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Is it possible to increase hit rates in structure-based virtual screening by pharmacophore filtering?: An investigation of the advantages and pitfalls of post-filtering
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2008 (English)In: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, E-ISSN 1873-4243, Vol. 26, no 8, 1237-1251 p.Article in journal (Refereed) Published
Abstract [en]

We have investigated the influence of post-filtering virtual screening results, with pharmacophoric features generated from an X-ray structure, on enrichment rates. This was performed using three docking softwares, zdock+, Surflex and FRED, as virtual screening tools and pharmacophores generated in UNITY from co-crystallized complexes. Sets of known actives along with 9997 pharmaceutically relevant decoy compounds were docked against six chemically diverse protein targets namely CDK2, COX2, ERalpha, fXa, MMP3, and NA. To try to overcome the inherent limitations of the well-known docking problem, we generated multiple poses for each compound. The compounds were first ranked according to their scores alone and enrichment rates were calculated using only the top scoring pose of each compound. Subsequently, all poses for each compound were passed through the different pharmacophores generated from co-crystallized complexes and the enrichment factors were re-calculated based on the top-scoring passing pose of each compound. Post-filtering with a pharmacophore generated from only one X-ray complex was shown to increase enrichment rates in all investigated targets compared to docking alone. This indicates that this is a general method, which works for diverse targets and different docking softwares.

Place, publisher, year, edition, pages
2008. Vol. 26, no 8, 1237-1251 p.
Keyword [en]
Flo(+), surflex, FRED, enrichment factor, docking performance, structure-based virtual screening, pharmacophore filtering
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-102967DOI: 10.1016/j.jmgm.2007.11.005ISI: 000256271600005PubMedID: 18203638OAI: oai:DiVA.org:uu-102967DiVA: diva2:217114
Available from: 2009-05-13 Created: 2009-05-13 Last updated: 2017-12-13Bibliographically approved

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