Molecular dynamics simulations of the structure of aldose reductase complexed with the inhibitor tolrestat.

ABSTRACT

This study reports a molecular dynamics (MD) investigation on the structure of aldose reductase (ALR2) complexed with the potent inhibitor tolrestat. The simulations predict four different orientations of tolrestat into the ALR2 binding site; these orientations have in common a strong interaction of the anionic carboxylate with Tyr48, His110, Trp111 and NADP+, but completely differ for the orientation of the aromatic portion of the inhibitor. Interestingly, the orientation in which tolrestat gives the most attractive interaction energy with the enzyme is in full accord with the x-ray crystal structure of the complex that has been reported in the literature after this work was completed. In addition, the suggestion of more than one orientation of tolrestat during MD is in agreement with recent electrospray mass spectrometry experiments on the ALR2-tolrestat complex.