A priori prediction of activity for HIV-1 protease inhibitors employing energy minimization in the active site

M K Holloway; J M Wai; T A Halgren; P M Fitzgerald; J P Vacca; B D Dorsey; R B Levin; W J Thompson; L J Chen; S J deSolms

doi:10.1021/jm00002a012

A priori prediction of activity for HIV-1 protease inhibitors employing energy minimization in the active site

J Med Chem. 1995 Jan 20;38(2):305-17. doi: 10.1021/jm00002a012.

Authors

M K Holloway¹, J M Wai, T A Halgren, P M Fitzgerald, J P Vacca, B D Dorsey, R B Levin, W J Thompson, L J Chen, S J deSolms

Affiliation

¹ Department of Molecular Systems, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.

PMID: 7830273
DOI: 10.1021/jm00002a012

Abstract

We have observed a high correlation between the intermolecular interaction energy (Einter) calculated for HIV-1 protease inhibitor complexes and the observed in vitro enzyme inhibition. A training set of 33 inhibitors containing modifications in the P1' and P2' positions was used to develop a regression equation which relates Einter and pIC50. This correlation was subsequently employed to successfully predict the activity of proposed HIV-1 protease inhibitors in advance of synthesis in a structure-based design program. This included a precursor, 47, to the current phase II clinical candidate, L-735,524 (51). The development of the correlation, its applications, and its limitations are discussed, and the force field (MM2X) and host molecular mechanics program (OPTIMOL) used in this work are described.

MeSH terms

Binding Sites
Computer-Aided Design
Drug Design
HIV Protease / chemistry*
HIV Protease / ultrastructure
HIV Protease Inhibitors / chemistry*
Models, Molecular
Protein Structure, Tertiary
Structure-Activity Relationship
Thermodynamics

Substances

HIV Protease Inhibitors
HIV Protease