FREE-ENERGY PERTURBATION STUDIES ON BINDING OF THE INHIBITOR 5,6-DIHYDROBENZO[H]CINNOLIN-3(2H)ONE-2-ACETIC ACID AND ITS METHOXYLATED ANALOGS TO ALDOSE REDUCTASE

Free energy perturbation simulations have been employed to rationalize the binding differences between a benzocinnolinone carboxylic acid in hibitor of aldose reductase;Ind its methoxylated analogs in four selec ted substitution sites. The calculated free energy differences are in qualitative agreement with the experimental results. The balance betwe en the cost for desolvation and the gain in enzyme binding correctly p redicts and rationalizes the different inhibitory activities of each m ethoxylated compound. The implications for perturbations occurring at the interface between protein residues and water molecules present at the active site are discussed. (C) 1998 Elsevier Science Ltd. All righ ts reserved.