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A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments.

ABSTRACT: Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a free web-based protocol dedicated to small-molecule virtual screening that includes three major steps: ADME-Tox filtering (via the web service FAF-Drugs4), docking-based virtual screening (via the web service MTiOpenScreen), and molecular mechanics optimization (via the web service AMMOS2 [Automatic Molecular Mechanics Optimization for in silico Screening]). The online tools FAF-Drugs4, MTiOpenScreen, and AMMOS2 are implemented in the freely accessible RPBS (Ressource Parisienne en Bioinformatique Structurale) platform. The proposed protocol allows users to screen thousands of small molecules and to download the top 1500 docked molecules that can be further processed online. Users can then decide to purchase a small list of compounds for in vitro validation. To demonstrate the potential of this online-based protocol, we performed virtual screening experiments of 4574 approved drugs against three cancer targets. The results were analyzed in the light of published drugs that have already been repositioned on these targets. We show that our protocol is able to identify active drugs within the top-ranked compounds. The web-based protocol is user-friendly and can successfully guide the identification of new promising molecules for chemical biology and drug discovery purposes.

SUBMITTER: Lagarde N

PROVIDER: S-EPMC6769597 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments.

Lagarde Nathalie N Goldwaser Elodie E Pencheva Tania T Jereva Dessislava D Pajeva Ilza I Rey Julien J Tuffery Pierre P Villoutreix Bruno O BO Miteva Maria A MA

International journal of molecular sciences 20190919 18

Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a free web-based protocol dedicated to small-molecule virtual screening that includes three major steps: ADME-Tox filtering (via the web service FAF-Drugs4), docking-based virtual screening (via the web servi ...[more]

PMID: 31546814

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Project description:The drug development process is a major challenge in the pharmaceutical industry since it takes a substantial amount of time and money to move through all the phases of developing of a new drug. One extensively used method to minimize the cost and time for the drug development process is computer-aided drug design (CADD). CADD allows better focusing on experiments, which can reduce the time and cost involved in researching new drugs. In this context, structure-based virtual screening (SBVS) is robust and useful and is one of the most promising in silico techniques for drug design. SBVS attempts to predict the best interaction mode between two molecules to form a stable complex, and it uses scoring functions to estimate the force of non-covalent interactions between a ligand and molecular target. Thus, scoring functions are the main reason for the success or failure of SBVS software. Many software programs are used to perform SBVS, and since they use different algorithms, it is possible to obtain different results from different software using the same input. In the last decade, a new technique of SBVS called consensus virtual screening (CVS) has been used in some studies to increase the accuracy of SBVS and to reduce the false positives obtained in these experiments. An indispensable condition to be able to utilize SBVS is the availability of a 3D structure of the target protein. Some virtual databases, such as the Protein Data Bank, have been created to store the 3D structures of molecules. However, sometimes it is not possible to experimentally obtain the 3D structure. In this situation, the homology modeling methodology allows the prediction of the 3D structure of a protein from its amino acid sequence. This review presents an overview of the challenges involved in the use of CADD to perform SBVS, the areas where CADD tools support SBVS, a comparison between the most commonly used tools, and the techniques currently used in an attempt to reduce the time and cost in the drug development process. Finally, the final considerations demonstrate the importance of using SBVS in the drug development process.

Dataset Information

A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments.

Publications

A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments.

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