds from chemical libraries, including large libraries that have become publically available. In this review, we discussed the new developments in exploring virtual screening methods for enhanced performance in searching large chemical libraries, their applications in screening libraries of ~ 1 million or more compounds in the last five years, the difficulties in their applications, and the strategies for further improving these methods.

TIPdb: a database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan.

PubMed

Lin, Ying-Chi; Wang, Chia-Chi; Chen, Ih-Sheng; Jheng, Jhao-Liang; Li, Jih-Heng; Tung, Chun-Wei

2013-01-01

The unique geographic features of Taiwan are attributed to the rich indigenous and endemic plant species in Taiwan. These plants serve as resourceful bank for biologically active phytochemicals. Given that these plant-derived chemicals are prototypes of potential drugs for diseases, databases connecting the chemical structures and pharmacological activities may facilitate drug development. To enhance the utility of the data, it is desirable to develop a database of chemical compounds and corresponding activities from indigenous plants in Taiwan. A database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan was constructed. The database, TIPdb, is composed of a standardized format of published anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan. A browse function was implemented for users to browse the database in a taxonomy-based manner. Search functions can be utilized to filter records of interest by botanical name, part, chemical class, or compound name. The structured and searchable database TIPdb was constructed to serve as a comprehensive and standardized resource for anticancer, antiplatelet, and antituberculosis compounds search. The manually curated chemical structures and activities provide a great opportunity to develop quantitative structure-activity relationship models for the high-throughput screening of potential anticancer, antiplatelet, and antituberculosis drugs.

TIPdb: A Database of Anticancer, Antiplatelet, and Antituberculosis Phytochemicals from Indigenous Plants in Taiwan

PubMed Central

Lin, Ying-Chi; Wang, Chia-Chi; Chen, Ih-Sheng; Jheng, Jhao-Liang; Li, Jih-Heng; Tung, Chun-Wei

2013-01-01

The unique geographic features of Taiwan are attributed to the rich indigenous and endemic plant species in Taiwan. These plants serve as resourceful bank for biologically active phytochemicals. Given that these plant-derived chemicals are prototypes of potential drugs for diseases, databases connecting the chemical structures and pharmacological activities may facilitate drug development. To enhance the utility of the data, it is desirable to develop a database of chemical compounds and corresponding activities from indigenous plants in Taiwan. A database of anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan was constructed. The database, TIPdb, is composed of a standardized format of published anticancer, antiplatelet, and antituberculosis phytochemicals from indigenous plants in Taiwan. A browse function was implemented for users to browse the database in a taxonomy-based manner. Search functions can be utilized to filter records of interest by botanical name, part, chemical class, or compound name. The structured and searchable database TIPdb was constructed to serve as a comprehensive and standardized resource for anticancer, antiplatelet, and antituberculosis compounds search. The manually curated chemical structures and activities provide a great opportunity to develop quantitative structure-activity relationship models for the high-throughput screening of potential anticancer, antiplatelet, and antituberculosis drugs. PMID:23766708

Corifungin, a New Drug Lead against Naegleria, Identified from a High-Throughput Screen

PubMed Central

Debnath, Anjan; Tunac, Josefino B.; Galindo-Gómez, Silvia; Silva-Olivares, Angélica; Shibayama, Mineko

2012-01-01

Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. The drug of choice in treating PAM is the antifungal antibiotic amphotericin B, but its use is associated with severe adverse effects. Moreover, few patients treated with amphotericin B have survived PAM. Therefore, fast-acting and efficient drugs are urgently needed for the treatment of PAM. To facilitate drug screening for this pathogen, an automated, high-throughput screening methodology was developed and validated for the closely related species Naegleria gruberi. Five kinase inhibitors and an NF-kappaB inhibitor were hits identified in primary screens of three compound libraries. Most importantly for a preclinical drug discovery pipeline, we identified corifungin, a water-soluble polyene macrolide with a higher activity against Naegleria than that of amphotericin B. Transmission electron microscopy of N. fowleri trophozoites incubated with different concentrations of corifungin showed disruption of cytoplasmic and plasma membranes and alterations in mitochondria, followed by complete lysis of amebae. In vivo efficacy of corifungin in a mouse model of PAM was confirmed by an absence of detectable amebae in the brain and 100% survival of mice for 17 days postinfection for a single daily intraperitoneal dose of 9 mg/kg of body weight given for 10 days. The same dose of amphotericin B did not reduce ameba growth, and mouse survival was compromised. Based on these results, the U.S. FDA has approved orphan drug status for corifungin for the treatment of PAM. PMID:22869574

Performance Studies on Distributed Virtual Screening

PubMed Central

Krüger, Jens; de la Garza, Luis; Kohlbacher, Oliver; Nagel, Wolfgang E.

2014-01-01

Virtual high-throughput screening (vHTS) is an invaluable method in modern drug discovery. It permits screening large datasets or databases of chemical structures for those structures binding possibly to a drug target. Virtual screening is typically performed by docking code, which often runs sequentially. Processing of huge vHTS datasets can be parallelized by chunking the data because individual docking runs are independent of each other. The goal of this work is to find an optimal splitting maximizing the speedup while considering overhead and available cores on Distributed Computing Infrastructures (DCIs). We have conducted thorough performance studies accounting not only for the runtime of the docking itself, but also for structure preparation. Performance studies were conducted via the workflow-enabled science gateway MoSGrid (Molecular Simulation Grid). As input we used benchmark datasets for protein kinases. Our performance studies show that docking workflows can be made to scale almost linearly up to 500 concurrent processes distributed even over large DCIs, thus accelerating vHTS campaigns significantly. PMID:25032219

High Throughput Screening for Anti–Trypanosoma cruzi Drug Discovery

PubMed Central

Alonso-Padilla, Julio; Rodríguez, Ana

2014-01-01

The discovery of new therapeutic options against Trypanosoma cruzi, the causative agent of Chagas disease, stands as a fundamental need. Currently, there are only two drugs available to treat this neglected disease, which represents a major public health problem in Latin America. Both available therapies, benznidazole and nifurtimox, have significant toxic side effects and their efficacy against the life-threatening symptomatic chronic stage of the disease is variable. Thus, there is an urgent need for new, improved anti–T. cruzi drugs. With the objective to reliably accelerate the drug discovery process against Chagas disease, several advances have been made in the last few years. Availability of engineered reporter gene expressing parasites triggered the development of phenotypic in vitro assays suitable for high throughput screening (HTS) as well as the establishment of new in vivo protocols that allow faster experimental outcomes. Recently, automated high content microscopy approaches have also been used to identify new parasitic inhibitors. These in vitro and in vivo early drug discovery approaches, which hopefully will contribute to bring better anti–T. cruzi drug entities in the near future, are reviewed here. PMID:25474364

High throughput screening for anti-Trypanosoma cruzi drug discovery.

PubMed

Alonso-Padilla, Julio; Rodríguez, Ana

2014-12-01

The discovery of new therapeutic options against Trypanosoma cruzi, the causative agent of Chagas disease, stands as a fundamental need. Currently, there are only two drugs available to treat this neglected disease, which represents a major public health problem in Latin America. Both available therapies, benznidazole and nifurtimox, have significant toxic side effects and their efficacy against the life-threatening symptomatic chronic stage of the disease is variable. Thus, there is an urgent need for new, improved anti-T. cruzi drugs. With the objective to reliably accelerate the drug discovery process against Chagas disease, several advances have been made in the last few years. Availability of engineered reporter gene expressing parasites triggered the development of phenotypic in vitro assays suitable for high throughput screening (HTS) as well as the establishment of new in vivo protocols that allow faster experimental outcomes. Recently, automated high content microscopy approaches have also been used to identify new parasitic inhibitors. These in vitro and in vivo early drug discovery approaches, which hopefully will contribute to bring better anti-T. cruzi drug entities in the near future, are reviewed here.

Pharmacovigilance of drug allergy and hypersensitivity using the ENDA-DAHD database and the GALEN platform. The Galenda project.

PubMed

Bousquet, P-J; Demoly, P; Romano, A; Aberer, W; Bircher, A; Blanca, M; Brockow, K; Pichler, W; Torres, M J; Terreehorst, I; Arnoux, B; Atanaskovic-Markovic, M; Barbaud, A; Bijl, A; Bonadonna, P; Burney, P G; Caimmi, S; Canonica, G W; Cernadas, J; Dahlen, B; Daures, J-P; Fernandez, J; Gomes, E; Gueant, J-L; Kowalski, M L; Kvedariene, V; Mertes, P-M; Martins, P; Nizankowska-Mogilnicka, E; Papadopoulos, N; Ponvert, C; Pirmohamed, M; Ring, J; Salapatas, M; Sanz, M L; Szczeklik, A; Van Ganse, E; De Weck, A L; Zuberbier, T; Merk, H F; Sachs, B; Sidoroff, A

2009-02-01

Nonallergic hypersensitivity and allergic reactions are part of the many different types of adverse drug reactions (ADRs). Databases exist for the collection of ADRs. Spontaneous reporting makes up the core data-generating system of pharmacovigilance, but there is a large under-estimation of allergy/hypersensitivity drug reactions. A specific database is therefore required for drug allergy and hypersensitivity using standard operating procedures (SOPs), as the diagnosis of drug allergy/hypersensitivity is difficult and current pharmacovigilance algorithms are insufficient. Although difficult, the diagnosis of drug allergy/hypersensitivity has been standardized by the European Network for Drug Allergy (ENDA) under the aegis of the European Academy of Allergology and Clinical Immunology and SOPs have been published. Based on ENDA and Global Allergy and Asthma European Network (GA(2)LEN, EU Framework Programme 6) SOPs, a Drug Allergy and Hypersensitivity Database (DAHD((R))) has been established under FileMaker((R)) Pro 9. It is already available online in many different languages and can be accessed using a personal login. GA(2)LEN is a European network of 27 partners (16 countries) and 59 collaborating centres (26 countries), which can coordinate and implement the DAHD across Europe. The GA(2)LEN-ENDA-DAHD platform interacting with a pharmacovigilance network appears to be of great interest for the reporting of allergy/hypersensitivity ADRs in conjunction with other pharmacovigilance instruments.

Rapid screening of pharmaceutical drugs using thermal desorption - SALDI mass spectrometry

NASA Astrophysics Data System (ADS)

Grechnikov, A. A.; Kubasov, A. E.; Georgieva, V. B.; Borodkov, A. S.; Nikiforov, S. M.; Simanovsky, Ya O.; Alimpiev, S. S.

2012-12-01

A novel approach to the rapid screening of pharmaceutical drugs by surface assisted laser desorption-ionization (SALDI) mass spectrometry with the rotating ball interface coupled with temperature programmed thermal desorption has been developed. Analytes were thermally desorbed and deposited onto the surface of amorphous silicon substrate attached to the rotating ball. The ball was rotated and the deposited analytes were analyzed using SALDI. The effectiveness of coupling SALDI mass spectrometry with thermal desorption was evaluated by the direct and rapid analysis of tablets containing lidocaine, diphenhydramine and propranolol without any sample pretreatment. The overall duration of the screening procedure was 30÷40 sec. Real urine samples were studied for drug analysis. It is shown that with simple preparation steps, urine samples can be quantitatively analyzed using the proposed technique with the detection limits in the range of 0.2÷0.5 ng/ml.

Impact of a Brief Training on Medical Resident Screening for Alcohol Misuse and Illicit Drug Use

PubMed Central

Gunderson, Erik W.; Levin, Frances R.; Owen, Patricia

2011-01-01

Educational initiatives are needed to improve primary care substance use screening. This study assesses the impact on 24 medical residents of a 2.5-day curriculum combining experiential and manual-based training on screening for alcohol misuse and illicit drug use. A retrospective chart review of new primary care outpatients demonstrated that nearly all were asked about current alcohol use before and after curriculum participation. Adherence to national screening guidelines on quantification of alcohol consumption modestly improved (p < .05), as did inquiry about current illicit drug use (p < .05). Continued efforts are needed to enhance educational initiatives for primary care physicians. PMID:18393059

Impact of a brief training on medical resident screening for alcohol misuse and illicit drug use.

PubMed

Gunderson, Erik W; Levin, Frances R; Owen, Patricia

2008-01-01

Educational initiatives are needed to improve primary care substance use screening. This study assesses the impact on 24 medical residents of a 2.5-day curriculum combining experiential and manual-based training on screening for alcohol misuse and illicit drug use. A retrospective chart review of new primary care outpatients demonstrated that nearly all were asked about current alcohol use before and after curriculum participation. Adherence to national screening guidelines on quantification of alcohol consumption modestly improved (p < .05), as did inquiry about current illicit drug use (p < .05). Continued efforts are needed to enhance educational initiatives for primary care physicians.

[Validation of interaction databases in psychopharmacotherapy].

PubMed

Hahn, M; Roll, S C

2018-03-01

Drug-drug interaction databases are an important tool to increase drug safety in polypharmacy. There are several drug interaction databases available but it is unclear which one shows the best results and therefore increases safety for the user of the databases and the patients. So far, there has been no validation of German drug interaction databases. Validation of German drug interaction databases regarding the number of hits, mechanisms of drug interaction, references, clinical advice, and severity of the interaction. A total of 36 drug interactions which were published in the last 3-5 years were checked in 5 different databases. Besides the number of hits, it was also documented if the mechanism was correct, clinical advice was given, primary literature was cited, and the severity level of the drug-drug interaction was given. All databases showed weaknesses regarding the hit rate of the tested drug interactions, with a maximum of 67.7% hits. The highest score in this validation was achieved by MediQ with 104 out of 180 points. PsiacOnline achieved 83 points, arznei-telegramm® 58, ifap index® 54 and the ABDA-database 49 points. Based on this validation MediQ seems to be the most suitable databank for the field of psychopharmacotherapy. The best results in this comparison were achieved by MediQ but this database also needs improvement with respect to the hit rate so that the users can rely on the results and therefore increase drug therapy safety.

In silico modeling to predict drug-induced phospholipidosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov

2013-06-01

Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the constructionmore » and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ≥ 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. - Highlights: • New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. • The training set data in the models is derived from the FDA's phospholipidosis database. • We find excellent predictivity values of the models based on external validation. • The models can support drug screening and regulatory decision-making on DIPL.« less

A screen to identify drug resistant variants to target-directed anti-cancer agents

PubMed Central

Azam, Mohammad; Raz, Tal; Nardi, Valentina; Opitz, Sarah L.

2003-01-01

The discovery of oncogenes and signal transduction pathways important for mitogenesis has triggered the development of target-specific small molecule anti-cancer compounds. As exemplified by imatinib (Gleevec), a specific inhibitor of the Chronic Myeloid Leukemia (CML)-associated Bcr-Abl kinase, these agents promise impressive activity in clinical trials, with low levels of clinical toxicity. However, such therapy is susceptible to the emergence of drug resistance due to amino acid substitutions in the target protein. Defining the spectrum of such mutations is important for patient monitoring and the design of next-generation inhibitors. Using imatinib and BCR/ABL as a paradigm for a drug-target pair, we recently reported a retroviral vector-based screening strategy to identify the spectrum of resistance-conferring mutations. Here we provide a detailed methodology for the screen, which can be generally applied to any drug-target pair. PMID:14615817

An Automated System Combining Safety Signal Detection and Prioritization from Healthcare Databases: A Pilot Study.

PubMed

Arnaud, Mickael; Bégaud, Bernard; Thiessard, Frantz; Jarrion, Quentin; Bezin, Julien; Pariente, Antoine; Salvo, Francesco

2018-04-01

Signal detection from healthcare databases is possible, but is not yet used for routine surveillance of drug safety. One challenge is to develop methods for selecting signals that should be assessed with priority. The aim of this study was to develop an automated system combining safety signal detection and prioritization from healthcare databases and applicable to drugs used in chronic diseases. Patients present in the French EGB healthcare database for at least 1 year between 2005 and 2015 were considered. Noninsulin glucose-lowering drugs (NIGLDs) were selected as a case study, and hospitalization data were used to select important medical events (IME). Signal detection was performed quarterly from 2008 to 2015 using sequence symmetry analysis. NIGLD/IME associations were screened if one or more exposed case was identified in the quarter, and three or more exposed cases were identified in the population at the date of screening. Detected signals were prioritized using the Longitudinal-SNIP (L-SNIP) algorithm based on strength (S), novelty (N), and potential impact of signal (I), and pattern of drug use (P). Signals scored in the top 10% were identified as of high priority. A reference set was built based on NIGLD summaries of product characteristics (SPCs) to compute the performance of the developed system. A total of 815 associations were screened and 241 (29.6%) were detected as signals; among these, 58 (24.1%) were prioritized. The performance for signal detection was sensitivity = 47%; specificity = 80%; positive predictive value (PPV) 33%; negative predictive value = 82%. The use of the L-SNIP algorithm increased the early identification of positive controls, restricted to those mentioned in the SPCs after 2008: PPV = 100% versus PPV = 14% with its non-use. The system revealed a strong new signal with dipeptidylpeptidase-4 inhibitors and venous thromboembolism. The developed system seems promising for the routine use of healthcare data for safety

The drug discovery portal: a computational platform for identifying drug leads from academia.

PubMed

Clark, Rachel L; Johnston, Blair F; Mackay, Simon P; Breslin, Catherine J; Robertson, Murray N; Sutcliffe, Oliver B; Dufton, Mark J; Harvey, Alan L

2010-05-01

The Drug Discovery Portal (DDP) is a research initiative based at the University of Strathclyde in Glasgow, Scotland. It was initiated in 2007 by a group of researchers with expertise in virtual screening. Academic research groups in the university working in drug discovery programmes estimated there was a historical collection of physical compounds going back 50 years that had never been adequately catalogued. This invaluable resource has been harnessed to form the basis of the DDP library, and has attracted a high-percentage uptake from the Universities and Research Groups internationally. Its unique attributes include the diversity of the academic database, sourced from synthetic, medicinal and phytochemists working an academic laboratories and the ability to link biologists with appropriate chemical expertise through a target-matching virtual screening approach, and has resulted in seven emerging hit development programmes between international contributors.

Perinatal Illicit Drug and Marijuana Use: An Observational Study Examining Prevalence, Screening, and Disclosure

PubMed Central

Chang, Judy C.; Holland, Cynthia L.; Tarr, Jill A.; Rubio, Doris; Rodriguez, Keri L.; Kraemer, Kevin L.; Day, Nancy; Arnold, Robert M.

2016-01-01

Purpose To assess use, screening, and disclosure of perinatal marijuana and other illicit drugs during first obstetric visits. Design Observational study that qualitatively assesses provider screening and patient disclosure of substance use. Setting Study sites were five urban outpatient prenatal clinics and practices located in Pittsburgh, Pennsylvania. Participants Pregnant patients and obstetric providers were recruited as participants. Methods We audio recorded patient-provider conversations during first obstetric visits and obtained patient urine samples for drug analyses. Audio recordings were reviewed for provider screening and patient disclosure of illicit drug use. Urine analyses were compared with audio recordings to determine disclosure. Results Four hundred and twenty-two pregnant patients provided complete audio recordings and urine samples for analyses. Providers asked about illicit drug use in 81% of the visits. One hundred twenty-three patients (29%) disclosed any current or past illicit drug use; 48 patients (11%) disclosed current use of marijuana while pregnant. One hundred and forty-five samples (34%) tested positive for one or more substances; marijuana was most commonly detected (N = 114, 27%). Of patients who tested positive for any substance, 66 (46%) did not disclose any use; only 36% of patients who tested positive for marijuana disclosed current use. Conclusion Although marijuana is illegal in Pennsylvania, a high proportion of pregnant patients used marijuana, with many not disclosing use to their obstetric care providers. (Am J Health Promot 0000; 00[0]:000–000.) PMID:26559718

Urine benzodiazepines screening of involuntarily drugged and robbed or raped patients.

PubMed

Boussairi, A; Dupeyron, J P; Hernandez, B; Delaitre, D; Beugnet, L; Espinoza, P; Diamant-Berger, O

1996-01-01

This study involved 35 patients who claimed to have been drugged before being robbed or raped, despite urine negative toxicologic screening by immunoenzymatic methods. The urines were frozen for further investigations, including enzymatic hydrolysis of urinary conjugates, liquid-solid extraction and, finally, immunoenzymatic screening of concentrated urine extract. Urine benzodiazepines were analyzed by immunoenzymatic assay before and after enzymatic hydrolysis combined with extraction. On direct immunoenzymatic screening, 17 of the 35 urine samples were benzodiazepine positive. Enrichment of preserved specimens improved the detection threshold from 200 ng/mL to 50 ng/mL and 10 of the 18 negative urines became positive. This method allowed us to demonstrate the benzodiazepines in half of previously negative urine samples. Benzodiazepine screening is particularly problematic because of low dosage, rapid elimination, failure to detect conjugated metabolites by immunoenzymatic reagents and high threshold of sensitivity for certain substances.

Predicting Adverse Drug Effects from Literature- and Database-Mined Assertions.

PubMed

La, Mary K; Sedykh, Alexander; Fourches, Denis; Muratov, Eugene; Tropsha, Alexander

2018-06-06

Given that adverse drug effects (ADEs) have led to post-market patient harm and subsequent drug withdrawal, failure of candidate agents in the drug development process, and other negative outcomes, it is essential to attempt to forecast ADEs and other relevant drug-target-effect relationships as early as possible. Current pharmacologic data sources, providing multiple complementary perspectives on the drug-target-effect paradigm, can be integrated to facilitate the inference of relationships between these entities. This study aims to identify both existing and unknown relationships between chemicals (C), protein targets (T), and ADEs (E) based on evidence in the literature. Cheminformatics and data mining approaches were employed to integrate and analyze publicly available clinical pharmacology data and literature assertions interrelating drugs, targets, and ADEs. Based on these assertions, a C-T-E relationship knowledge base was developed. Known pairwise relationships between chemicals, targets, and ADEs were collected from several pharmacological and biomedical data sources. These relationships were curated and integrated according to Swanson's paradigm to form C-T-E triangles. Missing C-E edges were then inferred as C-E relationships. Unreported associations between drugs, targets, and ADEs were inferred, and inferences were prioritized as testable hypotheses. Several C-E inferences, including testosterone → myocardial infarction, were identified using inferences based on the literature sources published prior to confirmatory case reports. Timestamping approaches confirmed the predictive ability of this inference strategy on a larger scale. The presented workflow, based on free-access databases and an association-based inference scheme, provided novel C-E relationships that have been validated post hoc in case reports. With refinement of prioritization schemes for the generated C-E inferences, this workflow may provide an effective computational method for

Screening applications in drug discovery based on microfluidic technology

PubMed Central

Eribol, P.; Uguz, A. K.; Ulgen, K. O.

