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Hierarchical database screenings for HIV-1 reverse transcriptase using a pharmacophore model, rigid docking, solvation docking, and MM-PB/SA.

Junmei Wang·Xinshan Kang·Irwin D Kuntz·Peter A Kollman
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Abstract

In this work, an efficient strategy was presented to search drug leads for human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) using hierarchical database screenings, which included a pharmacophore model, multiple-conformation rigid docking, solvation docking, and molecular mechanics-Poisson-Boltzmann/surface area (MM-PB/SA) sequentially. Encouraging results were achieved in searching a refined available chemical directory (ACD) database: the enrichment factor after the first three filters was estimated to be 25-fold; the hit rate for all the four filters was predicted to be 41% in a control test using 37 known HIV-1 non-nucleoside reverse transcriptase inhibitors; 10 out of 30 promising solvation-docking hits had MM-PB/SA binding free energies better than -6.8 kcal/mol and the best one, HIT15, had -17.0 kcal/mol. In conclusion, the hierarchical multiple-filter database searching strategy is an attractive strategy in drug lead exploration.

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Allosteric SiteAnti-HIV AgentsCrystallography, X-RayDatabases, FactualDrug DesignHIV Reverse TranscriptaseModels, MolecularMolecular ConformationMolecular StructureProtein BindingQuantitative Structure-Activity RelationshipReverse Transcriptase InhibitorsStatistics as TopicThermodynamicsJournal ArticleResearch Support, U.S. Gov't, Non-P.H.S.Research Support, U.S. Gov't, P.H.S.

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Junmei Wang, Xinshan Kang, Irwin D Kuntz, Peter A Kollman. 2005-04-07. Hierarchical database screenings for HIV-1 reverse transcriptase using a pharmacophore model, rigid docking, solvation docking, and MM-PB/SA.. https://doi.org/10.1021/jm049606e

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