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

J Med Chem. 2005 Apr 7;48(7):2432-44. doi: 10.1021/jm049606e.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Site
  • Anti-HIV Agents / chemistry*
  • Crystallography, X-Ray
  • Databases, Factual*
  • Drug Design
  • HIV Reverse Transcriptase / chemistry*
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Protein Binding
  • Quantitative Structure-Activity Relationship*
  • Reverse Transcriptase Inhibitors / chemistry*
  • Statistics as Topic
  • Thermodynamics


  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase