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

AbstractNovel oxotriazinoindoles (OTIs) were recently reported as highly efficient and selective aldose reductase inhibitors. Here, a series of novelN(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 derivative14 (N(2)-CH2CH2COOH) compared to the unsubstituted leadOTI 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 otherN(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 additionalC-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.

Source: Medicinal Chemistry Research - February 14, 2024 Category: Chemistry Source Type: research