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      USR-VS: a web server for large-scale prospective virtual screening using ultrafast shape recognition techniques

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          Abstract

          Ligand-based Virtual Screening (VS) methods aim at identifying molecules with a similar activity profile across phenotypic and macromolecular targets to that of a query molecule used as search template. VS using 3D similarity methods have the advantage of biasing this search toward active molecules with innovative chemical scaffolds, which are highly sought after in drug design to provide novel leads with improved properties over the query molecule (e.g. patentable, of lower toxicity or increased potency). Ultrafast Shape Recognition (USR) has demonstrated excellent performance in the discovery of molecules with previously-unknown phenotypic or target activity, with retrospective studies suggesting that its pharmacophoric extension (USRCAT) should obtain even better hit rates once it is used prospectively. Here we present USR-VS ( http://usr.marseille.inserm.fr/), the first web server using these two validated ligand-based 3D methods for large-scale prospective VS. In about 2 s, 93.9 million 3D conformers, expanded from 23.1 million purchasable molecules, are screened and the 100 most similar molecules among them in terms of 3D shape and pharmacophoric properties are shown. USR-VS functionality also provides interactive visualization of the similarity of the query molecule against the hit molecules as well as vendor information to purchase selected hits in order to be experimentally tested.

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          Most cited references 43

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          Automated design of ligands to polypharmacological profiles

          The clinical efficacy and safety of a drug is determined by its activity profile across multiple proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to rationally design drugs a priori against profiles of multiple proteins would have immense value in drug discovery. We describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads where multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.
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            Virtual screening: an endless staircase?

            Computational chemistry--in particular, virtual screening--can provide valuable contributions in hit- and lead-compound discovery. Numerous software tools have been developed for this purpose. However, despite the applicability of virtual screening technology being well established, it seems that there are relatively few examples of drug discovery projects in which virtual screening has been the key contributor. Has virtual screening reached its peak? If not, what aspects are limiting its potential at present, and how can significant progress be made in the future?
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              Identification of a chemical probe for NAADP by virtual screening

              Research into the biological role of the Ca2+-releasing second messenger NAADP (nicotinic acid adenine dinucleotide phosphate) has been hampered by a lack of chemical probes. To find new chemical probes for exploring NAADP signaling, we turned to virtual screening, which can evaluate millions of molecules rapidly and inexpensively. We used NAADP as the query ligand to screen the chemical library ZINC for compounds with 3D-shape and electrostatic similarity. We tested the top-ranking hits in a sea urchin egg bioassay and found that one hit, Ned-19, blocks NAADP signaling at nanomolar concentrations. In intact cells, Ned-19 blocked NAADP signaling and fluorescently labeled NAADP receptors. Moreover, we show the utility of Ned-19 as a chemical probe by using it to demonstrate that NAADP is a key causal link between glucose sensing and Ca2+ increases in mouse pancreatic beta cells.
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                Author and article information

                Journal
                Nucleic Acids Res
                Nucleic Acids Res
                nar
                nar
                Nucleic Acids Research
                Oxford University Press
                0305-1048
                1362-4962
                08 July 2016
                22 April 2016
                22 April 2016
                : 44
                : Web Server issue
                : W436-W441
                Affiliations
                [1 ]Institute of Future Cities, Chinese University of Hong Kong, Hong Kong
                [2 ]Department of Computer Science and Engineering, Chinese University of Hong Kong, Sha Tin, New Territories, Hong Kong
                [3 ]Cancer Research Center of Marseille, INSERM U1068, 13009-Marseille, France
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +33 486 977 421; Fax: +33 486 977 499; Email: pedro.ballester@ 123456inserm.fr
                Article
                10.1093/nar/gkw320
                4987897
                27106057
                © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Pages: 6
                Product
                Categories
                Web Server issue
                Custom metadata
                08 July 2016

                Genetics

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