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 inhibitor of aldose reductase and its methoxylated analogs in four selected substitution sites. The calculated free energy differences are in qualitative agreement with the experimental results. The balance between the cost for desolvation and the gain in enzyme binding correctly predicts and rationalizes the different inhibitory activities of each methoxylated compound. The implications for perturbations occurring at the interface between protein residues and water molecules present at the active site are discussed.