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.
Highlights
Chemical biology and drug discovery are complex and costly processes and usually involve high-throughput screening campaigns, computations, and/or wet lab experiments, prioritization of the hit compounds, and different levels of compound optimization
One can use FAF-Drugs4, which is a free web-based package that allows compound libraries to be filtered based on physicochemical rules, undesirable toxic/reactive groups, and pan-assay interference compounds (PAINS) [23]
The preparation of the chemical library is of critical importance for the success of the virtual screening exercise
Summary
Chemical biology and drug discovery are complex and costly processes and usually involve high-throughput screening campaigns, computations, and/or wet lab experiments, prioritization of the hit compounds, and different levels of compound optimization. In silico screening methodologies 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. [1,2,3,4,5,6] 2s01s9t,a2g0,exs of drug discovery and have impressively progressed during the las2todf e1c5ades. Several challenges exist, such as how to deal with the flexibility of the binding pocket [7], how to imcparnovasesissctotrhiengva[r8io],usanstdagheoswoftdoruagutdoimscaovteertyheanpdrohcaevseseims parmesosinvgelyotphreorgsre[9ss–e1d1]d.uTriongdtahte,lassetveral web sdeercvaidceess.hSativlle, sbeeveenradl cehvaellloenpgeeds ienxitsht,astudcihreacsthioonw: tdoedneoalvwo idthruthgedfleesxiigbnili(tey-LofEtAheDb3in[d12in]g), pdoocckkeitng of sever[a7l]s, mhoawll tmo oimlepcurolevse (sec.ogr.i,nSgw[8is],sDanodckho[1w3]t,oCaouvtoamleantteDthoeckpr[1o4ce])s,seasnadmpornegdioctthinergsb[9in–1d1in].gTaoffidantiet,ies of proteidsneov–celkiriganalgnwodef bsceosvmeerrvpaillcesexmsehaslal[v1me5o]b.leeSecounmledsee(voee.tglho.,peSrewdseiisrnsvDtihcoeactsk da[1irr3ee],cmtCiooonrve:aldsepenetnDcoiovaclokizd[e1rd4u]gi)n,dalenasdriggpner-e(sdec‐iacLltEeinAvgDibr3tinu[da1i2ln]l)gi,gand screenafifningit(iee.sgo.,fiSpcroreteeinn–[l1ig6a],nDd OcoCmKplBelxaesste[1r5[]1. 7S]o,mUeSRot-hVeSr s[e1r8v]i)c.es are more specialized in large‐scale
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