A-PRIORI PREDICTION OF ACTIVITY FOR HIV-1 PROTEASE INHIBITORS EMPLOYING ENERGY MINIMIZATION IN THE ACTIVE-SITE

We have observed a high correlation between the intermolecular interac tion energy (E(inter)) calculated for HTV-1 protease inhibitor complex es and the observed in vitro enzyme inhibition. A training set of 33 i nhibitors containing modifications in the P-1' and P-2' positions was used to develop a regression equation which relates E(inter) and PIC50 . This correlation was subsequently employed to successfully predict t he activity of proposed HIV-1 protease inhibitors in advance of synthe sis in a structure-based design program. This included a precursor, 47 , to the current phase II clinical candidate, L-735,524(51). The devel opment of the correlation, its applications, and its limitations are d iscussed, and the force field (MM2X) and host molecular mechanics prog ram (OPTIMOL) used in this work are described.