2016-01-01

Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays. PMID:26865904

Screening applications in drug discovery based on microfluidic technology.

PubMed

Eribol, P; Uguz, A K; Ulgen, K O

2016-01-01

Microfluidics has been the focus of interest for the last two decades for all the advantages such as low chemical consumption, reduced analysis time, high throughput, better control of mass and heat transfer, downsizing a bench-top laboratory to a chip, i.e., lab-on-a-chip, and many others it has offered. Microfluidic technology quickly found applications in the pharmaceutical industry, which demands working with leading edge scientific and technological breakthroughs, as drug screening and commercialization are very long and expensive processes and require many tests due to unpredictable results. This review paper is on drug candidate screening methods with microfluidic technology and focuses specifically on fabrication techniques and materials for the microchip, types of flow such as continuous or discrete and their advantages, determination of kinetic parameters and their comparison with conventional systems, assessment of toxicities and cytotoxicities, concentration generations for high throughput, and the computational methods that were employed. An important conclusion of this review is that even though microfluidic technology has been in this field for around 20 years there is still room for research and development, as this cutting edge technology requires ingenuity to design and find solutions for each individual case. Recent extensions of these microsystems are microengineered organs-on-chips and organ arrays.

Efficient method for high-throughput virtual screening based on flexible docking: discovery of novel acetylcholinesterase inhibitors.

PubMed

Mizutani, Miho Yamada; Itai, Akiko

2004-09-23

A method of easily finding ligands, with a variety of core structures, for a given target macromolecule would greatly contribute to the rapid identification of novel lead compounds for drug development. We have developed an efficient method for discovering ligand candidates from a number of flexible compounds included in databases, when the three-dimensional (3D) structure of the drug target is available. The method, named ADAM&EVE, makes use of our automated docking method ADAM, which has already been reported. Like ADAM, ADAM&EVE takes account of the flexibility of each molecule in databases, by exploring the conformational space fully and continuously. Database screening has been made much faster than with ADAM through the tuning of parameters, so that computational screening of several hundred thousand compounds is possible in a practical time. Promising ligand candidates can be selected according to various criteria based on the docking results and characteristics of compounds. Furthermore, we have developed a new tool, EVE-MAKE, for automatically preparing the additional compound data necessary for flexible docking calculation, prior to 3D database screening. Among several successful cases of lead discovery by ADAM&EVE, the finding of novel acetylcholinesterase (AChE) inhibitors is presented here. We performed a virtual screening of about 160 000 commercially available compounds against the X-ray crystallographic structure of AChE. Among 114 compounds that could be purchased and assayed, 35 molecules with various core structures showed inhibitory activities with IC(50) values less than 100 microM. Thirteen compounds had IC(50) values between 0.5 and 10 microM, and almost all their core structures are very different from those of known inhibitors. The results demonstrate the effectiveness and validity of the ADAM&EVE approach and provide a starting point for development of novel drugs to treat Alzheimer's disease.

Comparison of MDCK-MDR1 and Caco-2 cell based permeability assays for anti-malarial drug screening and drug investigations.

PubMed

Jin, Xiannu; Luong, Thu-Lan; Reese, Necole; Gaona, Heather; Collazo-Velez, Vanessa; Vuong, Chau; Potter, Brittney; Sousa, Jason C; Olmeda, Raul; Li, Qigui; Xie, Lisa; Zhang, Jing; Zhang, Ping; Reichard, Greg; Melendez, Victor; Marcsisin, Sean R; Pybus, Brandon S

2014-01-01

Malaria is a major health concern and affects over 300million people a year. Accordingly, there is an urgent need for new efficacious anti-malarial drugs. A major challenge in developing new anti-malarial drugs is to design active molecules that have preferable drug-like characteristics. These "drug-like" characteristics include physiochemical properties that affect drug absorption, distribution, metabolism, and excretion (ADME). Compounds with poor ADME profiles will likely fail in vivo due to poor pharmacokinetics and/or other drug delivery related issues. There have been numerous assays developed in order to pre-screen compounds that would likely fail in further development due to poor absorption properties including PAMPA, Caco-2, and MDCK permeability assays. The use of cell-based permeability assays such as Caco-2 and MDCK serve as surrogate indicators of drug absorption and transport, with the two approaches often used interchangeably. We sought to evaluate both approaches in support of anti-malarial drug development. Accordingly, a comparison of both assays was conducted utilizing apparent permeability coefficient (Papp) values determined from liquid chromatography/tandem mass spectrometry (LC-MS) analyses. Both Caco-2 and MDCK permeability assays produced similar Papp results for potential anti-malarial compounds with low and medium permeability. Differences were observed for compounds with high permeability and compounds that were P-gp substrates. Additionally, the utility of MDCK-MDR1 permeability measurements was demonstrated in probing the role of P-glycoprotein transport in Primaquine-Chloroquine drug-drug interactions in comparison with in vivo pharmacokinetic changes. This study provides an in-depth comparison of the Caco-2 and MDCK-MDR1 cell based permeability assays and illustrates the utility of cell-based permeability assays in anti-malarial drug screening/development in regard to understanding transporter mediated changes in drug absorption

Phynx: an open source software solution supporting data management and web-based patient-level data review for drug safety studies in the general practice research database and other health care databases.

PubMed

Egbring, Marco; Kullak-Ublick, Gerd A; Russmann, Stefan

2010-01-01

To develop a software solution that supports management and clinical review of patient data from electronic medical records databases or claims databases for pharmacoepidemiological drug safety studies. We used open source software to build a data management system and an internet application with a Flex client on a Java application server with a MySQL database backend. The application is hosted on Amazon Elastic Compute Cloud. This solution named Phynx supports data management, Web-based display of electronic patient information, and interactive review of patient-level information in the individual clinical context. This system was applied to a dataset from the UK General Practice Research Database (GPRD). Our solution can be setup and customized with limited programming resources, and there is almost no extra cost for software. Access times are short, the displayed information is structured in chronological order and visually attractive, and selected information such as drug exposure can be blinded. External experts can review patient profiles and save evaluations and comments via a common Web browser. Phynx provides a flexible and economical solution for patient-level review of electronic medical information from databases considering the individual clinical context. It can therefore make an important contribution to an efficient validation of outcome assessment in drug safety database studies.

Detecting signals of drug–drug interactions in a spontaneous reports database

PubMed Central

Thakrar, Bharat T; Grundschober, Sabine Borel; Doessegger, Lucette

2007-01-01

Aims The spontaneous reports database is widely used for detecting signals of ADRs. We have extended the methodology to include the detection of signals of ADRs that are associated with drug–drug interactions (DDI). In particular, we have investigated two different statistical assumptions for detecting signals of DDI. Methods Using the FDA's spontaneous reports database, we investigated two models, a multiplicative and an additive model, to detect signals of DDI. We applied the models to four known DDIs (methotrexate-diclofenac and bone marrow depression, simvastatin-ciclosporin and myopathy, ketoconazole-terfenadine and torsades de pointes, and cisapride-erythromycin and torsades de pointes) and to four drug-event combinations where there is currently no evidence of a DDI (fexofenadine-ketoconazole and torsades de pointes, methotrexade-rofecoxib and bone marrow depression, fluvastatin-ciclosporin and myopathy, and cisapride-azithromycine and torsade de pointes) and estimated the measure of interaction on the two scales. Results The additive model correctly identified all four known DDIs by giving a statistically significant (P< 0.05) positive measure of interaction. The multiplicative model identified the first two of the known DDIs as having a statistically significant or borderline significant (P< 0.1) positive measure of interaction term, gave a nonsignificant positive trend for the third interaction (P= 0.27), and a negative trend for the last interaction. Both models correctly identified the four known non interactions by estimating a negative measure of interaction. Conclusions The spontaneous reports database is a valuable resource for detecting signals of DDIs. In particular, the additive model is more sensitive in detecting such signals. The multiplicative model may further help qualify the strength of the signal detected by the additive model. PMID:17506784

Drug residues in urban water: A database for ecotoxicological risk management.

PubMed

Destrieux, Doriane; Laurent, François; Budzinski, Hélène; Pedelucq, Julie; Vervier, Philippe; Gerino, Magali

2017-12-31

Human-use drug residues (DR) are only partially eliminated by waste water treatment plants (WWTPs), so that residual amounts can reach natural waters and cause environmental hazards. In order to properly manage these hazards in the aquatic environment, a database is made available that integrates the concentration ranges for DR, which cause adverse effects for aquatic organisms, and the temporal variations of the ecotoxicological risks. To implement this database for the ecotoxicological risk assessment (ERA database), the required information for each DR is the predicted no effect concentrations (PNECs), along with the predicted environmental concentrations (PECs). The risk assessment is based on the ratio between the PNECs and the PECs. Adverse effect data or PNECs have been found in the publicly available literature for 45 substances. These ecotoxicity test data have been extracted from 125 different sources. This ERA database contains 1157 adverse effect data and 287 PNECs. The efficiency of this ERA database was tested with a data set coming from a simultaneous survey of WWTPs and the natural environment. In this data set, 26 DR were searched for in two WWTPs and in the river. On five sampling dates, concentrations measured in the river for 10 DR could pose environmental problems of which 7 were measured only downstream of WWTP outlets. From scientific literature and measurements, data implementation with unit homogenisation in a single database facilitates the actual ecotoxicological risk assessment, and may be useful for further risk coming from data arising from the future field survey. Moreover, the accumulation of a large ecotoxicity data set in a single database should not only improve knowledge of higher risk molecules but also supply an objective tool to help the rapid and efficient evaluation of the risk. Copyright © 2017 Elsevier B.V. All rights reserved.

Revitalizing the drug pipeline: AntibioticDB, an open access database to aid antibacterial research and development.

PubMed

Farrell, L J; Lo, R; Wanford, J J; Jenkins, A; Maxwell, A; Piddock, L J V

2018-06-11

The current state of antibiotic discovery, research and development is insufficient to respond to the need for new treatments for drug-resistant bacterial infections. The process has changed over the last decade, with most new agents that are in Phases 1-3, or recently approved, having been discovered in small- and medium-sized enterprises or academia. These agents have then been licensed or sold to large companies for further development with the goal of taking them to market. However, early drug discovery and development, including the possibility of developing previously discontinued agents, would benefit from a database of antibacterial compounds for scrutiny by the developers. This article describes the first free, open-access searchable database of antibacterial compounds, including discontinued agents, drugs under pre-clinical development and those in clinical trials: AntibioticDB (AntibioticDB.com). Data were obtained from publicly available sources. This article summarizes the compounds and drugs in AntibioticDB, including their drug class, mode of action, development status and propensity to select drug-resistant bacteria. AntibioticDB includes compounds currently in pre-clinical development and 834 that have been discontinued and that reached varying stages of development. These may serve as starting points for future research and development.

Ligand screening systems for human glucose transporters as tools in drug discovery

NASA Astrophysics Data System (ADS)

Schmidl, Sina; Iancu, Cristina V.; Choe, Jun-yong; Oreb, Mislav

2018-05-01

Hexoses are the major source of energy and carbon skeletons for biosynthetic processes in all kingdoms of life. Their cellular uptake is mediated by specialized transporters, including glucose transporters (GLUT, SLC2 gene family). Malfunction or altered expression pattern of GLUTs in humans is associated with several widespread diseases including cancer, diabetes and severe metabolic disorders. Their high relevance in the medical area makes these transporters valuable drug targets and potential biomarkers. Nevertheless, the lack of a suitable high-throughput screening system has impeded the determination of compounds that would enable specific manipulation of GLUTs so far. Availability of structural data on several GLUTs enabled in silico ligand screening, though limited by the fact that only two major conformations of the transporters can be tested. Recently, convenient high-throughput microbial and cell-free screening systems have been developed. These remarkable achievements set the foundation for further and detailed elucidation of the molecular mechanisms of glucose transport and will also lead to great progress in the discovery of GLUT effectors as therapeutic agents. In this mini-review, we focus on recent efforts to identify potential GLUT-targeting drugs, based on a combination of structural biology and different assay systems.

Fluorescent TEM-1 β-lactamase with wild-type activity as a rapid drug sensor for in vitro drug screening

PubMed Central

Cheong, Wing-Lam; Tsang, Ming-San; So, Pui-Kin; Chung, Wai-Hong; Leung, Yun-Chung; Chan, Pak-Ho

2014-01-01

We report the development of a novel fluorescent drug sensor from the bacterial drug target TEM-1 β-lactamase through the combined strategy of Val216→Cys216 mutation and fluorophore labelling for in vitro drug screening. The Val216 residue in TEM-1 is replaced with a cysteine residue, and the environment-sensitive fluorophore fluorescein-5-maleimide is specifically attached to the Cys216 residue in the V216C mutant for sensing drug binding at the active site. The labelled V216C mutant has wild-type catalytic activity and gives stronger fluorescence when β-lactam antibiotics bind to the active site. The labelled V216C mutant can differentiate between potent and impotent β-lactam antibiotics and can distinguish active-site binders from non-binders (including aggregates formed by small molecules in aqueous solution) by giving characteristic time-course fluorescence profiles. Mass spectrometric, molecular modelling and trypsin digestion results indicate that drug binding at the active site is likely to cause the fluorescein label to stay away from the active site and experience weaker fluorescence quenching by the residues around the active site, thus making the labelled V216C mutant to give stronger fluorescence in the drug-bound state. Given the ancestor's role of TEM-1 in the TEM family, the fluorescent TEM-1 drug sensor represents a good model to demonstrate the general combined strategy of Val216→Cys216 mutation and fluorophore labelling for fabricating tailor-made fluorescent drug sensors from other clinically significant TEM-type β-lactamase variants for in vitro drug screening. PMID:25074398

Validation of a Preclinical Drug Screening Platform for Pharmacoresistant Epilepsy.

PubMed

Barker-Haliski, Melissa L; Johnson, Kristina; Billingsley, Peggy; Huff, Jennifer; Handy, Laura J; Khaleel, Rizvana; Lu, Zhenmei; Mau, Matthew J; Pruess, Timothy H; Rueda, Carlos; Saunders, Gerald; Underwood, Tristan K; Vanegas, Fabiola; Smith, Misty D; West, Peter J; Wilcox, Karen S

2017-07-01

The successful identification of promising investigational therapies for the treatment of epilepsy can be credited to the use of numerous animal models of seizure and epilepsy for over 80 years. In this time, the maximal electroshock test in mice and rats, the subcutaneous pentylenetetrazol test in mice and rats, and more recently the 6 Hz assay in mice, have been utilized as primary models of electrically or chemically-evoked seizures in neurologically intact rodents. In addition, rodent kindling models, in which chronic network hyperexcitability has developed, have been used to identify new agents. It is clear that this traditional screening approach has greatly expanded the number of marketed drugs available to manage the symptomatic seizures associated with epilepsy. In spite of the numerous antiseizure drugs (ASDs) on the market today, the fact remains that nearly 30% of patients are resistant to these currently available medications. To address this unmet medical need, the National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP) revised its approach to the early evaluation of investigational agents for the treatment of epilepsy in 2015 to include a focus on preclinical approaches to model pharmacoresistant seizures. This present report highlights the in vivo and in vitro findings associated with the initial pharmacological validation of this testing approach using a number of mechanistically diverse, commercially available antiseizure drugs, as well as several probe compounds that are of potential mechanistic interest to the clinical management of epilepsy.

Utility of ELISA screening for the monitoring of abstinence from illegal and legal drugs in hair and urine.

PubMed

Agius, Ronald; Nadulski, Thomas

2014-06-01

Amphetamines, cannabinoids, cocaine, opiates, methadone, and benzodiazepines in authentic hair samples with drug concentrations around the medical and psychological assessment (MPA) guidelines cut-offs were screened by LUCIO-direct ELISA kits. Following confirmation of all positive and a significant number of negatively screened samples with gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods accredited for forensic purposes. Receiver operating characteristics (ROC) were plotted and the area under the curve (AUC) and overall misclassification rate (OMR) were calculated and compared to those obtained for the same drug classes in urine. While fulfilling the validation criteria of the German forensic guidelines, for almost all screening tests in hair and urine the AUC were greater than 0.8, indicating good to excellent performance. Moreover the AUC calculated for the detection of drugs in hair did not differ significantly to the AUC calculated for the detection of the same drug classes in urine, thus showing a comparable screening performance to the well accepted, previously published application of the same ELISAs for the detection of drugs at unconventionally low cut-offs in urine. For the first time, the validation of the immunoassay tests for the complete 6-drug panel MPA profile in hair and urine using a large population of authentic hair and urine samples with drug concentrations around MPA cut-offs, lower than conventional clinical or workplace drug testing guidelines cut-offs as well as those suggested by the Society of hair testing (SoHT) is presented. Copyright © 2014 John Wiley & Sons, Ltd.

In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database

NASA Astrophysics Data System (ADS)

Dai, Shao-Xing; Li, Wen-Xing; Han, Fei-Fei; Guo, Yi-Cheng; Zheng, Jun-Juan; Liu, Jia-Qian; Wang, Qian; Gao, Yue-Dong; Li, Gong-Hua; Huang, Jing-Fei

2016-05-01

There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database.

PubMed

Dai, Shao-Xing; Li, Wen-Xing; Han, Fei-Fei; Guo, Yi-Cheng; Zheng, Jun-Juan; Liu, Jia-Qian; Wang, Qian; Gao, Yue-Dong; Li, Gong-Hua; Huang, Jing-Fei

2016-05-05

There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents.

In silico identification of anti-cancer compounds and plants from traditional Chinese medicine database

PubMed Central

Dai, Shao-Xing; Li, Wen-Xing; Han, Fei-Fei; Guo, Yi-Cheng; Zheng, Jun-Juan; Liu, Jia-Qian; Wang, Qian; Gao, Yue-Dong; Li, Gong-Hua; Huang, Jing-Fei

2016-01-01

There is a constant demand to develop new, effective, and affordable anti-cancer drugs. The traditional Chinese medicine (TCM) is a valuable and alternative resource for identifying novel anti-cancer agents. In this study, we aim to identify the anti-cancer compounds and plants from the TCM database by using cheminformatics. We first predicted 5278 anti-cancer compounds from TCM database. The top 346 compounds were highly potent active in the 60 cell lines test. Similarity analysis revealed that 75% of the 5278 compounds are highly similar to the approved anti-cancer drugs. Based on the predicted anti-cancer compounds, we identified 57 anti-cancer plants by activity enrichment. The identified plants are widely distributed in 46 genera and 28 families, which broadens the scope of the anti-cancer drug screening. Finally, we constructed a network of predicted anti-cancer plants and approved drugs based on the above results. The network highlighted the supportive role of the predicted plant in the development of anti-cancer drug and suggested different molecular anti-cancer mechanisms of the plants. Our study suggests that the predicted compounds and plants from TCM database offer an attractive starting point and a broader scope to mine for potential anti-cancer agents. PMID:27145869

Evaluating the Predictivity of Virtual Screening for Abl Kinase Inhibitors to Hinder Drug Resistance

PubMed Central

Gani, Osman A B S M; Narayanan, Dilip; Engh, Richard A

2013-01-01

Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. ‘Dual active’ inhibitors against both targets were grouped together with inactive ligands chosen from different decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand-based methods, for example principal component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus inactive ligands, even without assuming knowledge of the binding mode. We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies. PMID:23746052

Database Dictionary for Ethiopian National Ground-Water DAtabase (ENGDA) Data Fields

USGS Publications Warehouse

Kuniansky, Eve L.; Litke, David W.; Tucci, Patrick

2007-01-01

Introduction This document describes the data fields that are used for both field forms and the Ethiopian National Ground-water Database (ENGDA) tables associated with information stored about production wells, springs, test holes, test wells, and water level or water-quality observation wells. Several different words are used in this database dictionary and in the ENGDA database to describe a narrow shaft constructed in the ground. The most general term is borehole, which is applicable to any type of hole. A well is a borehole specifically constructed to extract water from the ground; however, for this data dictionary and for the ENGDA database, the words well and borehole are used interchangeably. A production well is defined as any well used for water supply and includes hand-dug wells, small-diameter bored wells equipped with hand pumps, or large-diameter bored wells equipped with large-capacity motorized pumps. Test holes are borings made to collect information about the subsurface with continuous core or non-continuous core and/or where geophysical logs are collected. Test holes are not converted into wells. A test well is a well constructed for hydraulic testing of an aquifer in order to plan a larger ground-water production system. A water-level or water-quality observation well is a well that is used to collect information about an aquifer and not used for water supply. A spring is any naturally flowing, local, ground-water discharge site. The database dictionary is designed to help define all fields on both field data collection forms (provided in attachment 2 of this report) and for the ENGDA software screen entry forms (described in Litke, 2007). The data entered into each screen entry field are stored in relational database tables within the computer database. The organization of the database dictionary is designed based on field data collection and the field forms, because this is what the majority of people will use. After each field, however, the

Comprehensive screening and quantification of veterinary drugs in milk using UPLC–ToF-MS

PubMed Central

Rutgers, P.; Oosterink, E.; Lasaroms, J. J. P.; Peters, R. J. B.; van Rhijn, J. A.; Nielen, M. W. F.

