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首页> 外文期刊>Journal of Medicinal Chemistry >Molecular modeling of the aldose reductase-inhibitor complex based on the X-ray crystal structure and studies with single-site-directed mutants.
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Molecular modeling of the aldose reductase-inhibitor complex based on the X-ray crystal structure and studies with single-site-directed mutants.

机译：基于X射线晶体结构的醛糖还原酶抑制剂复合物的分子模型以及对单点定向突变体的研究。

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摘要

Aldose reductase (AR) has been implicated in the etiology of the secondary complications of diabetes. This enzyme catalyzes the reduction of glucose to sorbitol using nicotinamide adenine dinucleotide phosphate as an essential cofactor. AR has been localized at the sites of tissue damage, and inhibitors of this enzyme prevent the development of neuropathy, nephropathy, retinopathy, and cataract formation in animal models of diabetes. The crystal structure of AR complexed with zopolrestat, a potent inhibitor of AR, has been described.(1) We have generated a model of the AR-inhibitor complex based on the reported Calpha coordinates of the protein and results of a structure-activity relationship study using four structurally distinct classes of inhibitors, recombinant human AR, and four single-site-directed mutants of this enzyme. The effects of the site-directed mutations on residues within the active site of the enzyme were evaluated by average interaction energy calculations and by calculations of carbon atom surface area changes. These values correlated well with the IC(50) values for zopolrestat with the wild-type and mutant enzymes, validating the model. On the basis of the zopolrestat-binding model, we have proposed binding models for 10 other AR inhibitors. Our models have enabled us to gain a qualitative understanding of the binding domains of the enzyme and how different inhibitors impact the size and shape of the binding site.
机译：醛糖还原酶（AR）与糖尿病继发并发症的病因有关。使用烟酰胺腺嘌呤二核苷酸磷酸作为必需辅因子，该酶催化葡萄糖还原为山梨糖醇。 AR已经定位在组织损伤的部位，并且该酶的抑制剂阻止了糖尿病动物模型中神经病，肾病，视网膜病和白内障形成的发展。描述了与AR的强效抑制剂zopolrestat络合的AR的晶体结构。（1）根据报道的蛋白质Calpha坐标和结构-活性关系的结果，我们建立了AR-抑制剂复合物的模型。研究人员使用四种结构上不同的抑制剂，重组人AR和该酶的四个单点定向突变体进行了研究。通过平均相互作用能计算和碳原子表面积变化的计算，评估了定点突变对酶活性位点内残基的影响。这些值与带有野生型和突变型酶的唑泊司他的IC（50）值相关性很好，从而验证了模型。在zopolrestat结合模型的基础上，我们提出了其他10种AR抑制剂的结合模型。我们的模型使我们能够对酶的结合域以及不同抑制剂如何影响结合位点的大小和形状进行定性了解。

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