醛糖还原酶
醛还原酶
化学
选择性
醛
立体化学
生物信息学
醛糖还原酶抑制剂
还原酶
生物化学
酶
基因
催化作用
作者
Lucia Kováčiková,Sunil Gaikwad,Kristína Almášiová,Ambróz Almássy,Gabriela Addová,Magdaléna Májeková,Gilles Hanquet,Vladimir Dobričić,Andrej Boháč,Milan Štefek
标识
DOI:10.1007/s00044-024-03194-3
摘要
Abstract 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.
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