2008-01-01

Ultra-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC–ToF-MS) has been used for screening and quantification of more than 100 veterinary drugs in milk. The veterinary drugs represent different classes including benzimidazoles, macrolides, penicillins, quinolones, sulphonamides, pyrimidines, tetracylines, nitroimidazoles, tranquillizers, ionophores, amphenicols and non-steroidal anti-inflammatory agents (NSAIDs). After protein precipitation, centrifugation and solid-phase extraction (SPE), the extracts were analysed by UPLC–ToF-MS. From the acquired full scan data the drug-specific ions were extracted for construction of the chromatograms and evaluation of the results. The analytical method was validated according to the EU guidelines (2002/657/EC) for a quantitative screening method. At the concentration level of interest (MRL level) the results for repeatability (%RSD < 20% for 86% of the compounds), reproducibility (%RSD < 40% for 96% of the compounds) and the accuracy (80–120% for 88% of the compounds) were satisfactory. Evaluation of the CCβ values and the linearity results demonstrates that the developed method shows adequate sensitivity and linearity to provide quantitative results. Furthermore, the method is accurate enough to differentiate between suspected and negative samples or drug concentrations below or above the MRL. A set of 100 samples of raw milk were screened for residues. No suspected (positive) results were obtained except for the included blind reference sample containing sulphamethazine (88 μg/l) that tested positive for this compound. UPLC–ToF-MS combines high resolution for both LC and MS with high mass accuracy which is very powerful for the multi-compound analysis of veterinary drugs. The technique seems to be powerful enough for the analysis of not only veterinary drugs but also organic contaminants like pesticides, mycotoxins and plant toxins in one single method. PMID:18491081

Chemical & RNAi screening at MSKCC: a collaborative platform to discover & repurpose drugs to fight disease

PubMed Central

Bhinder, Bhavneet; Antczak, Christophe; Shum, David; Radu, Constantin; Mahida, Jeni P.; Liu-Sullivan, Nancy; Ibáñez, Glorymar; Raja, Balajee Somalinga; Calder, Paul A.; Djaballah, Hakim

2014-01-01

Memorial Sloan-Kettering Cancer Center (MSKCC) has implemented the creation of a full service state-of-the-art High-throughput Screening Core Facility (HTSCF) equipped with modern robotics and custom-built screening data management resources to rapidly store and query chemical and RNAi screening data outputs. The mission of the facility is to provide oncology clinicians and researchers alike with access to cost-effective HTS solutions for both chemical and RNAi screening, with an ultimate goal of novel target identification and drug discovery. HTSCF was established in 2003 to support the institution’s commitment to growth in molecular pharmacology and in the realm of therapeutic agents to fight chronic diseases such as cancer. This endeavor required broad range of expertise in technology development to establish robust and innovative assays, large collections of diverse chemical and RNAi duplexes to probe specific cellular events, sophisticated compound and data handling capabilities, and a profound knowledge in assay development, hit validation, and characterization. Our goal has been to strive for constant innovation, and we strongly believe in shifting the paradigm from traditional drug discovery towards translational research now, making allowance for unmet clinical needs in patients. Our efforts towards repurposing FDA-approved drugs fructified when digoxin, identified through primary HTS, was administered in the clinic for treatment of stage Vb retinoblastoma. In summary, the overall aim of our facility is to identify novel chemical probes, to study cellular processes relevant to investigator’s research interest in chemical biology and functional genomics, and to be instrumental in accelerating the process of drug discovery in academia. PMID:24661215

Adaptation of High-Throughput Screening in Drug Discovery—Toxicological Screening Tests

PubMed Central

Szymański, Paweł; Markowicz, Magdalena; Mikiciuk-Olasik, Elżbieta

2012-01-01

High-throughput screening (HTS) is one of the newest techniques used in drug design and may be applied in biological and chemical sciences. This method, due to utilization of robots, detectors and software that regulate the whole process, enables a series of analyses of chemical compounds to be conducted in a short time and the affinity of biological structures which is often related to toxicity to be defined. Since 2008 we have implemented the automation of this technique and as a consequence, the possibility to examine 100,000 compounds per day. The HTS method is more frequently utilized in conjunction with analytical techniques such as NMR or coupled methods e.g., LC-MS/MS. Series of studies enable the establishment of the rate of affinity for targets or the level of toxicity. Moreover, researches are conducted concerning conjugation of nanoparticles with drugs and the determination of the toxicity of such structures. For these purposes there are frequently used cell lines. Due to the miniaturization of all systems, it is possible to examine the compound’s toxicity having only 1–3 mg of this compound. Determination of cytotoxicity in this way leads to a significant decrease in the expenditure and to a reduction in the length of the study. PMID:22312262

Discovery of a drug targeting microenvironmental support for lymphoma cells by screening using patient-derived xenograft cells

PubMed Central

Sugimoto, Keiki; Hayakawa, Fumihiko; Shimada, Satoko; Morishita, Takanobu; Shimada, Kazuyuki; Katakai, Tomoya; Tomita, Akihiro; Kiyoi, Hitoshi; Naoe, Tomoki

2015-01-01

Cell lines have been used for drug discovery as useful models of cancers; however, they do not recapitulate cancers faithfully, especially in the points of rapid growth rate and microenvironment independency. Consequently, the majority of conventional anti-cancer drugs are less sensitive to slow growing cells and do not target microenvironmental support, although most primary cancer cells grow slower than cell lines and depend on microenvironmental support. Here, we developed a novel high throughput drug screening system using patient-derived xenograft (PDX) cells of lymphoma that maintained primary cancer cell phenotype more than cell lines. The library containing 2613 known pharmacologically active substance and off-patent drugs were screened by this system. We could find many compounds showing higher cytotoxicity than conventional anti-tumor drugs. Especially, pyruvinium pamoate showed the highest activity and its strong anti-tumor effect was confirmed also in vivo. We extensively investigated its mechanism of action and found that it inhibited glutathione supply from stromal cells to lymphoma cells, implying the importance of the stromal protection from oxidative stress for lymphoma cell survival and a new therapeutic strategy for lymphoma. Our system introduces a primary cancer cell phenotype into cell-based phenotype screening and sheds new light on anti-cancer drug development. PMID:26278963

The Screening Compound Collection: A Key Asset for Drug Discovery.

PubMed

Boss, Christoph; Hazemann, Julien; Kimmerlin, Thierry; von Korff, Modest; Lüthi, Urs; Peter, Oliver; Sander, Thomas; Siegrist, Romain

2017-10-25

In this case study on an essential instrument of modern drug discovery, we summarize our successful efforts in the last four years toward enhancing the Actelion screening compound collection. A key organizational step was the establishment of the Compound Library Committee (CLC) in September 2013. This cross-functional team consisting of computational scientists, medicinal chemists and a biologist was endowed with a significant annual budget for regular new compound purchases. Based on an initial library analysis performed in 2013, the CLC developed a New Library Strategy. The established continuous library turn-over mode, and the screening library size of 300'000 compounds were maintained, while the structural library quality was increased. This was achieved by shifting the selection criteria from 'druglike' to 'leadlike' structures, enriching for non-flat structures, aiming for compound novelty, and increasing the ratio of higher cost 'Premium Compounds'. Novel chemical space was gained by adding natural compounds, macrocycles, designed and focused libraries to the collection, and through mutual exchanges of proprietary compounds with agrochemical companies. A comparative analysis in 2016 provided evidence for the positive impact of these measures. Screening the improved library has provided several highly promising hits, including a macrocyclic compound, that are currently followed up in different Hit-to-Lead and Lead Optimization programs. It is important to state that the goal of the CLC was not to achieve higher HTS hit rates, but to increase the chances of identified hits to serve as the basis of successful early drug discovery programs. The experience gathered so far legitimates the New Library Strategy.

Results of drug screening from a producer's view.

PubMed

Adams, J B

1994-07-01

The dairy industry is faced with increasing governmental and public concern about the safety of the nation's milk supply. New regulations under the Grade A Pasteurized Milk Ordinance require that prescription drugs be properly labeled and that all tanker loads of milk be tested for beta-lactam antimicrobial residues. Concern over the use of animal drugs in an extralabel manner has prompted the National Milk Producers Federation and the American Veterinary Medical Association to develop a quality assurance program for on-farm residue prevention known as the Dairy Quality Assurance 10-Point Milk and Dairy Beef Residue Prevention Protocol. The program promotes the concept of Hazard Analysis Critical Control Points, applied to a pre-harvest farm environment. Screening limitations at point of milk receipt necessitates widespread adoption of the Dairy Quality Assurance protocol to address controlled use of all animal medications under a valid relationship among veterinarian, client, and animals, thus minimizing the potential for violative residues in the milk and meat supply.

Improving database enrichment through ensemble docking

NASA Astrophysics Data System (ADS)

Rao, Shashidhar; Sanschagrin, Paul C.; Greenwood, Jeremy R.; Repasky, Matthew P.; Sherman, Woody; Farid, Ramy

2008-09-01

While it may seem intuitive that using an ensemble of multiple conformations of a receptor in structure-based virtual screening experiments would necessarily yield improved enrichment of actives relative to using just a single receptor, it turns out that at least in the p38 MAP kinase model system studied here, a very large majority of all possible ensembles do not yield improved enrichment of actives. However, there are combinations of receptor structures that do lead to improved enrichment results. We present here a method to select the ensembles that produce the best enrichments that does not rely on knowledge of active compounds or sophisticated analyses of the 3D receptor structures. In the system studied here, the small fraction of ensembles of up to 3 receptors that do yield good enrichments of actives were identified by selecting ensembles that have the best mean GlideScore for the top 1% of the docked ligands in a database screen of actives and drug-like "decoy" ligands. Ensembles of two receptors identified using this mean GlideScore metric generally outperform single receptors, while ensembles of three receptors identified using this metric consistently give optimal enrichment factors in which, for example, 40% of the known actives outrank all the other ligands in the database.

[Screening antihydatid drugs using cultivated germinal cells of Echinococcus granulosus].

PubMed

Feng, J J; Xiao, S H; Guo, H F; Shen, B G; Jiao, W

1993-01-01

Germinal cells isolated from Echinococcus granulosus cysts harbored in mice have been maintained in an in vitro culture system containing RPMI 1640 supplemented by 20% calf serum, and used as a model for screening anti-hydatid drugs. When the germinal cells were maintained in the medium for 6 days, the cell proliferation rate was rather high in the first four days but declined in the last two days. In screening drugs, 1.4 x 10(6) germinal cells were exposed to known effective drugs against metacestodes of E. granulosus in mice, such as mebendazole (Meb), albendazole (Alb) or praziquantel (Pra) at various concentrations. One to three days after exposure, cell counts were made daily in 3 samples of each drug concentration. The mean cell number of each group was compared with that of the control and the inhibition rate of the cell was then calculated. The results showed that the minimal effective concentrations of Meb, Alb and Pra, were 1.0 (48 h), 2.5 (24 h) and 10.0 (72 h) micrograms/ml, respectively, while the inhibition rates of the cell were 34.1, 55.7 and 18.5%. Interestingly, the in vitro effects of Meb, Alb and Pra were consistent to those obtained from the in vivo tests, ie Meb > Alb > Pra. Nevertheless, after exposure of germinal cells to Meb at 2.5 micrograms/ml for 24 h, the cells appeared in roughness, indistinction, shrunk or swelling, collapse, deformation and hole-like feature detected by light microscopy and scanning electron-microscopy, while the ultrastructure alterations of the cells noted by transmission electron-microscopy were lysis in cytoplasm, disruption or disappearance of nucleus and even darkness of the whole cell.(ABSTRACT TRUNCATED AT 250 WORDS)

Monitoring of drug intake during pregnancy by questionnaires and LC-MS/MS drug urine screening: evaluation of both monitoring methods.

PubMed

Hoeke, Henrike; Roeder, Stefan; Bertsche, Thilo; Lehmann, Irina; Borte, Michael; von Bergen, Martin; Wissenbach, Dirk K

2015-08-01

Various studies pointed towards a relationship between chronic diseases such as asthma and allergy and environmental risk factors, which are one aspect of the so-called Exposome. These environmental risk factors include also the intake of drugs. One critical step in human development is the prenatal period, in which exposures might have critical impact on the child's health outcome. Thereby, the health effects of drugs taken during gestation are discussed controversially with regard to newborns' disease risk. Due to this, the drug intake of pregnant women in the third trimester was monitored by questionnaire, in addition to biomonitoring using a local birth cohort study, allowing correlations of drug exposure with disease risk. Therefore, 622 urine samples were analyzed by an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) urine screening and the results were compared to self-administered questionnaires. In total, 48% (n = 296) reported an intake of pharmaceuticals, with analgesics as the most frequent reported drug class in addition to dietary supplements. 182 times compounds were detected by urine screening, with analgesics (42%; n = 66) as the predominantly drug class. A comparison of reported and detected drug intake was performed for three different time spans between completion of the questionnaires and urine sampling. Even if the level of accordance was low in general, similar percentages (~25%, ~19%, and ~ 20%) were found for all groups. This study illustrates that a comprehensive evaluation of drug intake is neither achieved by questionnaires nor by biomonitoring alone. Instead, a combination of both monitoring methods, providing complementary information, should be considered. Copyright © 2014 John Wiley & Sons, Ltd.

DoD Identity Matching Engine for Security and Analysis (IMESA) Access to Criminal Justice Information (CJI) and Terrorist Screening Databases (TSDB)

DTIC Science & Technology

2016-05-04

IMESA) Access to Criminal Justice Information (CJI) and Terrorist Screening Databases (TSDB) References: See Enclosure 1 1. PURPOSE. In...CJI database mirror image files. (3) Memorandums of understanding with the FBI CJIS as the data broker for DoD organizations that need access ...not for access determinations. (3) Legal restrictions established by the Sex Offender Registration and Notification Act (SORNA) jurisdictions on

ARQiv-HTS, a versatile whole-organism screening platform enabling in vivo drug discovery at high-throughput rates

PubMed Central

White, David T; Eroglu, Arife Unal; Wang, Guohua; Zhang, Liyun; Sengupta, Sumitra; Ding, Ding; Rajpurohit, Surendra K; Walker, Steven L; Ji, Hongkai; Qian, Jiang; Mumm, Jeff S

2017-01-01

The zebrafish has emerged as an important model for whole-organism small-molecule screening. However, most zebrafish-based chemical screens have achieved only mid-throughput rates. Here we describe a versatile whole-organism drug discovery platform that can achieve true high-throughput screening (HTS) capacities. This system combines our automated reporter quantification in vivo (ARQiv) system with customized robotics, and is termed ‘ARQiv-HTS’. We detail the process of establishing and implementing ARQiv-HTS: (i) assay design and optimization, (ii) calculation of sample size and hit criteria, (iii) large-scale egg production, (iv) automated compound titration, (v) dispensing of embryos into microtiter plates, and (vi) reporter quantification. We also outline what we see as best practice strategies for leveraging the power of ARQiv-HTS for zebrafish-based drug discovery, and address technical challenges of applying zebrafish to large-scale chemical screens. Finally, we provide a detailed protocol for a recently completed inaugural ARQiv-HTS effort, which involved the identification of compounds that elevate insulin reporter activity. Compounds that increased the number of insulin-producing pancreatic beta cells represent potential new therapeutics for diabetic patients. For this effort, individual screening sessions took 1 week to conclude, and sessions were performed iteratively approximately every other day to increase throughput. At the conclusion of the screen, more than a half million drug-treated larvae had been evaluated. Beyond this initial example, however, the ARQiv-HTS platform is adaptable to almost any reporter-based assay designed to evaluate the effects of chemical compounds in living small-animal models. ARQiv-HTS thus enables large-scale whole-organism drug discovery for a variety of model species and from numerous disease-oriented perspectives. PMID:27831568

[Implementation of a computerized pharmacological database for pediatric use].

PubMed

Currò, V; Grimaldi, V; Polidori, G; Cascioli, E; Lanni, R; De Luca, F; D'Atri, A; Bernabei, A

1990-01-01

The authors present a pharmacological database to support teaching and care activity carried out in the Divisional Paediatric Ambulatory of the Catholic University of Rome. This database is included in a integrated system, ARPIA (Ambulatory and Research in Pediatric by Information Assistance), devoted to manage ambulatory paediatric data. ARPIA has been implemented by using a relational DBMS, very cheap and highly diffused on personal computers. The database specifies: active ingredient and code number related to it, clinical uses, doses, contra-indications and precautions, adverse effects, besides the possible wrapping available on the market. All this is showed on a single for that appears on the screen and allows a fast reading of the most important elements characterizing every drug. The search of the included drugs can be made on the basis of three different detailed lists: active ingredient, proprietary preparation and clinical use. It is, besides, possible to have a complete report about the drugs requested by the user. This system allows the user, without modifying the program, to interact with the included data modifying each element of the form. In the system there is also a fast consultation handbook containing for every active ingredient, the complete list of italian proprietary medicines. This system aims to give a better knowledge of the most commonly used drugs, not only limited to the paediatrician but also to the ambulatory health staff; an improvement of the therapy furthering, a more effective use of several pharmacological agents and first of all a training device not only to specialists but also to students.

[Hepatox: database on hepatotoxic drugs].

PubMed

Quinton, A; Latry, P; Biour, M

1993-01-01

Hepatox is a data base on the hepatotoxic drugs file published every year in Gastroentérologie Clinique et Biologique. The program was developed under Omnis 7 for Apple computers, and under Visual Basic Professional Toolkit and Code Base for IBM PC and compatibles computers. The data base includes forms of 866 drugs identified by their approved name and those of their 1,300 corresponding proprietary names in France; drugs are distributed among 104 pharmacological classes. It is possible to have instantaneously access to the card of a drug identified by its approved name. Acceding to a drug identified by its proprietary name gives a list of the approved name of its components; going from a name of this list to the correspondent card of hepatoxicity is immediate. It is easy to extract lists of drugs responsible of a type of hepatic injury, and a table of types of hepatic injuries induced by the drugs of a pharmacological class.

iDrug: a web-accessible and interactive drug discovery and design platform

PubMed Central

2014-01-01

Background The progress in computer-aided drug design (CADD) approaches over the past decades accelerated the early-stage pharmaceutical research. Many powerful standalone tools for CADD have been developed in academia. As programs are developed by various research groups, a consistent user-friendly online graphical working environment, combining computational techniques such as pharmacophore mapping, similarity calculation, scoring, and target identification is needed. Results We presented a versatile, user-friendly, and efficient online tool for computer-aided drug design based on pharmacophore and 3D molecular similarity searching. The web interface enables binding sites detection, virtual screening hits identification, and drug targets prediction in an interactive manner through a seamless interface to all adapted packages (e.g., Cavity, PocketV.2, PharmMapper, SHAFTS). Several commercially available compound databases for hit identification and a well-annotated pharmacophore database for drug targets prediction were integrated in iDrug as well. The web interface provides tools for real-time molecular building/editing, converting, displaying, and analyzing. All the customized configurations of the functional modules can be accessed through featured session files provided, which can be saved to the local disk and uploaded to resume or update the history work. Conclusions iDrug is easy to use, and provides a novel, fast and reliable tool for conducting drug design experiments. By using iDrug, various molecular design processing tasks can be submitted and visualized simply in one browser without installing locally any standalone modeling softwares. iDrug is accessible free of charge at http://lilab.ecust.edu.cn/idrug. PMID:24955134

[Adverse Effect Predictions Based on Computational Toxicology Techniques and Large-scale Databases].

PubMed

Uesawa, Yoshihiro

2018-01-01

　Understanding the features of chemical structures related to the adverse effects of drugs is useful for identifying potential adverse effects of new drugs. This can be based on the limited information available from post-marketing surveillance, assessment of the potential toxicities of metabolites and illegal drugs with unclear characteristics, screening of lead compounds at the drug discovery stage, and identification of leads for the discovery of new pharmacological mechanisms. This present paper describes techniques used in computational toxicology to investigate the content of large-scale spontaneous report databases of adverse effects, and it is illustrated with examples. Furthermore, volcano plotting, a new visualization method for clarifying the relationships between drugs and adverse effects via comprehensive analyses, will be introduced. These analyses may produce a great amount of data that can be applied to drug repositioning.

Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1

PubMed Central

Gendarme, Mathieu; Baumann, Jan; Ignashkova, Tatiana I.; Lindemann, Ralph K.; Reiling, Jan H.

2017-01-01

The Golgi apparatus is increasingly recognized as a major hub for cellular signaling and is involved in numerous pathologies, including neurodegenerative diseases and cancer. The study of Golgi stress-induced signaling pathways relies on the selectivity of the available tool compounds of which currently only a few are known. To discover novel Golgi-fragmenting agents, transcriptomic profiles of cells treated with brefeldin A, golgicide A, or monensin were generated and compared with a database of gene expression profiles from cells treated with other bioactive small molecules. In parallel, a phenotypic screen was performed for compounds that alter normal Golgi structure. Histone deacetylase (HDAC) inhibitors and DNA-damaging agents were identified as novel Golgi disruptors. Further analysis identified HDAC1/HDAC9 as well as BRD8 and DNA-PK as important regulators of Golgi breakdown mediated by HDAC inhibition. We provide evidence that combinatorial HDACi/(+)-JQ1 treatment spurs synergistic Golgi dispersal in several cancer cell lines, pinpointing a possible link between drug-induced toxicity and Golgi morphology alterations. PMID:29074567

CMHC practices related to tardive dyskinesia screening and informed consent for neuroleptic drugs.

PubMed

Benjamin, S; Munetz, M R

1994-04-01

The authors conducted a national survey of community mental health centers to determine their policies and practices about screening patients for tardive dyskinesia and obtaining informed consent for use of neuroleptic drugs. Clinical directors of 235 centers in the United States, selected by geographic region and population, were surveyed through a nine-item questionnaire. Although nearly all the 160 respondents reported that they screened patients for tardive dyskinesia, only about two-fifths had formal screening policies, and about two-fifths had screening programs. The Abnormal Involuntary Movement Scale examination was used by almost two-thirds of respondents who screened patients, and about one-fifth relied on unstructured observation. Slightly more than half of respondents specified a frequency for screening examinations, at a modal interval of six months. Seventy percent used nonpsychiatric clinicians for screening. Almost three-quarters of the respondents had informed consent policies for use of neuroleptics. Urban centers tended to be more aware than rural centers of the American Psychiatric Association's tardive dyskinesia screening guidelines. They also used fewer nonmedical practitioners for screening and were more likely to obtain informed consent for neuroleptics. Despite the existence of APA guidelines and state policies and regulations about tardive dyskinesia screening, a national effort to educate clinicians about prevention of tardive dyskinesia is still needed.

Exploration of natural product ingredients as inhibitors of human HMG-CoA reductase through structure-based virtual screening.

