抗糖尿病并发症醛糖还原酶抑制剂的虚拟筛选（基于SPECS分子库）.docVIP

  抗糖尿病并发症醛糖还原酶抑制剂的虚拟 筛选（基于 SPECS 分子库）# 张建羽，李哲，罗海彬** 5 10 15 （中山大学药学院，广州 510006） 摘要：醛糖还原酶抑制剂（ARI）通过抑制醛糖还原酶的活性，使得葡萄糖代谢途径恢复良 性进而控制或治疗并发症，而成为当今治疗糖尿病并发症的新药研发热点，并相继有多种药 物进入临床试验以及上市。醛糖还原酶（ALR2）属于醛-酮还原酶超家族中的一员，由于与 体内的醛还原酶（ALR1）有着高度的同源性，活性口袋相似，因而目前的 ARI，一方面普 遍疗效较低，缺乏良好的动力学参数，另一方面也会抑制体内 ALR1 的正常活性而产生毒副 作用。因而寻找高效、对 ALR2 有高选择性的抑制剂成为 ARI 研发的关键。相对于传统筛 选模型，利用计算机药物辅助设计技术（虚拟筛选）寻找活性化合物，再进一步进行生物学 实验，可大大缩短药物发现的时程。本文采用 Accelrys Discovery Studio 中的 LigandFit 和 CODCKER 对接方法对小分子 SPECS 数据库中的 400,000 多个分子，基于 ALR2 的 3 个靶 标分子（1US0、2FZD 和 2PDK）的活性结合口袋进行虚拟筛选，并采用 3H4G 代表 ALR1 作为活性筛选的对照蛋白，得到了 13 个具备较好预测活性与选择性的目标小分子。本研究 为基于靶标结构的药物分子设计提供了指导思想。 关键词：计算机药物辅助设计；糖尿病及其并发症；醛糖还原酶；虚拟筛选 中图分类号：R914.2 20 Virtual Screening of Aldose Reductase Inhibitors for Diabetic Complications on SPECS ZHANG Jianyu, LI Zhe, LUO Haibin (School of Pharmaceutical Sciences, Sun Yat-sen University, GuangZhou 510006) 25 30 35 40 Abstract: Aldose reductase inhibitors (ARI) can decrease the activity of aldose reductase (ALR2) and thus can be used for the treatment of diabetic complications. A variety of ARIs have been approved in clinical trials or in the market. ALR2 belongs to the aldo-keto reductase (AKR) superfamily of enzymes, while aldehyde reductase (ALR1), the homologous enzyme, shares a high degree of sequence identity and similar binding-site pocket as ALR2. As a result, the existing ARIs generally have side effects due to their low selectivity towards ALR1. Therefore, the screening of new leads for ALR2 with high selectivity is the key for the development of ARI. In the present work, we describe a virtual screening experiment on SPECS (a database of 400, 000 molecules) by using the molecular docking methods, LigandFit and CDOCKER in Accelrys Discovery Studio 2.5.5 based on three crystal structures (1US0, 2FZD, and 2PDK), and finally achieve a result of 13 hit molecules which exhibit strong binding affinities with ALR2 theoretically and high selectivity towards ALR1. Keywords: Aldose reductase; virtual screening; CA