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

Research output: Contribution to journalArticle

64 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2432-2444
Number of pages13
JournalJournal of Medicinal Chemistry
Volume48
Issue number7
DOIs
StatePublished - Apr 7 2005

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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