MOLECULAR MODELING STUDIES OF THE BINDING MODES OF ALDOSE REDUCTASE INHIBITORS AT THE ACTIVE-SITE OF HUMAN ALDOSE REDUCTASE

Molecular modeling studies using the CHARMM method have been conducted to study the binding modes of aldose reductase inhibitors at the acti ve site of aldose reductase. The energy minimized structures of aldose reductase with six structurally diverse inhibitors (spirofluorene-9,5 '-imidazolidine-2',4'-dione (1), 9-fluoreneacetic acid (2), AL1576 (3) , 2,7-difluoro-9-fluoreneacetic acid (4), FK366 (5), and Epalrestat (9 )) indicate that the side chains of Tyr48, His110, and Trp111 can form numerous hydrogen bonds with either the carboxylate or the hydantoin group of the inhibitors while the side chains of Trp20, Trp111, and Ph e122 are positioned to form aromatic-aromatic interactions. Of the thr ee residues (Tyr 48, His 110, and Trp 111) that can form hydrogen bond s with the ionized portion of aldose reductase inhibitors, protonated His110 appears to play an important role in directing charged inhibito rs to bind at the active site through charge interaction. Based on the binding mode of the inhibitors and their observed inhibitory activiti es, pharmacophore requirements for aldose reductase inhibitors are dis cussed. Published by Elsevier Science Ltd.