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dc.contributor.authorBallester, Pedro
dc.contributor.authorMangold, Martina
dc.contributor.authorHoward, Nigel
dc.contributor.authorMarchese Robinson, Richard
dc.contributor.authorAbell, Chris
dc.contributor.authorBlumberger, Jochen
dc.contributor.authorMitchell, John B. O.
dc.identifier.citationBallester , P , Mangold , M , Howard , N , Marchese Robinson , R , Abell , C , Blumberger , J & Mitchell , J B O 2012 , ' Hierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identification ' , Journal of the Royal Society Interface , vol. 9 , no. 77 , pp. 3196-3207 .
dc.identifier.otherPURE: 26961569
dc.identifier.otherPURE UUID: c831b0b4-304f-43a2-ab7f-b8af8a3db471
dc.identifier.otherScopus: 84868556569
dc.identifier.otherWOS: 000310573100003
dc.identifier.otherORCID: /0000-0002-0379-6097/work/34033398
dc.description.abstractOne of the initial steps of modern drug discovery is the identification of small organic molecules able to inhibit a target macromolecule of therapeutic interest. A small proportion of these hits are further developed into lead compounds, which in turn may ultimately lead to a marketed drug. A commonly used screening protocol used for this task is high-throughput screening (HTS). However, the performance of HTS against antibacterial targets has generally been unsatisfactory, with high costs and low rates of hit identification. Here, we present a novel computational methodology that is able to identify a high proportion of structurally diverse inhibitors by searching unusually large molecular databases in a time-, cost- and resource-efficient manner. This virtual screening methodology was tested prospectively on two versions of an antibacterial target (type II dehydroquinase from Mycobacterium tuberculosis and Streptomyces coelicolor), for which HTS has not provided satisfactory results and consequently practically all known inhibitors are derivatives of the same core scaffold. Overall, our protocols identified 100 new inhibitors, with calculated Ki ranging from 4 to 250 μM (confirmed hit rates are 60% and 62% against each version of the target). Most importantly, over 50 new active molecular scaffolds were discovered that underscore the benefits that a wide application of prospectively validated in silico screening tools is likely to bring to antibacterial hit identification.
dc.relation.ispartofJournal of the Royal Society Interfaceen
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.en
dc.subjectVirtual screeningen
dc.subjectAntibacterial hit identificationen
dc.subjectMachine learningen
dc.subjectHigh-throughput screeningen
dc.subjectQD Chemistryen
dc.titleHierarchical virtual screening for the discovery of new molecular scaffolds in antibacterial hit identificationen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Chemistryen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.EaSTCHEMen
dc.description.statusPeer revieweden

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