PubMed

Lin, Shih-Hung; Huang, Kao-Jean; Weng, Ching-Feng; Shiuan, David

2015-01-01

Cholesterol plays an important role in living cells. However, a very high level of cholesterol may lead to atherosclerosis. HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase is the key enzyme in the cholesterol biosynthesis pathway, and the statin-like drugs are inhibitors of human HMG-CoA reductase (hHMGR). The present study aimed to virtually screen for potential hHMGR inhibitors from natural product to discover hypolipidemic drug candidates with fewer side effects and lesser toxicities. We used the 3D structure 1HWK from the PDB (Protein Data Bank) database of hHMGR as the target to screen for the strongly bound compounds from the traditional Chinese medicine database. Many interesting molecules including polyphenolic compounds, polisubstituted heterocyclics, and linear lipophilic alcohols were identified and their ADMET (absorption, disrtibution, metabolism, excretion, toxicity) properties were predicted. Finally, four compounds were obtained for the in vitro validation experiments. The results indicated that curcumin and salvianolic acid C can effectively inhibit hHMGR, with IC50 (half maximal inhibitory concentration) values of 4.3 µM and 8 µM, respectively. The present study also demonstrated the feasibility of discovering new drug candidates through structure-based virtual screening.

Adverse drug reactions in Colombian patients, 2007-2013: Analysis of population databases.

PubMed

Machado-Alba, Jorge Enrique; Londoño-Builes, Manuel José; Echeverri-Cataño, Luis Felipe; Ochoa-Orozco, Sergio Andrés

2016-03-03

Recognizing adverse drug reactions (ADRs) is becoming more important in clinical practice.  To determine the frequency of adverse drug reactions and ADR suspicions among the population affiliated to the Colombian health system and to describe the drugs, reactions and associated variables.  We revised ADRs and ADRs suspicion databases from drugs dispensed by Audifarma, S.A., both for inpatient and outpatient care from 2007 to 2013. Variables included ADR report date, city, drug, drug's Anatomical Therapeutic Classification (ATC), ADR severity, ADR type, ADR classification and ADR probability according to the World Health Organization's definitions.  We obtained 5,342 reports for 468 different drugs. The ATC groups with the most reports were anti-infectives for systemic use (25.5%), nervous system agents (17.1%) and cardiovascular system drugs (15.0%). The drugs with the highest number of reports were metamizole (4.2%), enalapril (3.8%), clarithromycin (2.8%), warfarin (2.5%) and ciprofloxacin (2.4%). The most common ADR, classified following the World Health Organization adverse reaction terminology, were: skin and appendages disorders (35.3%), general disorders (14.2%) and gastrointestinal system disorders (11.8%). Overall, 49.4% of the ADRs were classified as "moderate" and 45.1% as "mild".  An increasing number of ADR reports were found coinciding with a worldwide tendency. Differences between inpatient and outpatient ADR reports were found when compared to scientific publications. The information on ADR reports, mainly gathered by the Instituto Nacional de Vigilancia de Medicamentos y Alimentos - Invima, should be made public for academic and institutional use.

Repositioning approved drugs for the treatment of problematic cancers using a screening approach

PubMed Central

Kuttler, Fabien; Banfi, Damiano; Turcatti, Gerardo; Dyson, Paul J.

2017-01-01

Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan. PMID:28166232

Fragment virtual screening based on Bayesian categorization for discovering novel VEGFR-2 scaffolds.

PubMed

Zhang, Yanmin; Jiao, Yu; Xiong, Xiao; Liu, Haichun; Ran, Ting; Xu, Jinxing; Lu, Shuai; Xu, Anyang; Pan, Jing; Qiao, Xin; Shi, Zhihao; Lu, Tao; Chen, Yadong

2015-11-01

The discovery of novel scaffolds against a specific target has long been one of the most significant but challengeable goals in discovering lead compounds. A scaffold that binds in important regions of the active pocket is more favorable as a starting point because scaffolds generally possess greater optimization possibilities. However, due to the lack of sufficient chemical space diversity of the databases and the ineffectiveness of the screening methods, it still remains a great challenge to discover novel active scaffolds. Since the strengths and weaknesses of both fragment-based drug design and traditional virtual screening (VS), we proposed a fragment VS concept based on Bayesian categorization for the discovery of novel scaffolds. This work investigated the proposal through an application on VEGFR-2 target. Firstly, scaffold and structural diversity of chemical space for 10 compound databases were explicitly evaluated. Simultaneously, a robust Bayesian classification model was constructed for screening not only compound databases but also their corresponding fragment databases. Although analysis of the scaffold diversity demonstrated a very unevenly distribution of scaffolds over molecules, results showed that our Bayesian model behaved better in screening fragments than molecules. Through a literature retrospective research, several generated fragments with relatively high Bayesian scores indeed exhibit VEGFR-2 biological activity, which strongly proved the effectiveness of fragment VS based on Bayesian categorization models. This investigation of Bayesian-based fragment VS can further emphasize the necessity for enrichment of compound databases employed in lead discovery by amplifying the diversity of databases with novel structures.

Mining collections of compounds with Screening Assistant 2.

PubMed

Guilloux, Vincent Le; Arrault, Alban; Colliandre, Lionel; Bourg, Stéphane; Vayer, Philippe; Morin-Allory, Luc

2012-08-31

High-throughput screening assays have become the starting point of many drug discovery programs for large pharmaceutical companies as well as academic organisations. Despite the increasing throughput of screening technologies, the almost infinite chemical space remains out of reach, calling for tools dedicated to the analysis and selection of the compound collections intended to be screened. We present Screening Assistant 2 (SA2), an open-source JAVA software dedicated to the storage and analysis of small to very large chemical libraries. SA2 stores unique molecules in a MySQL database, and encapsulates several chemoinformatics methods, among which: providers management, interactive visualisation, scaffold analysis, diverse subset creation, descriptors calculation, sub-structure / SMART search, similarity search and filtering. We illustrate the use of SA2 by analysing the composition of a database of 15 million compounds collected from 73 providers, in terms of scaffolds, frameworks, and undesired properties as defined by recently proposed HTS SMARTS filters. We also show how the software can be used to create diverse libraries based on existing ones. Screening Assistant 2 is a user-friendly, open-source software that can be used to manage collections of compounds and perform simple to advanced chemoinformatics analyses. Its modular design and growing documentation facilitate the addition of new functionalities, calling for contributions from the community. The software can be downloaded at http://sa2.sourceforge.net/.

Thailand mutation and variation database (ThaiMUT).

PubMed

Ruangrit, Uttapong; Srikummool, Metawee; Assawamakin, Anunchai; Ngamphiw, Chumpol; Chuechote, Suparat; Thaiprasarnsup, Vilasinee; Agavatpanitch, Gallissara; Pasomsab, Ekawat; Yenchitsomanus, Pa-Thai; Mahasirimongkol, Surakameth; Chantratita, Wasun; Palittapongarnpim, Prasit; Uyyanonvara, Bunyarit; Limwongse, Chanin; Tongsima, Sissades

2008-08-01

With the completion of the human genome project, novel sequencing and genotyping technologies had been utilized to detect mutations. Such mutations have continually been produced at exponential rate by researchers in various communities. Based on the population's mutation spectra, occurrences of Mendelian diseases are different across ethnic groups. A proportion of Mendelian diseases can be observed in some countries at higher rates than others. Recognizing the importance of mutation effects in Thailand, we established a National and Ethnic Mutation Database (NEMDB) for Thai people. This database, named Thailand Mutation and Variation database (ThaiMUT), offers a web-based access to genetic mutation and variation information in Thai population. This NEMDB initiative is an important informatics tool for both research and clinical purposes to retrieve and deposit human variation data. The mutation data cataloged in ThaiMUT database were derived from journal articles available in PubMed and local publications. In addition to collected mutation data, ThaiMUT also records genetic polymorphisms located in drug related genes. ThaiMUT could then provide useful information for clinical mutation screening services for Mendelian diseases and pharmacogenomic researches. ThaiMUT can be publicly accessed from http://gi.biotec.or.th/thaimut.

Toxicology screen

MedlinePlus

... Analgesics - screen; Antidepressants - screen; Narcotics - screen; Phenothiazines - screen; Drug abuse screen; Blood alcohol test ... poisoning) Complicated alcohol abstinence (delirium tremens) Delirium ... Fetal alcohol syndrome Intentional overdose Seizures Stroke ...

77 FR 42323 - Notice of Proposed Information Collection for Public Comment; Screening and Eviction for Drug...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-18

... Information Collection for Public Comment; Screening and Eviction for Drug Abuse and Other Criminal Activity... collection requirements consist of PHA screening requirements to obtain criminal conviction records from law enforcement agencies to prevent admission of criminals into the public housing and Section 8 programs and to...

A Review of Human Pluripotent Stem Cell-Derived Cardiomyocytes for High-Throughput Drug Discovery, Cardiotoxicity Screening and Publication Standards

PubMed Central

Mordwinkin, Nicholas M.; Burridge, Paul W.; Wu, Joseph C.

2013-01-01

Drug attrition rates have increased in past years, resulting in growing costs for the pharmaceutical industry and consumers. The reasons for this include the lack of in vitro models that correlate with clinical results, and poor preclinical toxicity screening assays. The in vitro production of human cardiac progenitor cells and cardiomyocytes from human pluripotent stem cells provides an amenable source of cells for applications in drug discovery, disease modeling, regenerative medicine, and cardiotoxicity screening. In addition, the ability to derive human induced pluripotent stem cells from somatic tissues, combined with current high-throughput screening and pharmacogenomics, may help realize the use of these cells to fulfill the potential of personalized medicine. In this review, we discuss the use of pluripotent stem cell-derived cardiomyocytes for drug discovery and cardiotoxicity screening, as well as current hurdles that must be overcome for wider clinical applications of this promising approach. PMID:23229562

A review of human pluripotent stem cell-derived cardiomyocytes for high-throughput drug discovery, cardiotoxicity screening, and publication standards.

PubMed

Mordwinkin, Nicholas M; Burridge, Paul W; Wu, Joseph C

2013-02-01

Drug attrition rates have increased in past years, resulting in growing costs for the pharmaceutical industry and consumers. The reasons for this include the lack of in vitro models that correlate with clinical results and poor preclinical toxicity screening assays. The in vitro production of human cardiac progenitor cells and cardiomyocytes from human pluripotent stem cells provides an amenable source of cells for applications in drug discovery, disease modeling, regenerative medicine, and cardiotoxicity screening. In addition, the ability to derive human-induced pluripotent stem cells from somatic tissues, combined with current high-throughput screening and pharmacogenomics, may help realize the use of these cells to fulfill the potential of personalized medicine. In this review, we discuss the use of pluripotent stem cell-derived cardiomyocytes for drug discovery and cardiotoxicity screening, as well as current hurdles that must be overcome for wider clinical applications of this promising approach.

Resolution V fractional factorial design for screening of factors affecting weakly basic drugs liposomal systems.

PubMed

Nageeb El-Helaly, Sara; Habib, Basant A; Abd El-Rahman, Mohamed K

2018-07-01

This study aims to investigate factors affecting weakly basic drugs liposomal systems. Resolution V fractional factorial design (2 V 5-1 ) is used as an example of screening designs that would better be used as a wise step before proceeding with detailed factors effects or optimization studies. Five factors probable to affect liposomal systems of weakly basic drugs were investigated using Amisulpride as a model drug. Factors studied were; A: Preparation technique B: Phosphatidyl choline (PhC) amount (mg) C: Cholesterol: PhC molar ratio, D: Hydration volume (ml) and E: Sonication type. Levels investigated were; Ammonium sulphate-pH gradient technique or Transmembrane zinc chelation-pH gradient technique, 200 or 400 mg, 0 or 0.5, 10 or 20 ml and bath or probe sonication for A, B, C, D and E respectively. Responses measured were Particle size (PS) (nm), Zeta potential (ZP) (mV) and Entrapment efficiency percent (EE%). Ion selective electrode was used as a novel method for measuring unentrapped drug concentration and calculating entrapment efficiency without the need for liposomal separation. Factors mainly affecting the studied responses were Cholesterol: PhC ratio and hydration volume for PS, preparation technique for ZP and preparation technique and hydration volume for EE%. The applied 2 V 5-1 design enabled the use of only 16 trial combinations for screening the influence of five factors on weakly basic drugs liposomal systems. This clarifies the value of the use of screening experiments before extensive investigation of certain factors in detailed optimization studies. Copyright © 2018 Elsevier B.V. All rights reserved.

Urine Multi-drug Screening with GC-MS or LC-MS-MS Using SALLE-hybrid PPT/SPE.

PubMed

Lee, Junhui; Park, Jiwon; Go, Ahra; Moon, Heesung; Kim, Sujin; Jung, Sohee; Jeong, Wonjoon; Chung, Heesun

2018-05-14

To intoxicated patients in the emergency room, toxicological analysis can be considerably helpful for identifying the involved toxicants. In order to develop a urine multi-drug screening (UmDS) method, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) were used to determine targeted and unknown toxicants in urine. A GC-MS method in scan mode was validated for selectivity, limit of detection (LOD) and recovery. An LC-MS-MS multiple reaction monitoring (MRM) method was validated for lower LOD, recovery and matrix effect. The results of the screening analysis were compared with patient medical records to check the reliability of the screen. Urine samples collected from an emergency room were extracted through a combination of salting-out assisted liquid-liquid extraction (SALLE) and hybrid protein precipitation/solid phase extraction (hybrid PPT/SPE) plates and examined by GC-MS and LC-MS-MS. GC-MS analysis was performed as unknown drug screen and LC-MS-MS analysis was conducted as targeted drug screen. After analysis by GC-MS, a library search was conducted using an in-house library established with the automated mass spectral deconvolution and identification system (AMDISTM). LC-MS-MS used Cliquid®2.0 software for data processing and acquisition in MRM mode. An UmDS method by GC-MS and LC-MS-MS was developed by using a SALLE-hybrid PPT/SPE and in-house library. The results of UmDS by GC-MS and LC-MS-MS showed that toxicants could be identified from 185 emergency room patient samples containing unknown toxicants. Zolpidem, acetaminophen and citalopram were the most frequently encountered drugs in emergency room patients. The UmDS analysis developed in this study can be used effectively to detect toxic substances in a short time. Hence, it could be utilized in clinical and forensic toxicology practices.

Psychometric properties of the Turkish versions of the Drug Use Disorders Identification Test (DUDIT) and the Drug Abuse Screening Test (DAST-10) in the prison setting.

PubMed

Evren, Cuneyt; Ogel, Kultegin; Evren, Bilge; Bozkurt, Muge

2014-01-01

The aim of this study was to evaluate psychometric properties of the Drug Use Disorders Identification Test (DUDIT) and the Drug Abuse Screening Test (DAST-10) in prisoners with (n = 124) or without (n = 78) drug use disorder. Participants were evaluated with the DUDIT, the DAST-10, and the Addiction Profile Index-Short (API-S). The DUDIT and the DAST-10 were found to be psychometrically sound drug abuse screening measures with high convergent validity when compared with each other (r = 0.86), and API-S (r = 0.88 and r = 0.84, respectively), and to have a Cronbach's α of 0.93 and 0.87, respectively. In addition, a single component accounted for 58.28% of total variance for DUDIT, whereas this was 47.10% for DAST-10. The DUDIT had sensitivity and specificity scores of 0.95 and 0.79, respectively, when using the optimal cut-off score of 10, whereas these scores were 0.88 and 0.74 for the DAST-10 when using the optimal cut-off score of 4. Additionally, both the DUDIT and the DAST-10 showed good discriminant validity as they differentiated prisoners with drug use disorder from those without. Findings support the Turkish versions of both the DUDIT and the DAST-10 as reliable and valid drug abuse screening instruments that measure unidimensional constructs.

Design, development, and validation of a high-throughput drug-screening assay for targeting of human leukemia

PubMed Central

Karjalainen, Katja; Pasqualini, Renata; Cortes, Jorge E.; Kornblau, Steven M.; Lichtiger, Benjamin; O'Brien, Susan; Kantarjian, Hagop M.; Sidman, Richard L.; Arap, Wadih; Koivunen, Erkki

2015-01-01

Background We introduce an ex vivo methodology to perform drug library screening against human leukemia. Method Our strategy relies on human blood or bone marrow cultures under hypoxia; under these conditions, leukemia cells deplete oxygen faster than normal cells, causing a hemoglobin oxygenation shift. We demonstrate several advantages: (I) partial recapitulation of the leukemia microenvironment, (ii) use of native hemoglobin oxygenation as real-time sensor/reporter, (iii) cost-effectiveness, (iv) species-specificity, and (v) format that enables high-throughput screening. Results As a proof-of-concept, we screened a chemical library (size ∼20,000) against human leukemia cells. We identified 70 compounds (“hit” rate=0.35%; Z-factor=0.71) with activity; we examined 20 to find 18 true-positives (90%). Finally, we show that carbonohydraxonic diamide group-containing compounds are potent anti-leukemia agents that induce cell death in leukemia cells and patient-derived samples. Conclusions This unique functional assay can identify novel drug candidates as well as find future applications in personalized drug selection for leukemia patients. PMID:24496871

Drug repurposing screens and synergistic drug‐combinations for infectious diseases

PubMed Central

Sun, Wei; Simeonov, Anton

2017-01-01

Infectious diseases account for nearly one fifth of the worldwide death toll every year. The continuous increase of drug‐resistant pathogens is a big challenge for treatment of infectious diseases. In addition, outbreaks of infections and new pathogens are potential threats to public health. Lack of effective treatments for drug‐resistant bacteria and recent outbreaks of Ebola and Zika viral infections have become a global public health concern. The number of newly approved antibiotics has decreased significantly in the last two decades compared with previous decades. In parallel with this, is an increase in the number of drug‐resistant bacteria. For these threats and challenges to be countered, new strategies and technology platforms are critically needed. Drug repurposing has emerged as an alternative approach for rapid identification of effective therapeutics to treat the infectious diseases. For treatment of severe infections, synergistic drug combinations using approved drugs identified from drug repurposing screens is a useful option which may overcome the problem of weak activity of individual drugs. Collaborative efforts including government, academic researchers and private drug industry can facilitate the translational research to produce more effective new therapeutic agents such as narrow spectrum antibiotics against drug‐resistant bacteria for these global challenges. Linked Articles This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc PMID:28685814

Disease modeling and drug screening for neurological diseases using human induced pluripotent stem cells.

PubMed

Xu, Xiao-hong; Zhong, Zhong

2013-06-01

With the general decline of pharmaceutical research productivity, there are concerns that many components of the drug discovery process need to be redesigned and optimized. For example, the human immortalized cell lines or animal primary cells commonly used in traditional drug screening may not faithfully recapitulate the pathological mechanisms of human diseases, leading to biases in assays, targets, or compounds that do not effectively address disease mechanisms. Recent advances in stem cell research, especially in the development of induced pluripotent stem cell (iPSC) technology, provide a new paradigm for drug screening by permitting the use of human cells with the same genetic makeup as the patients without the typical quantity constraints associated with patient primary cells. In this article, we will review the progress made to date on cellular disease models using human stem cells, with a focus on patient-specific iPSCs for neurological diseases. We will discuss the key challenges and the factors that associated with the success of using stem cell models for drug discovery through examples from monogenic diseases, diseases with various known genetic components, and complex diseases caused by a combination of genetic, environmental and other factors.

Stem cells as a novel tool for drug screening and treatment of degenerative diseases.

PubMed

Zuba-Surma, Ewa K; Wojakowski, Wojciech; Madeja, Zbigniew; Ratajczak, Mariusz Z

2012-01-01

Degenerative diseases similarly as acute tissue injuries lead to massive cell loss and may cause organ failure of vital organs (e.g., heart, central nervous system). Therefore, they belong to a group of disorders that may significantly benefit from stem cells (SCs)-based therapies. Several stem and progenitor cell populations have already been described as valuable tools for developing therapeutic strategies in regenerative medicine. In particular, pluripotent stem cells (PSCs), including adult-tissue-derived PSCs, neonatal-tissue-derived SCs, embryonic stem cells (ESCs), and recently described induced pluripotent stem cells (iPSCs), are the focus of particular attention because of their capacity to differentiate into all the cell lineages. Although PSCs are predominantly envisioned to be applied for organ regeneration, they may be also successfully employed in drug screening and disease modeling. In particular, adult PSCs and iPSCs derived from patient tissues may not only be a source of cells for autologous therapies but also for individual customized in vitro drug testing and studies on the molecular mechanisms of disease. In this review, we will focus on the potential applications of SCs, especially PSCs i) in regenerative medicine therapies, ii) in studying mechanisms of disease, as well as iii) in drug screening and toxicology tests that are crucial in new drug development. In particular, we will discuss the application of SCs in developing new therapeutic approaches to treat degenerative diseases of the neural system and heart. The advantage of adult PSCs in all the above-mentioned settings is that they can be directly harvested from patient tissues and used not only as a safe non-immunogenic source of cells for therapy but also as tools for personalized drug screening and pharmacological therapies.

Experimental and Chemoinformatics Study of Tautomerism in a Database of Commercially Available Screening Samples

PubMed Central

2016-01-01

We investigated how many cases of the same chemical sold as different products (at possibly different prices) occurred in a prototypical large aggregated database and simultaneously tested the tautomerism definitions in the chemoinformatics toolkit CACTVS. We applied the standard CACTVS tautomeric transforms plus a set of recently developed ring–chain transforms to the Aldrich Market Select (AMS) database of 6 million screening samples and building blocks. In 30 000 cases, two or more AMS products were found to be just different tautomeric forms of the same compound. We purchased and analyzed 166 such tautomer pairs and triplets by 1H and 13C NMR to determine whether the CACTVS transforms accurately predicted what is the same “stuff in the bottle”. Essentially all prototropic transforms with examples in the AMS were confirmed. Some of the ring–chain transforms were found to be too “aggressive”, i.e. to equate structures with one another that were different compounds. PMID:27669079

Estimated prevalence of dementia based on analysis of drug databases in the Region of Madrid (Spain).

