CYCLIC HIV-1 PROTEASE INHIBITORS DERIVED FROM MANNITOL - SYNTHESIS, INHIBITORY POTENCIES, AND COMPUTATIONAL PREDICTIONS OF BINDING AFFINITIES

Ten C-2-symmetric cyclic urea and sulfamide derivatives have been synt hesized from L-mannonic gamma-lactone and D-mannitol. The results of e xperimental measurement of their inhibitory potencies against HIV-1 pr otease were compared to calculated free energies of binding derived fr om molecular dynamics (MD) simulations. The compounds were selected, f irstly, to enable elucidation of the role of stereochemistry for bindi ng affinity (1a-d) and, secondly, to allow evaluation of the effects o f variation in the link to the P1 and P1' phenyl groups on affinity (l a and 2-5). Thirdly, compounds with hydrogen bond-accepting or -donati ng groups attached to the phenyl groups in the P2 and P2' side chains (6 and 7) were selected. Binding free energies were estimated by a lin ear response method, whose predictive power for estimating binding aff inities from MD simulations was demonstrated.