Selectivity of N(2) -substituted oxotriazinoindole aldose reductase inhibitors is determined by the interaction pattern with Pro301-Arg312 loop of aldehyde reductase

Novel oxotriazinoindoles ( OTI s) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novel N(2) -substituted oxotriazinoindoles was developed with the aim to investigate molecular interactions within the aldose reductase (ALR2) inhibitor binding site. About twice increased inhibition efficacy of the most efficient derivative 14 ( N(2) -CH 2 CH 2 COOH) compared to the unsubstituted lead OTI was obtained, yet at the expense of selectivity relative to anti-target aldehyde reductase (ALR1). To explain the major drop in selectivity, observed also in other N(2) -substituted derivatives, in silico molecular modeling approach revealed the role of extra interactions with the residues of Arg309, Arg312 and Met302 located in the additional C -terminal loop of ALR1 missing in ALR2, which can prevent or enhance binding in ALR1. These key findings will be used for development of the next generation of selective OTI inhibitors.