Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase

William L Jorgensen; Juliana Ruiz-Caro; Julian Tirado-Rives; Aravind Basavapathruni; Karen S Anderson; Andrew D Hamilton

doi:10.1016/j.bmcl.2005.10.038

Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase

Bioorg Med Chem Lett. 2006 Feb;16(3):663-7. doi: 10.1016/j.bmcl.2005.10.038. Epub 2005 Nov 2.

Authors

William L Jorgensen¹, Juliana Ruiz-Caro, Julian Tirado-Rives, Aravind Basavapathruni, Karen S Anderson, Andrew D Hamilton

Affiliation

¹ Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA. william.jorgensen@yale.edu

PMID: 16263277
DOI: 10.1016/j.bmcl.2005.10.038

Abstract

Design principles are delineated for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs). Simultaneous optimization of binding affinity for wild-type RT, tolerance for viral mutations, and physical properties is pursued. Automated lead generation with the growing program BOMB, Monte Carlo simulations with free-energy perturbation theory for lead optimization, and property analysis with QikProp are featured. An initial 30 microM lead has been optimized rapidly to the 10 nM level.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Computer-Aided Design*
Drug Resistance, Multiple, Viral
HIV Infections / drug therapy
HIV Infections / virology
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / genetics
Models, Molecular
Molecular Structure
Monte Carlo Method
Mutation
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*

Substances

Reverse Transcriptase Inhibitors
HIV Reverse Transcriptase

Abstract

Publication types

MeSH terms

Substances

Grants and funding