Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Eur J Med Chem. 2010 Mar;45(3):1140-5. doi: 10.1016/j.ejmech.2009.12.019. Epub 2009 Dec 21.
The structure of aldehyde reductase (ALR1) in ternary complex with the coenzyme NADPH and [5-(3-carboxymethoxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid (CMD), a potent inhibitor of aldose reductase (ALR2), was determined at 1.99A resolution. The partially disordered inhibitor formed a tight network of hydrogen bonds with the active site residues (Tyr50 and His113) and coenzyme. Molecular modelling calculations and inhibitory activity measurements of CMD and [5-(3-hydroxy-4-methoxybenzylidene)-2,4-dioxothiazolidin-3-yl]acetic acid (HMD) indicated that pi-stacking interactions with several conserved active site tryptophan residues and hydrogen-bonding interactions with the non-conserved C-terminal residue Leu300 in ALR2 (Pro301 in ALR1) contributed to inhibitor selectivity. In particular for the potent inhibitor CMD, the rotameric state of the conserved residue Trp219 (Trp220 in ALR1) is important in forming a pi-stacking interaction with the inhibitor in ALR2 and contributes to the difference in the binding of the inhibitor to the enzymes.
醛还原酶（ALR1）与辅酶 NADPH 和 [5-(3-羧甲氧基-4-甲氧基苄叉基）-2,4-二氧代噻唑烷-3-基]乙酸（CMD）的三元复合物的结构已在 1.99A 分辨率下确定，CMD 是醛还原酶（ALR2）的一种有效抑制剂。部分无序抑制剂与活性位点残基（Tyr50 和 His113）和辅酶形成紧密的氢键网络。CMD 和 [5-(3-羟基-4-甲氧基苄叉基）-2,4-二氧代噻唑烷-3-基]乙酸（HMD）的分子建模计算和抑制活性测量表明，与几个保守的活性位点色氨酸残基的π堆积相互作用以及与非保守的 C 末端残基 Leu300（ALR2 中的 Pro301）的氢键相互作用有助于抑制剂的选择性。特别是对于强效抑制剂 CMD，保守残基 Trp219（ALR1 中的 Trp220）的构象状态对于与抑制剂在 ALR2 中形成π堆积相互作用很重要，并有助于抑制剂与酶结合的差异。
