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

Nathalie Lagarde (1) , Elodie Goldwaser (2) , Tania Pencheva (3) , Dessislava Jereva (3) , Ilza Pajeva (3) , Julien Rey (4) , Pierre Tuffery (4) , Bruno O. Villoutreix (5, 6) , Maria A Miteva (2)

1 GBCM - Laboratoire Génomique, bioinformatique et chimie moléculaire
2 ERL Inserm U1268 - Chimie médicinale et recherche translationnelle
3 BAS - Bulgarian Academy of Sciences
4 BFA (UMR_8251 / U1133) - Unité de Biologie Fonctionnelle et Adaptative
5 MTI - Molécules Thérapeutiques in silico
6 M2SV - Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177

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.

Mots clés: ADME-Tox; virtual screening; web server; structure refinement; molecular mechanics; docking

Domaines: Bio-Informatique, Biologie Systémique [q-bio.QM]; Chemo-informatique

Nathalie Lagarde, Elodie Goldwaser, Tania Pencheva, Dessislava Jereva, Ilza Pajeva, et al.. A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments. International Journal of Molecular Sciences, 2019, 20 (18), pp.4648. ⟨10.3390/ijms20184648⟩. ⟨hal-02308677⟩