PubMed

de Hoyos-Alonso, M C; Bonis, J; Tapias-Merino, E; Castell, M V; Otero, A

2016-01-01

The progressive rise in dementia prevalence increases the need for rapid methods that complement population-based prevalence studies. To estimate the prevalence of dementia in the population aged 65 and older based on use of cholinesterase inhibitors and memantine. Descriptive study of use and prescription of cholinesterase inhibitors and/or memantine in 2011 according to 2 databases: Farm@drid (pharmacy billing records for the Region of Madrid) and BIFAP (database for pharmacoepidemiology research in primary care, with diagnosis and prescription records). We tested the comparability of drug use results from each database using the chi-square test and prevalence ratios. The prevalence of dementia in Madrid was estimated based on the dose per 100 inhabitants/day, adjusting the result for data obtained from BIFAP on combination treatment in the general population (0.37%) and the percentage of dementia patients undergoing treatment (41.13%). Cholinesterase inhibitors and memantine were taken by 2.08% and 0.72% of Madrid residents aged 65 and older was respectively. Both databases displayed similar results for use of these drugs. The estimated prevalence of dementia in individuals aged 65 and older is 5.91% (95% CI%, 5.85-5.95) (52 287 people), and it is higher in women (7.16%) than in men (4.00%). The estimated prevalence of dementia is similar to that found in population-based studies. Analysing consumption of specific dementia drugs can be a reliable and inexpensive means of updating prevalence data periodically and helping rationalise healthcare resources. Copyright © 2014 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Modern approaches to accelerate discovery of new antischistosomal drugs.

PubMed

Neves, Bruno Junior; Muratov, Eugene; Machado, Renato Beilner; Andrade, Carolina Horta; Cravo, Pedro Vitor Lemos

2016-06-01

The almost exclusive use of only praziquantel for the treatment of schistosomiasis has raised concerns about the possible emergence of drug-resistant schistosomes. Consequently, there is an urgent need for new antischistosomal drugs. The identification of leads and the generation of high quality data are crucial steps in the early stages of schistosome drug discovery projects. Herein, the authors focus on the current developments in antischistosomal lead discovery, specifically referring to the use of automated in vitro target-based and whole-organism screens and virtual screening of chemical databases. They highlight the strengths and pitfalls of each of the above-mentioned approaches, and suggest possible roadmaps towards the integration of several strategies, which may contribute for optimizing research outputs and led to more successful and cost-effective drug discovery endeavors. Increasing partnerships and access to funding for drug discovery have strengthened the battle against schistosomiasis in recent years. However, the authors believe this battle also includes innovative strategies to overcome scientific challenges. In this context, significant advances of in vitro screening as well as computer-aided drug discovery have contributed to increase the success rate and reduce the costs of drug discovery campaigns. Although some of these approaches were already used in current antischistosomal lead discovery pipelines, the integration of these strategies in a solid workflow should allow the production of new treatments for schistosomiasis in the near future.

[Analysis of tools, methods and results of toxicological screening for detection of drug abuse in Italian professional drivers].

PubMed

Rosso, G L

2013-01-01

Three years after a protocol agreement between the State and the Regions came into force in 2008 (drug testing at the workplace Law) a large number of studies have been conducted to analyse and test the efficacy of on-site screening tests for detection of drug consumption (opiates, cocaine, cannabinoids, amphetamine and methamphetamine, MDMA and methadone), which are frequently used by the occupational health physician, and also to present data resulting from workplace drug testing obtained during health surveillance programmes. The aim of the present study was to verify whether the features of sensitivity and specificity of the most common on-site testing ensure correct application of the provisions of current Italian legislation and also to analyse published studies showing the frequency of positive drug testing. A review of Italian and international literature was carried out aimed at identifying studies relating to: (1) performance of on-site screening tests frequently used by the occupational health physician, (2) prevalence of drug use/abuse among Italian public and commercial transport drivers. A comparison between the studies was then carried out. Several rapid on-site screening tests are commercially available (Italian law does not provide standards for the technical specifications of the tests), the sensitivity and specificity of which varies depending on the model and the substance tested. The sensitivity of these tools is poor when used for the detection of low concentrations of drugs and/or their metabolites in urine (close to the cut-off). Studies are lacking that compare on-site tests performed by the occupational health physician and confirmative tests in specialized laboratories (with particular regard to false positives found by the occupational health physician). The major studies in terms of methods and/or size reported a positive rate (confirmed at the first level) between 1.6% and 1.9%. The drugs most frequently used/abused were cannabis and

Databases in the Area of Pharmacogenetics

PubMed Central

Sim, Sarah C.; Altman, Russ B.; Ingelman-Sundberg, Magnus

2012-01-01

In the area of pharmacogenetics and personalized health care it is obvious that databases, providing important information of the occurrence and consequences of variant genes encoding drug metabolizing enzymes, drug transporters, drug targets, and other proteins of importance for drug response or toxicity, are of critical value for scientists, physicians, and industry. The primary outcome of the pharmacogenomic field is the identification of biomarkers that can predict drug toxicity and drug response, thereby individualizing and improving drug treatment of patients. The drug in question and the polymorphic gene exerting the impact are the main issues to be searched for in the databases. Here, we review the databases that provide useful information in this respect, of benefit for the development of the pharmacogenomic field. PMID:21309040

Combinatorial Drug Screening Identifies Ewing Sarcoma-specific Sensitivities.

PubMed

Radic-Sarikas, Branka; Tsafou, Kalliopi P; Emdal, Kristina B; Papamarkou, Theodore; Huber, Kilian V M; Mutz, Cornelia; Toretsky, Jeffrey A; Bennett, Keiryn L; Olsen, Jesper V; Brunak, Søren; Kovar, Heinrich; Superti-Furga, Giulio

2017-01-01

Improvements in survival for Ewing sarcoma pediatric and adolescent patients have been modest over the past 20 years. Combinations of anticancer agents endure as an option to overcome resistance to single treatments caused by compensatory pathways. Moreover, combinations are thought to lessen any associated adverse side effects through reduced dosing, which is particularly important in childhood tumors. Using a parallel phenotypic combinatorial screening approach of cells derived from three pediatric tumor types, we identified Ewing sarcoma-specific interactions of a diverse set of targeted agents including approved drugs. We were able to retrieve highly synergistic drug combinations specific for Ewing sarcoma and identified signaling processes important for Ewing sarcoma cell proliferation determined by EWS-FLI1 We generated a molecular target profile of PKC412, a multikinase inhibitor with strong synergistic propensity in Ewing sarcoma, revealing its targets in critical Ewing sarcoma signaling routes. Using a multilevel experimental approach including quantitative phosphoproteomics, we analyzed the molecular rationale behind the disease-specific synergistic effect of simultaneous application of PKC412 and IGF1R inhibitors. The mechanism of the drug synergy between these inhibitors is different from the sum of the mechanisms of the single agents. The combination effectively inhibited pathway crosstalk and averted feedback loop repression, in EWS-FLI1-dependent manner. Mol Cancer Ther; 16(1); 88-101. ©2016 AACR. ©2016 American Association for Cancer Research.

Application of the 4D Fingerprint Method with a Robust Scoring Function for Scaffold-Hopping and Drug Repurposing Strategies

PubMed Central

2015-01-01

Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function HWK (Hamza–Wei–Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and HWK scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP1 protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC50 values ranging from 70 to 100 μM against MycP1 and possessed high structural diversity, which provides departure points for further structure–activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the HWK scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy. PMID:25229183

Application of the 4D fingerprint method with a robust scoring function for scaffold-hopping and drug repurposing strategies.

PubMed

Hamza, Adel; Wagner, Jonathan M; Wei, Ning-Ning; Kwiatkowski, Stefan; Zhan, Chang-Guo; Watt, David S; Korotkov, Konstantin V

2014-10-27

Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function HWK (Hamza-Wei-Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and HWK scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP1 protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC50 values ranging from 70 to 100 μM against MycP1 and possessed high structural diversity, which provides departure points for further structure-activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the HWK scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy.

Development of a chemotherapy regimen interaction database for the mobile internet: detecting interactions with psychotropics through OncoRx-MI.

PubMed

Yap, Kevin Yi-Lwern; Chui, Wai Keung; Chan, Alexandre

2011-09-01

Cancer patients are at high risks of drug-drug interactions (DDIs). Clinicians need to know the magnitude of DDIs so as to better manage their patients' drug therapies. We have previously created a novel interaction database for oncology prescriptions (OncoRx). In this project, we leverage on 3G networks to further develop this database into an iPhone-specific application for the mobile internet (OncoRx-MI). Data on anticancer drugs (ACDs), chemotherapy regimens (CRegs) and DDIs with psychotropics were compiled from various hardcopy and online resources, and published articles from PubMed, Scopus and Science Direct. The database and iPhone web documents were designed using Adobe Dreamweaver CS4 and associated with a combination of open-source programming scripts. OncoRx-MI currently detects over 5000 DDIs (69.3% pharmacokinetic, 30.7% pharmacodynamic) between 256 single-agent and combination CRegs with 51 psychotropic drugs. OncoRx-MI fits the iPhone screen configuration, and displays information regarding the regimen, pharmacokinetics of the drugs and detected DDIs in tabular format for improved usability. OncoRx-MI is the first mobile DDI application of its kind which detects interactions for combination CRegs. Future versions will include DDIs with other drug categories. Usability studies on its impact in clinical practice will also be carried out.

Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases.

PubMed

Takada, Mitsutaka; Fujimoto, Mai; Motomura, Haruka; Hosomi, Kouichi

2016-01-01

Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases. A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association. In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study. Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric cancer, and hematological malignancies.

Screening approach for identifying candidate drugs and drug-drug interactions related to hip fracture risk in persons with Alzheimer disease.

PubMed

Tolppanen, Anna-Maija; Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Lavikainen, Piia; Paananen, Jussi; Tiihonen, Jari; Hartikainen, Sirpa

2017-08-01

To assess whether a "drugome-wide" screen with case-crossover design is a feasible approach for identifying candidate drugs and drug-drug interactions. All community-dwelling residents of Finland who received a clinically verified Alzheimer disease diagnosis in 2005 to 2011 and experienced incident hip fracture (HF) afterwards (N = 4851). Three scenarios were used to test the sensitivity of this approach (1) hazard period 0 to 30 and control period 31 to 61 days before HF, (2) hazard period 0 to 30 and control period 336 to 366 days before HF, and (3) hazard period 0 to 14 and control period 16 to 30 days before HF. Nine, 44, and 5 drugs were associated with increased HF risk and 8, 23, and 4 with decreased risk in scenarios 1, 2, and 3, respectively. Six drugs were identified with scenario 1 only and 54 and 1 with scenarios 2 and 3, respectively. Only six drugs (metoprolol, simvastatin, trimethoprim, codeine combinations, fentanyl, and paracetamol) were associated with HF in all scenarios, four with 1 and 2 (cefalexin, buprenorphine, olanzapine, and memantine), and one with 1 and 3 (enalapril) or 2 and 3 (ciprofloxacin). The direction of associations was the same in all/both scenarios. The interaction results were equally versatile, with hydroxocobalamin*oxazepam being the only interaction observed in all scenarios. Case-crossover analysis is a potential approach for identifying candidate drugs and drug-drug interactions associated with adverse events as it implicitly controls for fixed confounders. The results are highly dependent on applied hazard and control periods, but the choice of periods can help in targeting the analyses to different phases of drug use. Copyright © 2017 John Wiley & Sons, Ltd.

Advantages of Crystallographic Fragment Screening: Functional and Mechanistic Insights from a Powerful Platform for Efficient Drug Discovery

PubMed Central

Patel, Disha; Bauman, Joseph D.; Arnold, Eddy

2015-01-01

X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this “chemical interrogation” of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility. PMID:25117499

Advantages of crystallographic fragment screening: functional and mechanistic insights from a powerful platform for efficient drug discovery.

PubMed

Patel, Disha; Bauman, Joseph D; Arnold, Eddy

2014-01-01

X-ray crystallography has been an under-appreciated screening tool for fragment-based drug discovery due to the perception of low throughput and technical difficulty. Investigators in industry and academia have overcome these challenges by taking advantage of key factors that contribute to a successful crystallographic screening campaign. Efficient cocktail design and soaking methodologies have evolved to maximize throughput while minimizing false positives/negatives. In addition, technical improvements at synchrotron beamlines have dramatically increased data collection rates thus enabling screening on a timescale comparable to other techniques. The combination of available resources and efficient experimental design has resulted in many successful crystallographic screening campaigns. The three-dimensional crystal structure of the bound fragment complexed to its target, a direct result of the screening effort, enables structure-based drug design while revealing insights regarding protein dynamics and function not readily obtained through other experimental approaches. Furthermore, this "chemical interrogation" of the target protein crystals can lead to the identification of useful reagents for improving diffraction resolution or compound solubility. Copyright © 2014. Published by Elsevier Ltd.

Discovery of Anthelmintic Drug Targets and Drugs Using Chokepoints in Nematode Metabolic Pathways

PubMed Central

Taylor, Christina M.; Wang, Qi; Rosa, Bruce A.; Huang, Stanley Ching-Cheng; Powell, Kerrie; Schedl, Tim; Pearce, Edward J.; Abubucker, Sahar; Mitreva, Makedonka

2013-01-01

Parasitic roundworm infections plague more than 2 billion people (1/3 of humanity) and cause drastic losses in crops and livestock. New anthelmintic drugs are urgently needed as new drug resistance and environmental concerns arise. A “chokepoint reaction” is defined as a reaction that either consumes a unique substrate or produces a unique product. A chokepoint analysis provides a systematic method of identifying novel potential drug targets. Chokepoint enzymes were identified in the genomes of 10 nematode species, and the intersection and union of all chokepoint enzymes were found. By studying and experimentally testing available compounds known to target proteins orthologous to nematode chokepoint proteins in public databases, this study uncovers features of chokepoints that make them successful drug targets. Chemogenomic screening was performed on drug-like compounds from public drug databases to find existing compounds that target homologs of nematode chokepoints. The compounds were prioritized based on chemical properties frequently found in successful drugs and were experimentally tested using Caenorhabditis elegans. Several drugs that are already known anthelmintic drugs and novel candidate targets were identified. Seven of the compounds were tested in Caenorhabditis elegans and three yielded a detrimental phenotype. One of these three drug-like compounds, Perhexiline, also yielded a deleterious effect in Haemonchus contortus and Onchocerca lienalis, two nematodes with divergent forms of parasitism. Perhexiline, known to affect the fatty acid oxidation pathway in mammals, caused a reduction in oxygen consumption rates in C. elegans and genome-wide gene expression profiles provided an additional confirmation of its mode of action. Computational modeling of Perhexiline and its target provided structural insights regarding its binding mode and specificity. Our lists of prioritized drug targets and drug-like compounds have potential to expedite the discovery

Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections.

PubMed

Don, Rob; Ioset, Jean-Robert

2014-01-01

The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation.

Digital Dental X-ray Database for Caries Screening

NASA Astrophysics Data System (ADS)

Rad, Abdolvahab Ehsani; Rahim, Mohd Shafry Mohd; Rehman, Amjad; Saba, Tanzila

2016-06-01

Standard database is the essential requirement to compare the performance of image analysis techniques. Hence the main issue in dental image analysis is the lack of available image database which is provided in this paper. Periapical dental X-ray images which are suitable for any analysis and approved by many dental experts are collected. This type of dental radiograph imaging is common and inexpensive, which is normally used for dental disease diagnosis and abnormalities detection. Database contains 120 various Periapical X-ray images from top to bottom jaw. Dental digital database is constructed to provide the source for researchers to use and compare the image analysis techniques and improve or manipulate the performance of each technique.

Screening, isolation and optimization of anti–white spot syndrome virus drug derived from marine plants

PubMed Central

Chakraborty, Somnath; Ghosh, Upasana; Balasubramanian, Thangavel; Das, Punyabrata

2014-01-01

Objective To screen, isolate and optimize anti-white spot syndrome virus (WSSV) drug derived from various marine floral ecosystems and to evaluate the efficacy of the same in host–pathogen interaction model. Methods Thirty species of marine plants were subjected to Soxhlet extraction using water, ethanol, methanol and hexane as solvents. The 120 plant isolates thus obtained were screened for their in vivo anti-WSSV property in Litopenaeus vannamei. By means of chemical processes, the purified anti-WSSV plant isolate, MP07X was derived. The drug was optimized at various concentrations. Viral and immune genes were analysed using reverse transcriptase PCR to confirm the potency of the drug. Results Nine plant isolates exhibited significant survivability in host. The drug MP07X thus formulated showing 85% survivability in host. The surviving shrimps were nested PCR negative at the end of the 15 d experimentation. The lowest concentration of MP07X required intramuscularly for virucidal property was 10 mg/mL. The oral dosage of 1 000 mg/kg body weight/day survived at the rate of 85%. Neither VP28 nor ie 1 was expressed in the test samples at 42nd hour and 84th hour post viral infection. Conclusions The drug MP07X derived from Rhizophora mucronata is a potent anti-WSSV drug. PMID:25183065

Screening, isolation and optimization of anti–white spot syndrome virus drug derived from terrestrial plants

PubMed Central

Ghosh, Upasana; Chakraborty, Somnath; Balasubramanian, Thangavel; Das, Punyabrata

2014-01-01

Objective To screen, isolate and optimize anti-white spot syndrome virus (WSSV) drug derived from various terrestrial plants and to evaluate the efficacy of the same in host–pathogen interaction model. Methods Thirty plants were subjected to Soxhlet extraction using water, ethanol, methanol and hexane as solvents. The 120 plant isolates thus obtained were screened for their in vivo anti–WSSV property in Litopenaeus vannamei. The best anti–WSSV plant isolate, TP22C was isolated and further analyzed. The drug was optimized at various concentrations. Viral and immune genes were analysed using reverse transcriptase PCR to confirm the potency of the drug. Results Seven plant isolates exhibited significant survivability in host. The drug TP22C thus formulated showed 86% survivability in host. The surviving shrimps were nested PCR negative at the end of the 15 d experimentation. The lowest concentration of TP22C required intramuscularly for virucidal property was 10 mg/mL. The oral dosage of 750 mg/kg body weight/day survived at the rate of 86%. Neither VP28 nor ie 1 was expressed in the test samples at 42nd hour and 84th hour post viral infection. Conclusions The drug TP22C derived from Momordica charantia is a potent anti-white spot syndrome virus drug. PMID:25183066

Identification of the Beer Component Hordenine as Food-Derived Dopamine D2 Receptor Agonist by Virtual Screening a 3D Compound Database

NASA Astrophysics Data System (ADS)

Sommer, Thomas; Hübner, Harald; El Kerdawy, Ahmed; Gmeiner, Peter; Pischetsrieder, Monika; Clark, Timothy

2017-03-01

The dopamine D2 receptor (D2R) is involved in food reward and compulsive food intake. The present study developed a virtual screening (VS) method to identify food components, which may modulate D2R signalling. In contrast to their common applications in drug discovery, VS methods are rarely applied for the discovery of bioactive food compounds. Here, databases were created that exclusively contain substances occurring in food and natural sources (about 13,000 different compounds in total) as the basis for combined pharmacophore searching, hit-list clustering and molecular docking into D2R homology models. From 17 compounds finally tested in radioligand assays to determine their binding affinities, seven were classified as hits (hit rate = 41%). Functional properties of the five most active compounds were further examined in β-arrestin recruitment and cAMP inhibition experiments. D2R-promoted G-protein activation was observed for hordenine, a constituent of barley and beer, with approximately identical ligand efficacy as dopamine (76%) and a Ki value of 13 μM. Moreover, hordenine antagonised D2-mediated β-arrestin recruitment indicating functional selectivity. Application of our databases provides new perspectives for the discovery of bioactive food constituents using VS methods. Based on its presence in beer, we suggest that hordenine significantly contributes to mood-elevating effects of beer.

Advantages and application of label-free detection assays in drug screening.

PubMed

Cunningham, Brian T; Laing, Lance G

2008-08-01

Adoption is accelerating for a new family of label-free optical biosensors incorporated into standard format microplates owing to their ability to enable highly sensitive detection of small molecules, proteins and cells for high-throughput drug discovery applications. Label-free approaches are displacing other detection technologies owing to their ability to provide simple assay procedures for hit finding/validation, accessing difficult target classes, screening the interaction of cells with drugs and analyzing the affinity of small molecule inhibitors to target proteins. This review describes several new drug discovery applications that are under development for microplate-based photonic crystal optical biosensors and the key issues that will drive adoption of the technology. Microplate-based optical biosensors are enabling a variety of cell-based assays, inhibition assays, protein-protein binding assays and protein-small molecule binding assays to be performed with high-throughput and high sensitivity.

Usefulness of Canadian Public Health Insurance Administrative Databases to Assess Breast and Ovarian Cancer Screening Imaging Technologies for BRCA1/2 Mutation Carriers.

PubMed

Larouche, Geneviève; Chiquette, Jocelyne; Plante, Marie; Pelletier, Sylvie; Simard, Jacques; Dorval, Michel

2016-11-01

In Canada, recommendations for clinical management of hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation have been available since 2007. Eight years later, very little is known about the uptake of screening and risk-reduction measures in this population. Because Canada's public health care system falls under provincial jurisdictions, using provincial health care administrative databases appears a valuable option to assess management of BRCA1/2 mutation carriers. The objective was to explore the usefulness of public health insurance administrative databases in British Columbia, Ontario, and Quebec to assess management after BRCA1/2 genetic testing. Official public health insurance documents were considered potentially useful if they had specific procedure codes, and pertained to procedures performed in the public and private health care systems. All 3 administrative databases have specific procedures codes for mammography and breast ultrasounds. Only Quebec and Ontario have a specific procedure code for breast magnetic resonance imaging. It is impossible to assess, on an individual basis, the frequency of others screening exams, with the exception of CA-125 testing in British Columbia. Screenings done in private practice are excluded from the administrative databases unless covered by special agreements for reimbursement, such as all breast imaging exams in Ontario and mammograms in British Columbia and Quebec. There are no specific procedure codes for risk-reduction surgeries for breast and ovarian cancer. Population-based assessment of breast and ovarian cancer risk management strategies other than mammographic screening, using only administrative data, is currently challenging in the 3 Canadian provinces studied. Copyright © 2016 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.

