Research Center for Drug Discovery & Institute of Human Virology, School of Pharmaceutical Sciences, Sun Yat-Sen University , Guangzhou 510006, China.
J Chem Inf Model. 2013 Sep 23;53(9):2409-22. doi: 10.1021/ci400322j. Epub 2013 Aug 26.
Aldose reductase reduces glucose to sorbitol. It plays a key role in many of the complications arising from diabetes. Thus, aldose reductase inhibitors (ARI) have been identified as promising therapeutic agents for treating such complications of diabetes, as neuropathy, nephropathy, retinopathy, and cataracts. In this paper, a virtual screening protocol applied to a library of compounds in house has been utilized to discover novel ARIs. IC50's were determined for 15 hits that inhibited ALR2 to greater than 50% at 50 μM, and ten of these have an IC50 of 10 μM or less, corresponding to a rather substantial hit rate of 14% at this level. The specificity of these compounds relative to their cross-reactivity with human ALR1 was also assessed by inhibition assays. This resulted in identification of novel inhibitors with IC50's comparable to the commercially available drug, epalrestat, and greater than an order of magnitude better selectivity.
醛糖还原酶将葡萄糖还原为山梨醇。它在糖尿病引起的许多并发症中起着关键作用。因此，醛糖还原酶抑制剂（ARI）已被确定为治疗糖尿病神经病变、肾病、视网膜病变和白内障等并发症的有前途的治疗药物。在本文中，应用于内部化合物库的虚拟筛选方案已被用于发现新型 ARI。对 15 个抑制 ALR2 超过 50%的化合物进行了 IC50 测定，其中 10 个化合物的 IC50 为 10 μM 或更低，这在该水平上的命中率相当高，为 14%。通过抑制试验还评估了这些化合物相对于其与人类 ALR1 的交叉反应性的特异性。这导致了与市售药物依帕司他具有可比 IC50 的新型抑制剂的鉴定，并且选择性要好一个数量级以上。
