REVERSED STEREOCHEMICAL PREFERENCE IN BINDING OF RO-31-8959 TO HIV-1 PROTEINASE - A FREE-ENERGY PERTURBATION ANALYSIS

Ro 31-8959 is a highly potent inhibitor of HIV-1 proteinase in phase I II clinical trials for treatment of AIDS. It is also the first subnano molar inhibitor that demonstrated reversed stereochemical preference a t the central hydroxyl group. Free energy perturbation calculations ha ve been carried out to rationalize the preference for the R-diastereom er by consideration of two models of the (weaker) S-diastereomer. Ln t he first model, the central hydroxyl group makes only one hydrogen bon d with the active site aspartates, whereas the hydroxyl group in the s econd model makes at least three strong hydrogen bonds. Using the firs t model, the free energy difference in binding of Ro 31-8959 and its S -diastereomer is calculated to be 3.4 kcal/mol, which is in close agre ement with the experimental value. Although the second model has a mor e favorable interaction with the active site aspartates compared to th e first model, it has a higher energy N-axial conformation at the deca hydroisoquinoline group in P-1'. We show here that the two contributio ns cancel each other and the two models of S-diastereomer are predicte d to have equivalent binding. The stereochemical preference in a hydro xyethylamine series of inhibitors appears to be affected by both inter molecular and intramolecular (conformational) energies. The binding da ta on the proline containing inhibitors are rationalized based on thes e results. (C) 1994 by John Wiley & Sons, Inc.