Multistage virtual screening and identification of novel HIV-1 protease inhibitors by integrating SVM, shape, pharmacophore and docking methods

Eur J Med Chem. 2015 Aug 28:101:409-18. doi: 10.1016/j.ejmech.2015.06.054. Epub 2015 Jul 6.

Abstract

The HIV-1 protease has proven to be a crucial component of the HIV replication machinery and a reliable target for anti-HIV drug discovery. In this study, we applied an optimized hierarchical multistage virtual screening method targeting HIV-1 protease. The method sequentially applied SVM (Support Vector Machine), shape similarity, pharmacophore modeling and molecular docking. Using a validation set (270 positives, 155,996 negatives), the multistage virtual screening method showed a high hit rate and high enrichment factor of 80.47% and 465.75, respectively. Furthermore, this approach was applied to screen the National Cancer Institute database (NCI), which contains 260,000 molecules. From the final hit list, 6 molecules were selected for further testing in an in vitro HIV-1 protease inhibitory assay, and 2 molecules (NSC111887 and NSC121217) showed inhibitory potency against HIV-1 protease, with IC50 values of 62 μM and 162 μM, respectively. With further chemical development, these 2 molecules could potentially serve as HIV-1 protease inhibitors.

Keywords: Docking; HIV-1 protease; Multistage virtual screening; Pharmacophore; SVM; Shape.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / analysis*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • Molecular Docking Simulation*
  • Molecular Structure
  • Structure-Activity Relationship
  • Support Vector Machine*

Substances

  • HIV Protease Inhibitors
  • HIV Protease