Mining collections of compounds with Screening Assistant 2

PubMed Central

2012-01-01

Background High-throughput screening assays have become the starting point of many drug discovery programs for large pharmaceutical companies as well as academic organisations. Despite the increasing throughput of screening technologies, the almost infinite chemical space remains out of reach, calling for tools dedicated to the analysis and selection of the compound collections intended to be screened. Results We present Screening Assistant 2 (SA2), an open-source JAVA software dedicated to the storage and analysis of small to very large chemical libraries. SA2 stores unique molecules in a MySQL database, and encapsulates several chemoinformatics methods, among which: providers management, interactive visualisation, scaffold analysis, diverse subset creation, descriptors calculation, sub-structure / SMART search, similarity search and filtering. We illustrate the use of SA2 by analysing the composition of a database of 15 million compounds collected from 73 providers, in terms of scaffolds, frameworks, and undesired properties as defined by recently proposed HTS SMARTS filters. We also show how the software can be used to create diverse libraries based on existing ones. Conclusions Screening Assistant 2 is a user-friendly, open-source software that can be used to manage collections of compounds and perform simple to advanced chemoinformatics analyses. Its modular design and growing documentation facilitate the addition of new functionalities, calling for contributions from the community. The software can be downloaded at http://sa2.sourceforge.net/. PMID:23327565

New drug candidates for liposomal delivery identified by computer modeling of liposomes' remote loading and leakage.

PubMed

Cern, Ahuva; Marcus, David; Tropsha, Alexander; Barenholz, Yechezkel; Goldblum, Amiram

2017-04-28

Remote drug loading into nano-liposomes is in most cases the best method for achieving high concentrations of active pharmaceutical ingredients (API) per nano-liposome that enable therapeutically viable API-loaded nano-liposomes, referred to as nano-drugs. This approach also enables controlled drug release. Recently, we constructed computational models to identify APIs that can achieve the desired high concentrations in nano-liposomes by remote loading. While those previous models included a broad spectrum of experimental conditions and dealt only with loading, here we reduced the scope to the molecular characteristics alone. We model and predict API suitability for nano-liposomal delivery by fixing the main experimental conditions: liposome lipid composition and size to be similar to those of Doxil® liposomes. On that basis, we add a prediction of drug leakage from the nano-liposomes during storage. The latter is critical for having pharmaceutically viable nano-drugs. The "load and leak" models were used to screen two large molecular databases in search of candidate APIs for delivery by nano-liposomes. The distribution of positive instances in both loading and leakage models was similar in the two databases screened. The screening process identified 667 molecules that were positives by both loading and leakage models (i.e., both high-loading and stable). Among them, 318 molecules received a high score in both properties and of these, 67 are FDA-approved drugs. This group of molecules, having diverse pharmacological activities, may be the basis for future liposomal drug development. Copyright © 2017 Elsevier B.V. All rights reserved.

Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains.

PubMed

Shi, Junwei; Wang, Eric; Milazzo, Joseph P; Wang, Zihua; Kinney, Justin B; Vakoc, Christopher R

2015-06-01

CRISPR-Cas9 genome editing technology holds great promise for discovering therapeutic targets in cancer and other diseases. Current screening strategies target CRISPR-Cas9-induced mutations to the 5' exons of candidate genes, but this approach often produces in-frame variants that retain functionality, which can obscure even strong genetic dependencies. Here we overcome this limitation by targeting CRISPR-Cas9 mutagenesis to exons encoding functional protein domains. This generates a higher proportion of null mutations and substantially increases the potency of negative selection. We also show that the magnitude of negative selection can be used to infer the functional importance of individual protein domains of interest. A screen of 192 chromatin regulatory domains in murine acute myeloid leukemia cells identifies six known drug targets and 19 additional dependencies. A broader application of this approach may allow comprehensive identification of protein domains that sustain cancer cells and are suitable for drug targeting.

Three-Dimensional Cell Culture-Based Screening Identifies the Anthelmintic Drug Nitazoxanide as a Candidate for Treatment of Colorectal Cancer.

PubMed

Senkowski, Wojciech; Zhang, Xiaonan; Olofsson, Maria Hägg; Isacson, Ruben; Höglund, Urban; Gustafsson, Mats; Nygren, Peter; Linder, Stig; Larsson, Rolf; Fryknäs, Mårten

2015-06-01

Because dormant cancer cells in hypoxic and nutrient-deprived regions of solid tumors provide a major obstacle to treatment, compounds targeting those cells might have clinical benefits. Here, we describe a high-throughput drug screening approach, using glucose-deprived multicellular tumor spheroids (MCTS) with inner hypoxia, to identify compounds that specifically target this cell population. We used a concept of drug repositioning-using known molecules for new indications. This is a promising strategy to identify molecules for rapid clinical advancement. By screening 1,600 compounds with documented clinical history, we aimed to identify candidates with unforeseen potential for repositioning as anticancer drugs. Our screen identified five molecules with pronounced MCTS-selective activity: nitazoxanide, niclosamide, closantel, pyrvinium pamoate, and salinomycin. Herein, we show that all five compounds inhibit mitochondrial respiration. This suggests that cancer cells in low glucose concentrations depend on oxidative phosphorylation rather than solely glycolysis. Importantly, continuous exposure to the compounds was required to achieve effective treatment. Nitazoxanide, an FDA-approved antiprotozoal drug with excellent pharmacokinetic and safety profile, is the only molecule among the screening hits that reaches high plasma concentrations persisting for up to a few hours after single oral dose. Nitazoxanide activated the AMPK pathway and downregulated c-Myc, mTOR, and Wnt signaling at clinically achievable concentrations. Nitazoxanide combined with the cytotoxic drug irinotecan showed anticancer activity in vivo. We here report that the FDA-approved anthelmintic drug nitazoxanide could be a potential candidate for advancement into cancer clinical trials. ©2015 American Association for Cancer Research.

Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs.

PubMed

Kamola, Piotr J; Maratou, Klio; Wilson, Paul A; Rush, Kay; Mullaney, Tanya; McKevitt, Tom; Evans, Paula; Ridings, Jim; Chowdhury, Probash; Roulois, Aude; Fairchild, Ann; McCawley, Sean; Cartwright, Karen; Gooderham, Nigel J; Gant, Timothy W; Moores, Kitty; Hughes, Stephen A; Edbrooke, Mark R; Clark, Kenneth; Parry, Joel D

2017-09-15

Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs. To rank ASOs based on their effect on the liver, we have developed an acute screen in the mouse that can be applied early in the drug development cycle. A single-dose (3-day) screen with streamlined endpoints (i.e., plasma transaminase levels and liver weights) was observed to be predictive of ASO hepatotoxicity ranking established based on a repeat-dose (15 day) study. Furthermore, to study the underlying mechanisms of liver toxicity, we applied transcriptome profiling and pathway analyses and show that adverse in vivo liver phenotypes correlate with the number of potent, hybridization-mediated off-target effects (OTEs). We propose that a combination of in silico OTE predictions, streamlined in vivo hepatotoxicity screening, and a transcriptome-wide selectivity screen is a valid approach to identifying and progressing safer compounds. Copyright © 2017 GSK R&D. Published by Elsevier Inc. All rights reserved.

Fragment screening for drug leads by weak affinity chromatography (WAC-MS).

PubMed

Ohlson, Sten; Duong-Thi, Minh-Dao

2018-02-23

Fragment-based drug discovery is an important tool for design of small molecule hit-to-lead compounds against various biological targets. Several approved drugs have been derived from an initial fragment screen and many such candidates are in various stages of clinical trials. Finding fragment hits, that are suitable for optimisation by medicinal chemists, is still a challenge as the binding between the small fragment and its target is weak in the range of mM to µM of K d and irrelevant non-specific interactions are abundant in this area of transient interactions. Fortunately, there are methods that can study weak interactions quite efficiently of which NMR, surface plasmon resonance (SPR) and X-ray crystallography are the most prominent. Now, a new technology based on zonal affinity chromatography, weak affinity chromatography (WAC), has been introduced which has remedied many of the problems with other technologies. By combining WAC with mass spectrometry (WAC-MS), it is a powerful tool to identify binders quantitatively in terms of affinity and kinetics either from fragment libraries or from complex mixtures of biological extracts. As WAC-MS can be multiplexed by analysing mixtures of fragments (20-100 fragments) in one sample, this approach yields high throughput, where a whole library of e.g. >2000 fragments can be analysed quantitatively within a day. WAC-MS is easy to perform, where the robustness and quality of HPLC is fully utilized. This review will highlight the rationale behind the application of WAC-MS for fragment screening in drug discovery. Copyright © 2018 Elsevier Inc. All rights reserved.

Exploiting pluripotent stem cell technology for drug discovery, screening, safety, and toxicology assessments.

PubMed

McGivern, Jered V; Ebert, Allison D

2014-04-01

In order for the pharmaceutical industry to maintain a constant flow of novel drugs and therapeutics into the clinic, compounds must be thoroughly validated for safety and efficacy in multiple biological and biochemical systems. Pluripotent stem cells, because of their ability to develop into any cell type in the body and recapitulate human disease, may be an important cellular system to add to the drug development repertoire. This review will discuss some of the benefits of using pluripotent stem cells for drug discovery and safety studies as well as some of the recent applications of stem cells in drug screening studies. We will also address some of the hurdles that need to be overcome in order to make stem cell-based approaches an efficient and effective tool in the quest to produce clinically successful drug compounds. Copyright © 2013 Elsevier B.V. All rights reserved.

Toxicophore exploration as a screening technology for drug design and discovery: techniques, scope and limitations.

PubMed

Singh, Pankaj Kumar; Negi, Arvind; Gupta, Pawan Kumar; Chauhan, Monika; Kumar, Raj

2016-08-01

Toxicity is a common drawback of newly designed chemotherapeutic agents. With the exception of pharmacophore-induced toxicity (lack of selectivity at higher concentrations of a drug), the toxicity due to chemotherapeutic agents is based on the toxicophore moiety present in the drug. To date, methodologies implemented to determine toxicophores may be broadly classified into biological, bioanalytical and computational approaches. The biological approach involves analysis of bioactivated metabolites, whereas the computational approach involves a QSAR-based method, mapping techniques, an inverse docking technique and a few toxicophore identification/estimation tools. Being one of the major steps in drug discovery process, toxicophore identification has proven to be an essential screening step in drug design and development. The paper is first of its kind, attempting to cover and compare different methodologies employed in predicting and determining toxicophores with an emphasis on their scope and limitations. Such information may prove vital in the appropriate selection of methodology and can be used as screening technology by researchers to discover the toxicophoric potentials of their designed and synthesized moieties. Additionally, it can be utilized in the manipulation of molecules containing toxicophores in such a manner that their toxicities might be eliminated or removed.

Solubility prediction, solvate and cocrystal screening as tools for rational crystal engineering.

PubMed

Loschen, Christoph; Klamt, Andreas

2015-06-01

The fact that novel drug candidates are becoming increasingly insoluble is a major problem of current drug development. Computational tools may address this issue by screening for suitable solvents or by identifying potential novel cocrystal formers that increase bioavailability. In contrast to other more specialized methods, the fluid phase thermodynamics approach COSMO-RS (conductor-like screening model for real solvents) allows for a comprehensive treatment of drug solubility, solvate and cocrystal formation and many other thermodynamics properties in liquids. This article gives an overview of recent COSMO-RS developments that are of interest for drug development and contains several new application examples for solubility prediction and solvate/cocrystal screening. For all property predictions COSMO-RS has been used. The basic concept of COSMO-RS consists of using the screening charge density as computed from first principles calculations in combination with fast statistical thermodynamics to compute the chemical potential of a compound in solution. The fast and accurate assessment of drug solubility and the identification of suitable solvents, solvate or cocrystal formers is nowadays possible and may be used to complement modern drug development. Efficiency is increased by avoiding costly quantum-chemical computations using a database of previously computed molecular fragments. COSMO-RS theory can be applied to a range of physico-chemical properties, which are of interest in rational crystal engineering. Most notably, in combination with experimental reference data, accurate quantitative solubility predictions in any solvent or solvent mixture are possible. Additionally, COSMO-RS can be extended to the prediction of cocrystal formation, which results in considerable predictive accuracy concerning coformer screening. In a recent variant costly quantum chemical calculations are avoided resulting in a significant speed-up and ease-of-use. © 2015 Royal

Stent thrombosis with bioabsorbable polymer drug-eluting stents: insights from the Food and Drug Administration database.

PubMed

Khan, Abdur R; Tripathi, Avnish; Farid, Talha A; Abaid, Bilal; Bhatt, Deepak L; Resar, Jon R; Flaherty, Michael P

2017-11-01

SYNERGY, a bioabsorbable polymer-based, everolimus-eluting stent (BP-DES), recently received regulatory approval in the USA for use in percutaneous coronary interventions. Yet, information on the safety of BP-DES in routine clinical practice is limited. Our aim was to compare the safety of the recently approved BP-DES with current durable polymer drug-eluting stents (DP-DES) by analyzing adverse events, namely, stent thrombosis (ST), reported to the Manufacturer and User Facility Device Experience (MAUDE) database. The MAUDE database requires nationwide mandatory notification for adverse events on devices approved for clinical use. This database was searched for adverse events reported between 1 October 2015 and 25 December 2016, encountered after the placement of either BP-DES or DP-DES. Only those adverse events were included where the exposure period to the stents was comparable after the index procedure. Of all the adverse events reported, the event of interest was ST. A total of 951 adverse events were reported. ST occurred in 48/951 of all events, 31/309 and 17/642 when BP-DES or DP-DES were used, respectively (P=0.00001). Of the 31 ST events with BP-DES, 68% (21/31) occurred within less than or equal to 24 h of the index procedure and 52% (16/31) occurred within less than or equal to 2 h. Our results raise the possibility of an increased risk of ST, particularly early ST (within 24 h), with the recently approved BP-DES. However, because of the inherent limitations of reporting within the MAUDE database, these data merely highlight a potential need for additional surveillance and randomized trials to assess further the safety of the bioabsorbable platform.

Virtual Screening Approaches towards the Discovery of Toll-Like Receptor Modulators

PubMed Central

Pérez-Regidor, Lucía; Zarioh, Malik; Ortega, Laura; Martín-Santamaría, Sonsoles

2016-01-01

This review aims to summarize the latest efforts performed in the search for novel chemical entities such as Toll-like receptor (TLR) modulators by means of virtual screening techniques. This is an emergent research field with only very recent (and successful) contributions. Identification of drug-like molecules with potential therapeutic applications for the treatment of a variety of TLR-regulated diseases has attracted considerable interest due to the clinical potential. Additionally, the virtual screening databases and computational tools employed have been overviewed in a descriptive way, widening the scope for researchers interested in the field. PMID:27618029

[Artificial Intelligence in Drug Discovery].

PubMed

Fujiwara, Takeshi; Kamada, Mayumi; Okuno, Yasushi

2018-04-01

According to the increase of data generated from analytical instruments, application of artificial intelligence(AI)technology in medical field is indispensable. In particular, practical application of AI technology is strongly required in "genomic medicine" and "genomic drug discovery" that conduct medical practice and novel drug development based on individual genomic information. In our laboratory, we have been developing a database to integrate genome data and clinical information obtained by clinical genome analysis and a computational support system for clinical interpretation of variants using AI. In addition, with the aim of creating new therapeutic targets in genomic drug discovery, we have been also working on the development of a binding affinity prediction system for mutated proteins and drugs by molecular dynamics simulation using supercomputer "Kei". We also have tackled for problems in a drug virtual screening. Our developed AI technology has successfully generated virtual compound library, and deep learning method has enabled us to predict interaction between compound and target protein.

The University of Kansas High-Throughput Screening Laboratory. Part II: enabling collaborative drug-discovery partnerships through cutting-edge screening technology

PubMed Central

McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

2011-01-01

The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core was established in 2002 at the University of Kansas with support from an NIH grant and the state of Kansas. It collaborates with investigators from national and international academic, nonprofit and pharmaceutical organizations in executing HTS-ready assay development and screening of chemical libraries for target validation, probe selection, hit identification and lead optimization. This is part two of a contribution from the KU HTS laboratory. PMID:21806374

The University of Kansas High-Throughput Screening Laboratory. Part II: enabling collaborative drug-discovery partnerships through cutting-edge screening technology.

PubMed

McDonald, Peter R; Roy, Anuradha; Chaguturu, Rathnam

2011-07-01

The University of Kansas High-Throughput Screening (KU HTS) core is a state-of-the-art drug-discovery facility with an entrepreneurial open-service policy, which provides centralized resources supporting public- and private-sector research initiatives. The KU HTS core was established in 2002 at the University of Kansas with support from an NIH grant and the state of Kansas. It collaborates with investigators from national and international academic, nonprofit and pharmaceutical organizations in executing HTS-ready assay development and screening of chemical libraries for target validation, probe selection, hit identification and lead optimization. This is part two of a contribution from the KU HTS laboratory.

Implementing screening, brief intervention, and referral for alcohol and drug use: the trauma service perspective.

PubMed

Sise, Michael J; Sise, C Beth; Kelley, Dorothy M; Simmons, Charles W; Kelso, Dennis J

2005-09-01

Most trauma surgeons are unfamiliar with screening, brief intervention, and referral (SBIR) programs for substance use disorders, and few trauma centers provide them. This report describes how an urban private-teaching hospital adapted a protocol from an existing emergency department-based program to include patients treated by the trauma service. We recorded the rates of SBIR completion and reasons for failure during each phase of the implementation, interviewed trauma service staff and health educators to assess attitudes toward the program, and evaluated patient satisfaction surveys. By adding SBIR staff to the trauma outpatient clinic and to trauma morning rounds, the capture rate increased from 12 to 71%. Most screened patients (59%) were found at risk for problems or probably dependent on alcohol or drugs. Trauma service staff and health educators reported high satisfaction with the program. Patients reported higher satisfaction with SBIR. SBIR services can be effectively integrated into all components of a busy, urban trauma service by adding specially trained health educators to the trauma service staff. This collaboration provides effective SBIR services to both trauma and emergency service patients without interfering with patient flow or medical procedures. The relatively high percentage of patients at risk for alcohol or drug problems supports the inclusion of routine alcohol and drug screening for all eligible trauma patients.

Hearing impairment in premature newborns—Analysis based on the national hearing screening database in Poland

PubMed Central

Greczka, Grazyna; Dabrowski, Piotr; Szyfter-Harris, Joanna; Mazela, Jan

2017-01-01

Objectives The incidence of sensorineural hearing loss is between 1 and 3 per 1000 in healthy neonates and 2–4 per 100 in high-risk infants. The national universal neonatal hearing screening carried out in Poland since 2002 enables selection of infants with suspicion and/or risk factors of hearing loss. In this study, we assessed the incidence and risk factors of hearing impairment in infants ≤33 weeks’ gestational age (wga). Methods We analyzed the database of the Polish Universal Newborns Hearing Screening Program from 2010 to 2013. The study group involved 11438 infants born before 33 wga, the control group—1487730 infants. Screening was performed by means of transient evoked otoacoustic emissions. The risk factors of hearing loss were recorded. Infants who failed the screening test and/or had risk factors were referred for further audiological evaluation. Results Hearing deficit was diagnosed in 11% of infants ≤25 wga, 5% at 26–27 wga, 3.46% at 28 wga and 2–3% at 29–32 wga. In the control group the incidence of hearing deficit was 0.2% (2.87% with risk factors). The most important risk factors were craniofacial malformations, very low birth weight, low Apgar score and mechanical ventilation. Hearing screening was positive in 22.42% newborns ≤28 wga and 10% at 29–32 wga and in the control group. Conclusions Hearing impairment is a severe consequence of prematurity. Its prevalence is inversely related to the maturity of the baby. Premature infants have many concomitant risk factors which influence the occurrence of hearing deficit. PMID:28910311

High performance in silico virtual drug screening on many-core processors.

PubMed

McIntosh-Smith, Simon; Price, James; Sessions, Richard B; Ibarra, Amaurys A

2015-05-01

Drug screening is an important part of the drug development pipeline for the pharmaceutical industry. Traditional, lab-based methods are increasingly being augmented with computational methods, ranging from simple molecular similarity searches through more complex pharmacophore matching to more computationally intensive approaches, such as molecular docking. The latter simulates the binding of drug molecules to their targets, typically protein molecules. In this work, we describe BUDE, the Bristol University Docking Engine, which has been ported to the OpenCL industry standard parallel programming language in order to exploit the performance of modern many-core processors. Our highly optimized OpenCL implementation of BUDE sustains 1.43 TFLOP/s on a single Nvidia GTX 680 GPU, or 46% of peak performance. BUDE also exploits OpenCL to deliver effective performance portability across a broad spectrum of different computer architectures from different vendors, including GPUs from Nvidia and AMD, Intel's Xeon Phi and multi-core CPUs with SIMD instruction sets.

High performance in silico virtual drug screening on many-core processors

PubMed Central

Price, James; Sessions, Richard B; Ibarra, Amaurys A

2015-01-01

Drug screening is an important part of the drug development pipeline for the pharmaceutical industry. Traditional, lab-based methods are increasingly being augmented with computational methods, ranging from simple molecular similarity searches through more complex pharmacophore matching to more computationally intensive approaches, such as molecular docking. The latter simulates the binding of drug molecules to their targets, typically protein molecules. In this work, we describe BUDE, the Bristol University Docking Engine, which has been ported to the OpenCL industry standard parallel programming language in order to exploit the performance of modern many-core processors. Our highly optimized OpenCL implementation of BUDE sustains 1.43 TFLOP/s on a single Nvidia GTX 680 GPU, or 46% of peak performance. BUDE also exploits OpenCL to deliver effective performance portability across a broad spectrum of different computer architectures from different vendors, including GPUs from Nvidia and AMD, Intel’s Xeon Phi and multi-core CPUs with SIMD instruction sets. PMID:25972727

Quantum probability ranking principle for ligand-based virtual screening.

PubMed

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

Quantum probability ranking principle for ligand-based virtual screening

NASA Astrophysics Data System (ADS)

Al-Dabbagh, Mohammed Mumtaz; Salim, Naomie; Himmat, Mubarak; Ahmed, Ali; Saeed, Faisal

2017-04-01

Chemical libraries contain thousands of compounds that need screening, which increases the need for computational methods that can rank or prioritize compounds. The tools of virtual screening are widely exploited to enhance the cost effectiveness of lead drug discovery programs by ranking chemical compounds databases in decreasing probability of biological activity based upon probability ranking principle (PRP). In this paper, we developed a novel ranking approach for molecular compounds inspired by quantum mechanics, called quantum probability ranking principle (QPRP). The QPRP ranking criteria would make an attempt to draw an analogy between the physical experiment and molecular structure ranking process for 2D fingerprints in ligand based virtual screening (LBVS). The development of QPRP criteria in LBVS has employed the concepts of quantum at three different levels, firstly at representation level, this model makes an effort to develop a new framework of molecular representation by connecting the molecular compounds with mathematical quantum space. Secondly, estimate the similarity between chemical libraries and references based on quantum-based similarity searching method. Finally, rank the molecules using QPRP approach. Simulated virtual screening experiments with MDL drug data report (MDDR) data sets showed that QPRP outperformed the classical ranking principle (PRP) for molecular chemical compounds.

Inverse Band Structure Design via Materials Database Screening: Application to Square Planar Thermoelectrics

DOE PAGES

Isaacs, Eric B.; Wolverton, Chris

2018-02-26

Electronic band structure contains a wealth of information on the electronic properties of a solid and is routinely computed. However, the more difficult problem of designing a solid with a desired band structure is an outstanding challenge. In order to address this inverse band structure design problem, we devise an approach using materials database screening with materials attributes based on the constituent elements, nominal electron count, crystal structure, and thermodynamics. Our strategy is tested in the context of thermoelectric materials, for which a targeted band structure containing both flat and dispersive components with respect to crystal momentum is highly desirable.more » We screen for thermodynamically stable or metastable compounds containing d 8 transition metals coordinated by anions in a square planar geometry in order to mimic the properties of recently identified oxide thermoelectrics with such a band structure. In doing so, we identify 157 compounds out of a total of over half a million candidates. After further screening based on electronic band gap and structural anisotropy, we explicitly compute the band structures for the several of the candidates in order to validate the approach. We successfully find two new oxide systems that achieve the targeted band structure. Electronic transport calculations on these two compounds, Ba 2PdO 3 and La 4PdO 7, confirm promising thermoelectric power factor behavior for the compounds. This methodology is easily adapted to other targeted band structures and should be widely applicable to a variety of design problems.« less

Inverse Band Structure Design via Materials Database Screening: Application to Square Planar Thermoelectrics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Isaacs, Eric B.; Wolverton, Chris

Electronic band structure contains a wealth of information on the electronic properties of a solid and is routinely computed. However, the more difficult problem of designing a solid with a desired band structure is an outstanding challenge. In order to address this inverse band structure design problem, we devise an approach using materials database screening with materials attributes based on the constituent elements, nominal electron count, crystal structure, and thermodynamics. Our strategy is tested in the context of thermoelectric materials, for which a targeted band structure containing both flat and dispersive components with respect to crystal momentum is highly desirable.more » We screen for thermodynamically stable or metastable compounds containing d 8 transition metals coordinated by anions in a square planar geometry in order to mimic the properties of recently identified oxide thermoelectrics with such a band structure. In doing so, we identify 157 compounds out of a total of over half a million candidates. After further screening based on electronic band gap and structural anisotropy, we explicitly compute the band structures for the several of the candidates in order to validate the approach. We successfully find two new oxide systems that achieve the targeted band structure. Electronic transport calculations on these two compounds, Ba 2PdO 3 and La 4PdO 7, confirm promising thermoelectric power factor behavior for the compounds. This methodology is easily adapted to other targeted band structures and should be widely applicable to a variety of design problems.« less

The 2018 Nucleic Acids Research database issue and the online molecular biology database collection.

PubMed

Rigden, Daniel J; Fernández, Xosé M

2018-01-04

The 2018 Nucleic Acids Research Database Issue contains 181 papers spanning molecular biology. Among them, 82 are new and 84 are updates describing resources that appeared in the Issue previously. The remaining 15 cover databases most recently published elsewhere. Databases in the area of nucleic acids include 3DIV for visualisation of data on genome 3D structure and RNArchitecture, a hierarchical classification of RNA families. Protein databases include the established SMART, ELM and MEROPS while GPCRdb and the newcomer STCRDab cover families of biomedical interest. In the area of metabolism, HMDB and Reactome both report new features while PULDB appears in NAR for the first time. This issue also contains reports on genomics resources including Ensembl, the UCSC Genome Browser and ENCODE. Update papers from the IUPHAR/BPS Guide to Pharmacology and DrugBank are highlights of the drug and drug target section while a number of proteomics databases including proteomicsDB are also covered. The entire Database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). The NAR online Molecular Biology Database Collection has been updated, reviewing 138 entries, adding 88 new resources and eliminating 47 discontinued URLs, bringing the current total to 1737 databases. It is available at http://www.oxfordjournals.org/nar/database/c/. © The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.

Developing science gateways for drug discovery in a grid environment.

PubMed

Pérez-Sánchez, Horacio; Rezaei, Vahid; Mezhuyev, Vitaliy; Man, Duhu; Peña-García, Jorge; den-Haan, Helena; Gesing, Sandra

2016-01-01

Methods for in silico screening of large databases of molecules increasingly complement and replace experimental techniques to discover novel compounds to combat diseases. As these techniques become more complex and computationally costly we are faced with an increasing problem to provide the research community of life sciences with a convenient tool for high-throughput virtual screening on distributed computing resources. To this end, we recently integrated the biophysics-based drug-screening program FlexScreen into a service, applicable for large-scale parallel screening and reusable in the context of scientific workflows. Our implementation is based on Pipeline Pilot and Simple Object Access Protocol and provides an easy-to-use graphical user interface to construct complex workflows, which can be executed on distributed computing resources, thus accelerating the throughput by several orders of magnitude.

Building a virtual ligand screening pipeline using free software: a survey.

PubMed

Glaab, Enrico

2016-03-01

Virtual screening, the search for bioactive compounds via computational methods, provides a wide range of opportunities to speed up drug development and reduce the associated risks and costs. While virtual screening is already a standard practice in pharmaceutical companies, its applications in preclinical academic research still remain under-exploited, in spite of an increasing availability of dedicated free databases and software tools. In this survey, an overview of recent developments in this field is presented, focusing on free software and data repositories for screening as alternatives to their commercial counterparts, and outlining how available resources can be interlinked into a comprehensive virtual screening pipeline using typical academic computing facilities. Finally, to facilitate the set-up of corresponding pipelines, a downloadable software system is provided, using platform virtualization to integrate pre-installed screening tools and scripts for reproducible application across different operating systems. © The Author 2015. Published by Oxford University Press.

Building a virtual ligand screening pipeline using free software: a survey

PubMed Central

2016-01-01

Virtual screening, the search for bioactive compounds via computational methods, provides a wide range of opportunities to speed up drug development and reduce the associated risks and costs. While virtual screening is already a standard practice in pharmaceutical companies, its applications in preclinical academic research still remain under-exploited, in spite of an increasing availability of dedicated free databases and software tools. In this survey, an overview of recent developments in this field is presented, focusing on free software and data repositories for screening as alternatives to their commercial counterparts, and outlining how available resources can be interlinked into a comprehensive virtual screening pipeline using typical academic computing facilities. Finally, to facilitate the set-up of corresponding pipelines, a downloadable software system is provided, using platform virtualization to integrate pre-installed screening tools and scripts for reproducible application across different operating systems. PMID:26094053

In vitro microfluidic models of tumor microenvironment to screen transport of drugs and nanoparticles.

PubMed

Ozcelikkale, Altug; Moon, Hye-Ran; Linnes, Michael; Han, Bumsoo

2017-09-01

Advances in nanotechnology have enabled numerous types of nanoparticles (NPs) to improve drug delivery to tumors. While many NP systems have been proposed, their clinical translation has been less than anticipated primarily due to failure of current preclinical evaluation techniques to adequately model the complex interactions between the NP and physiological barriers of tumor microenvironment. This review focuses on microfluidic tumor models for characterization of delivery efficacy and toxicity of cancer nanomedicine. Microfluidics offer significant advantages over traditional macroscale cell cultures by enabling recapitulation of tumor microenvironment through precise control of physiological cues such as hydrostatic pressure, shear stress, oxygen, and nutrient gradients. Microfluidic systems have recently started to be adapted for screening of drugs and NPs under physiologically relevant settings. So far the two primary application areas of microfluidics in this area have been high-throughput screening using traditional culture settings such as single cells or multicellular tumor spheroids, and mimicry of tumor microenvironment for study of cancer-related cell-cell and cell-matrix interactions. These microfluidic technologies are also useful in modeling specific steps in NP delivery to tumor and characterize NP transport properties and outcomes by systematic variation of physiological conditions. Ultimately, it will be possible to design drug-screening platforms uniquely tailored for individual patient physiology using microfluidics. These in vitro models can contribute to development of precision medicine by enabling rapid and patient-specific evaluation of cancer nanomedicine. WIREs Nanomed Nanobiotechnol 2017, 9:e1460. doi: 10.1002/wnan.1460 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

Advantageous use of HepaRG cells for the screening and mechanistic study of drug-induced steatosis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tolosa, Laia

Only a few in vitro assays have been proposed to evaluate the steatotic potential of new drugs. The present study examines the utility of HepaRG cells as a cell-based assay system for screening drug-induced liver steatosis. A high-content screening assay was run to evaluate multiple toxicity-related cell parameters in HepaRG cells exposed to 28 compounds, including drugs reported to cause steatosis through different mechanisms and non-steatotic compounds. Lipid content was the most sensitive parameter for all the steatotic drugs, whereas no effects on lipid levels were produced by non-steatotic compounds. Apart from fat accumulation, increased ROS production and altered mitochondrialmore » membrane potential were also found in the cells exposed to steatotic drugs, which indicates that all these cellular events contributed to drug-induced hepatotoxicity. These findings are of clinical relevance as most effects were observed at drug concentrations under 100-fold of the therapeutic peak plasmatic concentration. HepaRG cells showed increased lipid overaccumulation vs. HepG2 cells, which suggests greater sensitivity to drug-induced steatosis. An altered expression profile of transcription factors and the genes that code key proteins in lipid metabolism was also found in the cells exposed to drugs capable of inducing liver steatosis. Our results generally indicate the value of HepaRG cells for assessing the risk of liver damage associated with steatogenic compounds and for investigating the molecular mechanisms involved in drug-induced steatosis. - Highlights: • HepaRG cells were explored as an in vitro model to detect steatogenic potential. • Multiple toxicity-related endpoints were analysed by HCS. • HepaRG showed a greater sensitivity to drug-induced steatosis than HepG2 cells. • Changes in the expression of genes related to lipid metabolism were revealed. • HepaRG allow mechanistic understanding of liver damage induced by steatogenic drugs.« less

Getting the Most out of PubChem for Virtual Screening

PubMed Central

Kim, Sunghwan

2016-01-01

Introduction With the emergence of the “big data” era, the biomedical research community has great interest in exploiting publicly available chemical information for drug discovery. PubChem is an example of public databases that provide a large amount of chemical information free of charge. Areas covered This article provides an overview of how PubChem’s data, tools, and services can be used for virtual screening and reviews recent publications that discuss important aspects of exploiting PubChem for drug discovery. Expert opinion PubChem offers comprehensive chemical information useful for drug discovery. It also provides multiple programmatic access routes, which are essential to build automated virtual screening pipelines that exploit PubChem data. In addition, PubChemRDF allows users to download PubChem data and load them into a local computing facility, facilitating data integration between PubChem and other resources. PubChem resources have been used in many studies for developing bioactivity and toxicity prediction models, discovering polypharmacologic (multi-target) ligands, and identifying new macromolecule targets of compounds (for drug-repurposing or off-target side effect prediction). These studies demonstrate the usefulness of PubChem as a key resource for computer-aided drug discovery and related area. PMID:27454129

Evaluation of contents-based image retrieval methods for a database of logos on drug tablets

NASA Astrophysics Data System (ADS)

Geradts, Zeno J.; Hardy, Huub; Poortman, Anneke; Bijhold, Jurrien

2001-02-01

In this research an evaluation has been made of the different ways of contents based image retrieval of logos of drug tablets. On a database of 432 illicitly produced tablets (mostly containing MDMA), we have compared different retrieval methods. Two of these methods were available from commercial packages, QBIC and Imatch, where the implementation of the contents based image retrieval methods are not exactly known. We compared the results for this database with the MPEG-7 shape comparison methods, which are the contour-shape, bounding box and region-based shape methods. In addition, we have tested the log polar method that is available from our own research.

Faculty buy-in to teach alcohol and drug use screening.

PubMed

Puskar, Kathy; Mitchell, Ann M; Kane, Irene; Hagle, Holly; Talcott, Kimberly S

2014-09-01

Educating nursing faculty about the use of an evidence-based practice to screen and intervene earlier along the continuum of alcohol and other drug use, misuse, and dependence is essential in today's health care arena. Misuse of alcohol and other drugs is a significant problem for both individual health and societal economic welfare. The purpose of this article is to describe nursing faculty buy-in for the implementation of an evidence-based addiction training program at a university-based school of nursing. Derived from an academic-community partnership, the training program results suggest implications for continuing education and curriculum innovation in schools of nursing and clinical practice. The training content presented can be used in continuing education for nursing faculty across all types of nursing school programs and professional nursing staff employed in multiple settings. The training program was funded by the Health Resources and Services Administration.

Engineering a functional three-dimensional human cardiac tissue model for drug toxicity screening.

PubMed

Lu, Hong Fang; Leong, Meng Fatt; Lim, Tze Chiun; Chua, Ying Ping; Lim, Jia Kai; Du, Chan; Wan, Andrew C A

2017-05-11

Cardiotoxicity is one of the major reasons for clinical drug attrition. In vitro tissue models that can provide efficient and accurate drug toxicity screening are highly desired for preclinical drug development and personalized therapy. Here, we report the fabrication and characterization of a human cardiac tissue model for high throughput drug toxicity studies. Cardiac tissues were fabricated via cellular self-assembly of human transgene-free induced pluripotent stem cells-derived cardiomyocytes in pre-fabricated polydimethylsiloxane molds. The formed tissue constructs expressed cardiomyocyte-specific proteins, exhibited robust production of extracellular matrix components such as laminin, collagen and fibronectin, aligned sarcomeric organization, and stable spontaneous contractions for up to 2 months. Functional characterization revealed that the cardiac cells cultured in 3D tissues exhibited higher contraction speed and rate, and displayed a significantly different drug response compared to cells cultured in age-matched 2D monolayer. A panel of clinically relevant compounds including antibiotic, antidiabetic and anticancer drugs were tested in this study. Compared to conventional viability assays, our functional contractility-based assays were more sensitive in predicting drug-induced cardiotoxic effects, demonstrating good concordance with clinical observations. Thus, our 3D cardiac tissue model shows great potential to be used for early safety evaluation in drug development and drug efficiency testing for personalized therapy.

Optical diagnostics of osteoblast cells and osteogenic drug screening

NASA Astrophysics Data System (ADS)

Kolanti, Elayaraja; Veerla, Sarath C.; Khajuria, Deepak K.; Roy Mahapatra, D.

2016-02-01

Microfluidic device based diagnostics involving optical fibre path, in situ imaging and spectroscopy are gaining importance due to recent advances in diagnostics instrumentation and methods, besides other factors such as low amount of reagent required for analysis, short investigation times, and potential possibilities to replace animal model based study in near future. It is possible to grow and monitor tissues in vitro in microfluidic lab-on-chip. It may become a transformative way of studying how cells interact with drugs, pathogens and biomaterials in physiologically relevant microenvironments. To a large extent, progress in developing clinically viable solutions has been constrained because of (i) contradiction between in vitro and in vivo results and (ii) animal model based and clinical studies which is very expensive. Our study here aims to evaluate the usefulness of microfluidic device based 3D tissue growth and monitoring approach to better emulate physiologically and clinically relevant microenvironments in comparison to conventional in vitro 2D culture. Moreover, the microfluidic methodology permits precise high-throughput investigations through real-time imaging while using very small amounts of reagents and cells. In the present study, we report on the details of an osteoblast cell based 3D microfluidic platform which we employ for osteogenic drug screening. The drug formulation is functionalized with fluorescence and other biomarkers for imaging and spectroscopy, respectively. Optical fibre coupled paths are used to obtain insight regarding the role of stress/flow pressure fluctuation and nanoparticle-drug concentration on the osteoblast growth and osteogenic properties of bone.

tcpl: the ToxCast pipeline for high-throughput screening data.

PubMed

Filer, Dayne L; Kothiya, Parth; Setzer, R Woodrow; Judson, Richard S; Martin, Matthew T

2017-02-15

Large high-throughput screening (HTS) efforts are widely used in drug development and chemical toxicity screening. Wide use and integration of these data can benefit from an efficient, transparent and reproducible data pipeline. Summary: The tcpl R package and its associated MySQL database provide a generalized platform for efficiently storing, normalizing and dose-response modeling of large high-throughput and high-content chemical screening data. The novel dose-response modeling algorithm has been tested against millions of diverse dose-response series, and robustly fits data with outliers and cytotoxicity-related signal loss. tcpl is freely available on the Comprehensive R Archive Network under the GPL-2 license. martin.matt@epa.gov. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.

Chemogenomics profiling of drug targets of peptidoglycan biosynthesis pathway in Leptospira interrogans by virtual screening approaches.

PubMed

Bhattacharjee, Biplab; Simon, Rose Mary; Gangadharaiah, Chaithra; Karunakar, Prashantha

2013-06-28

Leptospirosis is a worldwide zoonosis of global concern caused by Leptospira interrogans. The availability of ligand libraries has facilitated the search for novel drug targets using chemogenomics approaches, compared with the traditional method of drug discovery, which is time consuming and yields few leads with little intracellular information for guiding target selection. Recent subtractive genomics studies have revealed the putative drug targets in peptidoglycan biosynthesis pathways in Leptospira interrogans. Aligand library for the murD ligase enzyme in the peptidoglycan pathway has also been identified. Our approach in this research involves screening of the pre-existing ligand library of murD with related protein family members in the putative drug target assembly in the peptidoglycan biosynthesis pathway. A chemogenomics approach has been implemented here, which involves screening of known ligands of a protein family having analogous domain architecture for identification of leads for existing druggable protein family members. By means of this approach, one murC and one murF inhibitor were identified, providing a platform for developing an antileptospirosis drug targeting the peptidoglycan biosynthesis pathway. Given that the peptidoglycan biosynthesis pathway is exclusive to bacteria, the in silico identified mur ligase inhibitors are expected to be broad-spectrum Gram-negative inhibitors if synthesized and tested in in vitro and in vivo assays.

High-throughput screening of PLGA thin films utilizing hydrophobic fluorescent dyes for hydrophobic drug compounds.

PubMed

Steele, Terry W J; Huang, Charlotte L; Kumar, Saranya; Widjaja, Effendi; Chiang Boey, Freddy Yin; Loo, Joachim S C; Venkatraman, Subbu S

2011-10-01

Hydrophobic, antirestenotic drugs such as paclitaxel (PCTX) and rapamycin are often incorporated into thin film coatings for local delivery using implantable medical devices and polymers such as drug-eluting stents and balloons. Selecting the optimum coating formulation through screening the release profile of these drugs in thin films is time consuming and labor intensive. We describe here a high-throughput assay utilizing three model hydrophobic fluorescent compounds: fluorescein diacetate (FDAc), coumarin-6, and rhodamine 6G that were incorporated into poly(d,l-lactide-co-glycolide) (PLGA) and PLGA-polyethylene glycol films. Raman microscopy determined the hydrophobic fluorescent dye distribution within the PLGA thin films in comparison with that of PCTX. Their subsequent release was screened in a high-throughput assay and directly compared with HPLC quantification of PCTX release. It was observed that PCTX controlled-release kinetics could be mimicked by a hydrophobic dye that had similar octanol-water partition coefficient values and homogeneous dissolution in a PLGA matrix as the drug. In particular, FDAc was found to be the optimal hydrophobic dye at modeling the burst release as well as the total amount of PCTX released over a period of 30 days. Copyright © 2011 Wiley-Liss, Inc.

Data-mining for detecting signals of adverse drug reactions of fluoxetine using the Korea Adverse Event Reporting System (KAERS) database.

PubMed

Kim, Seonji; Park, Kyounghoon; Kim, Mi-Sook; Yang, Bo Ram; Choi, Hyun Jin; Park, Byung-Joo

2017-10-01

Selective serotonin reuptake inhibitors (SSRIs) have become one of the most broadly used medications in psychiatry. Fluoxetine is the first representative antidepressant SSRI drug approved by the Food and Drug Administration (FDA) in 1987. Safety information on fluoxetine use alone was less reported than its combined use with other drugs. There were no published papers on adverse drug reactions (ADRs) of fluoxetine analyzing spontaneous adverse events reports. We detected signals of the adverse drug reactions of fluoxetine by data mining using the Korea Adverse Events Reporting System (KAERS) database. We defined signals in this study by the reporting odds ratios (ROR), proportional reporting ratios (PRR), and information components (IC) indices. The KAERS database included 860,224 AE reports, among which 866 reports contained fluoxetine. We compared the labels of fluoxetine among the United States, UK, Germany, France, China, and Korea. Some of the signals, including emotional lability, myositis, spinal stenosis, paradoxical drug reaction, drug dependence, extrapyramidal disorder, adrenal insufficiency, and intracranial hemorrhage, were not labeled in the six countries. In conclusion, we identified new signals that were not known at the time of market approval. However, certain factors should be required for signal evaluation, such as clinical significance, preventability, and causality of the detected signals. Copyright © 2017 Elsevier B.V. All rights reserved.

The feasibility and acceptability of screening for hypertension in private drug retail outlets: a pilot study in Mwanza region, Tanzania.

