Faculty of Pharmacy, Zarqa University, P.O. Box 132222, Zarqa, 13132, Jordan.
Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan.
Comput Biol Chem. 2019 Jun;80:102-110. doi: 10.1016/j.compbiolchem.2019.03.011. Epub 2019 Mar 25.
Glyoxalase system is an ubiquitous system in human cells which has been examined thoroughly for its role in different diseases. It comprises two enzymes; Glyoxalase I (Glo-I) and Glyoxalase II (Glo-II) which perform detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic bystanders. In silico computer Aided Drug Design approaches were used and ninety two diverse pharmacophore models were generated from eighteen Glyoxalase I crystallographic complexes. Subsequent QSAR modeling followed by ROC evaluation identified a single pharmacophore model which was able to predict the expected Glyoxalase I inhibition. Screening of the National Cancer Institute (NCI) database using the optimal pharmacophore Hypo(3VW9) identified several promising hits. Thirty eight hits were successfully predicted then ordered and evaluated in vitro. Seven hits out of the thirty eight tested compounds showed more than 50% inhibition with low micromolar IC.
糖氧化解毒系统是一种普遍存在于人类细胞中的系统，其在各种疾病中的作用已经得到了深入研究。它由两种酶组成：糖氧还蛋白 I（Glo-I）和糖氧还蛋白 II（Glo-II），它们能将内源性有害代谢物，主要是甲基乙二醛（MG）转化为无毒的旁观者。采用计算机辅助药物设计方法，从十八个糖氧还蛋白 I 晶体复合物中生成了 92 种不同的药效团模型。随后的 QSAR 建模和 ROC 评估确定了一个能够预测糖氧还蛋白 I 抑制作用的单一药效团模型。使用最优药效团 Hypo(3VW9)对国家癌症研究所（NCI）数据库进行筛选，确定了一些有前途的命中化合物。从 38 个命中化合物中成功预测并订购了 38 个化合物，并在体外进行了评估。在测试的 38 种化合物中有 7 种化合物的抑制率超过 50%，IC 为低微摩尔。