PubMed

Michael, Denna; Kezakubi, Dotto; Juma, Adinan; Todd, Jim; Reyburn, Hugh; Renju, Jenny

2016-09-01

Hypertension is a major contributor to ill health in sub-Saharan Africa. Developing countries need to increase access for screening. This study assesses the feasibility and acceptability of using private sector drug retail outlets to screen for hypertension in Mwanza region, Tanzania. A pilot study took place in eight drug retail outlets from August 2013 to February 2014. Customers ≥18 years were invited for screening. Socio-demographic characteristics, hypertension knowledge, hypertension screening and treatment history were collected. Subjects with systolic blood pressure over 140 mmHg were referred for follow up. Referral slips captured attendance. Mystery client visits and follow up phone calls were conducted to assess service quality. A total of 971 customers were screened, one person refused; 109 (11.2%) had blood pressure over 140/90 mmHg and were referred for ongoing assessment; 85/109 (78.0%) were newly diagnosed. Customers reported that the service was acceptable. Service providers were able to follow the protocol. Only 18/85 (21%) newly diagnosed participants visited the referral clinic within two weeks. Blood pressure screening was feasible and acceptable to customers of private drug retail outlets. However many who were referred failed to attend at a referral centre and further research is needed in this area. © The Author 2016. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

The acute social defeat stress and nest-building test paradigm: A potential new method to screen drugs for depressive-like symptoms.

PubMed

Otabi, Hikari; Goto, Tatsuhiko; Okayama, Tsuyoshi; Kohari, Daisuke; Toyoda, Atsushi

2017-02-01

Psychosocial stress can cause mental conditions such as depression in humans. To develop drug therapies for the treatment of depression, it is necessary to use animal models of depression to screen drug candidates that exhibit anti-depressive effects. Unfortunately, the present methods of drug screening for antidepressants, the forced-swim test and tail-suspension test, are limiting factors in drug discovery because they are not based on the constructive validity of objective phenotypes in depression. Previously, we discovered that the onset of nest building is severely delayed in mice exposed to subchronic mild social defeat stress (sCSDS). Therefore, a novel paradigm combining acute social defeat stress (ASDS) and the nest-building test (SNB) were established for the efficient screening of drugs for depressive-like symptoms. Since ASDS severely delayed the nest-building process as shown in chronically social defeated mice, we sought to rescue the delayed nest-building behavior in ASDS mice. Injecting a specific serotonin 2a receptor antagonist (SR-46349B), the nest-building deficit exhibited by ASDS mice was partially rescued. On the other hand, a selective serotonin reuptake inhibitor (fluoxetine) did not rescue the nest-building deficit in ASDS mice. Therefore, we conclude that the SNB paradigm is an another potential behavioral method for screening drugs for depressive-like symptoms including attention deficit, anxiety, low locomotion, and decreased motivation. Copyright © 2016 Elsevier B.V. All rights reserved.

Screening of pharmaceuticals and illicit drugs in wastewater and surface waters of Spain and Italy by high resolution mass spectrometry using UHPLC-QTOF MS and LC-LTQ-Orbitrap MS.

PubMed

Bade, Richard; Rousis, Nikolaos I; Bijlsma, Lubertus; Gracia-Lor, Emma; Castiglioni, Sara; Sancho, Juan V; Hernandez, Felix

2015-12-01

The existence of pharmaceuticals and illicit drugs (PIDs) in environmental waters has led many analytical chemists to develop screening methods for monitoring purposes. Water samples can contain a huge number of possible contaminants, commonly at low concentrations, which makes their detection and identification problematic. Liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) has proven itself effective in the screening of environmental contaminants. The present work investigates the use of the most popular HRMS instruments, quadrupole time-of-flight and linear trap quadrupole-Orbitrap, from two different laboratories. A suspect screening for PIDs was carried out on wastewater (influent and effluent) and surface water samples from Castellón, Eastern Spain, and Cremona, Northern Italy, incorporating a database of 107 PIDs (including 220 fragment ions). A comparison between the findings of both instruments and of the samples was made which highlights the advantages and drawbacks of the strategies applied in each case. In total, 28 compounds were detected and/or identified by either/both instruments with irbesartan, valsartan, benzoylecgonine and caffeine being the most commonly found compounds across all samples.

Drug library screening against metronidazole-sensitive and metronidazole-resistant Trichomonas vaginalis isolates.

PubMed

Goodhew, E Brook; Secor, W Evan

2013-09-01

Metronidazole and tinidazole are effective treatments for most patients with trichomoniasis but not for individuals who are infected with very resistant strains of Trichomonas vaginalis or persons with hypersensitivity to the 5-nitroimidazole drugs. Thus, there is a need for additional oral therapies to treat trichomoniasis. We screened the US Drug Collection Library against metronidazole-susceptible and resistant strains of T vaginalis. Activity was measured by incubating parasites and drugs for 48 h in the presence of tritiated thymidine. Growth inhibition was determined by the reduction of incorporated radioactivity by compounds at 20 μM in comparison to media control. Drugs that showed good initial activity were further tested to calculate IC50 values. Drugs with the most promise were tested together with metronidazole to see if there was any combinatorial effect. Of the 1040 drugs in the library, 83 (8%) reduced growth of a metronidazole-susceptible T vaginalis strain by at least 20%. Of these, IC50 values were calculated for 27 compounds and 8 drugs were evaluated in combination with metronidazole. Disulfiram and nithiamide were non-5-nitroimidazole drugs that showed the best activity against parasites when used alone. Albendazole and coenzyme B12 were the most promising compounds to boost the efficacy of metronidazole. No one drug was as effective as any of the 5-nitroimidazole compounds. However, disulfiram and nithiamide may be useful to treat individuals with hypersensitivity to 5-nitroimidazole drugs and albendazole and coenzyme B12 may be helpful in combination with metronidazole or tinidazole for treatment of persons with highly resistant T vaginalis infections.

Docking and Virtual Screening Strategies for GPCR Drug Discovery.

PubMed

Beuming, Thijs; Lenselink, Bart; Pala, Daniele; McRobb, Fiona; Repasky, Matt; Sherman, Woody

2015-01-01

Progress in structure determination of G protein-coupled receptors (GPCRs) has made it possible to apply structure-based drug design (SBDD) methods to this pharmaceutically important target class. The quality of GPCR structures available for SBDD projects fall on a spectrum ranging from high resolution crystal structures (<2 Å), where all water molecules in the binding pocket are resolved, to lower resolution (>3 Å) where some protein residues are not resolved, and finally to homology models that are built using distantly related templates. Each GPCR project involves a distinct set of opportunities and challenges, and requires different approaches to model the interaction between the receptor and the ligands. In this review we will discuss docking and virtual screening to GPCRs, and highlight several refinement and post-processing steps that can be used to improve the accuracy of these calculations. Several examples are discussed that illustrate specific steps that can be taken to improve upon the docking and virtual screening accuracy. While GPCRs are a unique target class, many of the methods and strategies outlined in this review are general and therefore applicable to other protein families.

Towards novel therapeutics for HIV through fragment-based screening and drug design.

PubMed

Tiefendbrunn, Theresa; Stout, C David

2014-01-01

Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-μM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins.

Southern African Treatment Resistance Network (SATuRN) RegaDB HIV drug resistance and clinical management database: supporting patient management, surveillance and research in southern Africa

PubMed Central

Manasa, Justen; Lessells, Richard; Rossouw, Theresa; Naidu, Kevindra; Van Vuuren, Cloete; Goedhals, Dominique; van Zyl, Gert; Bester, Armand; Skingsley, Andrew; Stott, Katharine; Danaviah, Siva; Chetty, Terusha; Singh, Lavanya; Moodley, Pravi; Iwuji, Collins; McGrath, Nuala; Seebregts, Christopher J.; de Oliveira, Tulio

2014-01-01

Abstract Substantial amounts of data have been generated from patient management and academic exercises designed to better understand the human immunodeficiency virus (HIV) epidemic and design interventions to control it. A number of specialized databases have been designed to manage huge data sets from HIV cohort, vaccine, host genomic and drug resistance studies. Besides databases from cohort studies, most of the online databases contain limited curated data and are thus sequence repositories. HIV drug resistance has been shown to have a great potential to derail the progress made thus far through antiretroviral therapy. Thus, a lot of resources have been invested in generating drug resistance data for patient management and surveillance purposes. Unfortunately, most of the data currently available relate to subtype B even though >60% of the epidemic is caused by HIV-1 subtype C. A consortium of clinicians, scientists, public health experts and policy markers working in southern Africa came together and formed a network, the Southern African Treatment and Resistance Network (SATuRN), with the aim of increasing curated HIV-1 subtype C and tuberculosis drug resistance data. This article describes the HIV-1 data curation process using the SATuRN Rega database. The data curation is a manual and time-consuming process done by clinical, laboratory and data curation specialists. Access to the highly curated data sets is through applications that are reviewed by the SATuRN executive committee. Examples of research outputs from the analysis of the curated data include trends in the level of transmitted drug resistance in South Africa, analysis of the levels of acquired resistance among patients failing therapy and factors associated with the absence of genotypic evidence of drug resistance among patients failing therapy. All these studies have been important for informing first- and second-line therapy. This database is a free password-protected open source database

Modeling Liver-Related Adverse Effects of Drugs Using kNN QSAR Method

PubMed Central

Rodgers, Amie D.; Zhu, Hao; Fourches, Dennis; Rusyn, Ivan; Tropsha, Alexander

2010-01-01

Adverse effects of drugs (AEDs) continue to be a major cause of drug withdrawals both in development and post-marketing. While liver-related AEDs are a major concern for drug safety, there are few in silico models for predicting human liver toxicity for drug candidates. We have applied the Quantitative Structure Activity Relationship (QSAR) approach to model liver AEDs. In this study, we aimed to construct a QSAR model capable of binary classification (active vs. inactive) of drugs for liver AEDs based on chemical structure. To build QSAR models, we have employed an FDA spontaneous reporting database of human liver AEDs (elevations in activity of serum liver enzymes), which contains data on approximately 500 approved drugs. Approximately 200 compounds with wide clinical data coverage, structural similarity and balanced (40/60) active/inactive ratio were selected for modeling and divided into multiple training/test and external validation sets. QSAR models were developed using the k nearest neighbor method and validated using external datasets. Models with high sensitivity (>73%) and specificity (>94%) for prediction of liver AEDs in external validation sets were developed. To test applicability of the models, three chemical databases (World Drug Index, Prestwick Chemical Library, and Biowisdom Liver Intelligence Module) were screened in silico and the validity of predictions was determined, where possible, by comparing model-based classification with assertions in publicly available literature. Validated QSAR models of liver AEDs based on the data from the FDA spontaneous reporting system can be employed as sensitive and specific predictors of AEDs in pre-clinical screening of drug candidates for potential hepatotoxicity in humans. PMID:20192250

Detection and identification of 700 drugs by multi-target screening with a 3200 Q TRAP LC-MS/MS system and library searching.

PubMed

Dresen, S; Ferreirós, N; Gnann, H; Zimmermann, R; Weinmann, W

2010-04-01

The multi-target screening method described in this work allows the simultaneous detection and identification of 700 drugs and metabolites in biological fluids using a hybrid triple-quadrupole linear ion trap mass spectrometer in a single analytical run. After standardization of the method, the retention times of 700 compounds were determined and transitions for each compound were selected by a "scheduled" survey MRM scan, followed by an information-dependent acquisition using the sensitive enhanced product ion scan of a Q TRAP hybrid instrument. The identification of the compounds in the samples analyzed was accomplished by searching the tandem mass spectrometry (MS/MS) spectra against the library we developed, which contains electrospray ionization-MS/MS spectra of over 1,250 compounds. The multi-target screening method together with the library was included in a software program for routine screening and quantitation to achieve automated acquisition and library searching. With the help of this software application, the time for evaluation and interpretation of the results could be drastically reduced. This new multi-target screening method has been successfully applied for the analysis of postmortem and traffic offense samples as well as proficiency testing, and complements screening with immunoassays, gas chromatography-mass spectrometry, and liquid chromatography-diode-array detection. Other possible applications are analysis in clinical toxicology (for intoxication cases), in psychiatry (antidepressants and other psychoactive drugs), and in forensic toxicology (drugs and driving, workplace drug testing, oral fluid analysis, drug-facilitated sexual assault).

Exposure to benzodiazepines (anxiolytics, hypnotics and related drugs) in seven European electronic healthcare databases: a cross-national descriptive study from the PROTECT-EU Project.

PubMed

Huerta, Consuelo; Abbing-Karahagopian, Victoria; Requena, Gema; Oliva, Belén; Alvarez, Yolanda; Gardarsdottir, Helga; Miret, Montserrat; Schneider, Cornelia; Gil, Miguel; Souverein, Patrick C; De Bruin, Marie L; Slattery, Jim; De Groot, Mark C H; Hesse, Ulrik; Rottenkolber, Marietta; Schmiedl, Sven; Montero, Dolores; Bate, Andrew; Ruigomez, Ana; García-Rodríguez, Luis Alberto; Johansson, Saga; de Vries, Frank; Schlienger, Raymond G; Reynolds, Robert F; Klungel, Olaf H; de Abajo, Francisco José

2016-03-01

Studies on drug utilization usually do not allow direct cross-national comparisons because of differences in the respective applied methods. This study aimed to compare time trends in BZDs prescribing by applying a common protocol and analyses plan in seven European electronic healthcare databases. Crude and standardized prevalence rates of drug prescribing from 2001-2009 were calculated in databases from Spain, United Kingdon (UK), The Netherlands, Germany and Denmark. Prevalence was stratified by age, sex, BZD type [(using ATC codes), i.e. BZD-anxiolytics BZD-hypnotics, BZD-related drugs and clomethiazole], indication and number of prescription. Crude prevalence rates of BZDs prescribing ranged from 570 to 1700 per 10,000 person-years over the study period. Standardization by age and sex did not substantially change the differences. Standardized prevalence rates increased in the Spanish (+13%) and UK databases (+2% and +8%) over the study period, while they decreased in the Dutch databases (-4% and -22%), the German (-12%) and Danish (-26%) database. Prevalence of anxiolytics outweighed that of hypnotics in the Spanish, Dutch and Bavarian databases, but the reverse was shown in the UK and Danish databases. Prevalence rates consistently increased with age and were two-fold higher in women than in men in all databases. A median of 18% of users received 10 or more prescriptions in 2008. Although similar methods were applied, the prevalence of BZD prescribing varied considerably across different populations. Clinical factors related to BZDs and characteristics of the databases may explain these differences. Copyright © 2015 John Wiley & Sons, Ltd.

Planning multi-arm screening studies within the context of a drug development program

PubMed Central

Wason, James M S; Jaki, Thomas; Stallard, Nigel

2013-01-01

Screening trials are small trials used to decide whether an intervention is sufficiently promising to warrant a large confirmatory trial. Previous literature examined the situation where treatments are tested sequentially until one is considered sufficiently promising to take forward to a confirmatory trial. An important consideration for sponsors of clinical trials is how screening trials should be planned to maximize the efficiency of the drug development process. It has been found previously that small screening trials are generally the most efficient. In this paper we consider the design of screening trials in which multiple new treatments are tested simultaneously. We derive analytic formulae for the expected number of patients until a successful treatment is found, and propose methodology to search for the optimal number of treatments, and optimal sample size per treatment. We compare designs in which only the best treatment proceeds to a confirmatory trial and designs in which multiple treatments may proceed to a multi-arm confirmatory trial. We find that inclusion of a large number of treatments in the screening trial is optimal when only one treatment can proceed, and a smaller number of treatments is optimal when more than one can proceed. The designs we investigate are compared on a real-life set of screening designs. Copyright © 2013 John Wiley & Sons, Ltd. PMID:23529936

Fully automated screening of veterinary drugs in milk by turbulent flow chromatography and tandem mass spectrometry

PubMed Central

Stolker, Alida A. M.; Peters, Ruud J. B.; Zuiderent, Richard; DiBussolo, Joseph M.

2010-01-01

There is an increasing interest in screening methods for quick and sensitive analysis of various classes of veterinary drugs with limited sample pre-treatment. Turbulent flow chromatography in combination with tandem mass spectrometry has been applied for the first time as an efficient screening method in routine analysis of milk samples. Eight veterinary drugs, belonging to seven different classes were selected for this study. After developing and optimising the method, parameters such as linearity, repeatability, matrix effects and carry-over were studied. The screening method was then tested in the routine analysis of 12 raw milk samples. Even without internal standards, the linearity of the method was found to be good in the concentration range of 50 to 500 µg/L. Regarding repeatability, RSDs below 12% were obtained for all analytes, with only a few exceptions. The limits of detection were between 0.1 and 5.2 µg/L, far below the maximum residue levels for milk set by the EU regulations. While matrix effects—ion suppression or enhancement—are obtained for all the analytes the method has proved to be useful for screening purposes because of its sensitivity, linearity and repeatability. Furthermore, when performing the routine analysis of the raw milk samples, no false positive or negative results were obtained. PMID:20379812

Women's ability to self-screen for contraindications to combined oral contraceptive pills in Tanzanian drug shops.

PubMed

Chin-Quee, Dawn; Ngadaya, Esther; Kahwa, Amos; Mwinyiheri, Thomas; Otterness, Conrad; Mfinanga, Sayoki; Nanda, Kavita

2013-10-01

To estimate the accuracy of self-screening for contraindications to combined oral contraceptive pills (COCs) and to estimate the proportion of women with contraindications to hormonal methods among those using drug shops in Tanzania. Trained nurses interviewed 1651 women aged 18-39 years who self-screened for contraindications to COCs with the help of a poster at drug shops in Tanzania. Nurse assessment of the women served as the gold standard for comparison with self-assessment. Blood pressure was also measured onsite. Nurses reported that 437 (26.5%) women were not eligible to use COCs, compared with 485 (29.4%) according to self-report. Overall, 133 (8.1%) women who said that they were eligible were deemed ineligible by nurses. The rate of ineligibility was artificially high owing to participant and nurse assessments that were incorrectly based on adverse effects of pill use and cultural reasons, and because of the sampling procedure, which intercepted women regardless of their reasons for visiting the drug shop. Adjusted rates of ineligibility were 8.6% and 12.7%, respectively, according to nurse and participant assessment. Both nurses and women underestimated the prevalence of hypertension in the present group. Self-screening among women in rural and peri-urban Tanzania with regard to contraindications to COC use was comparable to assessment by trained nurses. © 2013.

The 2015 Nucleic Acids Research Database Issue and molecular biology database collection.

PubMed

Galperin, Michael Y; Rigden, Daniel J; Fernández-Suárez, Xosé M

2015-01-01

The 2015 Nucleic Acids Research Database Issue contains 172 papers that include descriptions of 56 new molecular biology databases, and updates on 115 databases whose descriptions have been previously published in NAR or other journals. Following the classification that has been introduced last year in order to simplify navigation of the entire issue, these articles are divided into eight subject categories. This year's highlights include RNAcentral, an international community portal to various databases on noncoding RNA; ValidatorDB, a validation database for protein structures and their ligands; SASBDB, a primary repository for small-angle scattering data of various macromolecular complexes; MoonProt, a database of 'moonlighting' proteins, and two new databases of protein-protein and other macromolecular complexes, ComPPI and the Complex Portal. This issue also includes an unusually high number of cancer-related databases and other databases dedicated to genomic basics of disease and potential drugs and drug targets. The size of NAR online Molecular Biology Database Collection, http://www.oxfordjournals.org/nar/database/a/, remained approximately the same, following the addition of 74 new resources and removal of 77 obsolete web sites. The entire Database Issue is freely available online on the Nucleic Acids Research web site (http://nar.oxfordjournals.org/). Published by Oxford University Press on behalf of Nucleic Acids Research 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.

C-SPADE: a web-tool for interactive analysis and visualization of drug screening experiments through compound-specific bioactivity dendrograms

PubMed Central

Alam, Zaid; Peddinti, Gopal

2017-01-01

Abstract The advent of polypharmacology paradigm in drug discovery calls for novel chemoinformatic tools for analyzing compounds’ multi-targeting activities. Such tools should provide an intuitive representation of the chemical space through capturing and visualizing underlying patterns of compound similarities linked to their polypharmacological effects. Most of the existing compound-centric chemoinformatics tools lack interactive options and user interfaces that are critical for the real-time needs of chemical biologists carrying out compound screening experiments. Toward that end, we introduce C-SPADE, an open-source exploratory web-tool for interactive analysis and visualization of drug profiling assays (biochemical, cell-based or cell-free) using compound-centric similarity clustering. C-SPADE allows the users to visually map the chemical diversity of a screening panel, explore investigational compounds in terms of their similarity to the screening panel, perform polypharmacological analyses and guide drug-target interaction predictions. C-SPADE requires only the raw drug profiling data as input, and it automatically retrieves the structural information and constructs the compound clusters in real-time, thereby reducing the time required for manual analysis in drug development or repurposing applications. The web-tool provides a customizable visual workspace that can either be downloaded as figure or Newick tree file or shared as a hyperlink with other users. C-SPADE is freely available at http://cspade.fimm.fi/. PMID:28472495

Drug interaction databases in medical literature: transparency of ownership, funding, classification algorithms, level of documentation, and staff qualifications. A systematic review.

PubMed

Kongsholm, Gertrud Gansmo; Nielsen, Anna Katrine Toft; Damkier, Per

2015-11-01

It is well documented that drug-drug interaction databases (DIDs) differ substantially with respect to classification of drug-drug interactions (DDIs). The aim of this study was to study online available transparency of ownership, funding, information, classifications, staff training, and underlying documentation of the five most commonly used open access English language-based online DIDs and the three most commonly used subscription English language-based online DIDs in the literature. We conducted a systematic literature search to identify the five most commonly used open access and the three most commonly used subscription DIDs in the medical literature. The following parameters were assessed for each of the databases: Ownership, classification of interactions, primary information sources, and staff qualification. We compared the overall proportion of yes/no answers from open access databases and subscription databases by Fisher's exact test-both prior to and after requesting missing information. Among open access DIDs, 20/60 items could be verified from the webpage directly compared to 24/36 for the subscription DIDs (p = 0.0028). Following personal request, these numbers rose to 22/60 and 30/36, respectively (p < 0.0001). For items within the "classification of interaction" domain, proportions were 3/25 versus 11/15 available from the webpage (P = 0.0001) and 3/25 versus 15/15 (p < 0.0001) available upon personal request. Available information on online available transparency of ownership, funding, information, classifications, staff training, and underlying documentation varies substantially among various DIDs. Open access DIDs had a statistically lower score on parameters assessed.