Department of Molecular Genetics, National Institute of Genetic Engineering and Biotechnology, Tehran, Iran.
J Mol Graph Model. 2013 Feb;39:176-82. doi: 10.1016/j.jmgm.2012.11.007. Epub 2012 Nov 28.
Isopentenyl diphosphate isomerase is an essential enzyme in those living organisms such as pathogenic strains of Streptococcus and Staphylococcus genera which rely on the Mevalonate pathway for the production of isoprenoids. The pathogens contain type 2 IDI in contrast to human that contains type 1 IDI. Therefore, the type 2 IDI may be a potential target for the therapy of some infectious diseases. In the current study, a virtual screening by docking was performed among 2000 chemicals from CoCoCo library to find a specific inhibitor for type 2 IDIs. To this end, the structures of the type 2 IDIs of Bacillus licheniformis, Pseudomonas stutzeri, Streptococcus pyogenes, and Staphylococcus aureus were molded using comparative modeling and Hidden Markov Model (HMM) based prediction. The predicted models were evaluated based on Q-mean and Prosa score. Molegro Virtual Docker with MolDock scoring function was used for measuring the binding affinity of the found inhibitor to the active site of the models. Also the inhibition effect of the compound was virtually tested on the crystallography-solved structures of the Sulfolobus shibatae and Thermus thermophilus type 2 IDIs as well as the Escherichia coli type 1 IDI. Finally, the inhibition effect of the found inhibitor was virtually tested on the human type 1 IDI. Interestingly, the results suggest that the inhibitor efficiently binds to and inhibits the bacterial IDIs especially the type 2 IDIs of pathogens while it is not inhibiting the human IDI.
异戊烯二磷酸异构酶是依赖于甲羟戊酸途径生成异戊烯的病原体（如链球菌属和葡萄球菌属的致病菌株）中一种必不可少的酶。病原体中含有与人类的 1 型 IDI 相反的 2 型 IDI。因此，2 型 IDI 可能是治疗某些传染病的潜在靶点。在本研究中，通过对接对 CoCoCo 文库中的 2000 种化学物质进行虚拟筛选，以寻找针对 2 型 IDI 的特异性抑制剂。为此，使用基于比较建模和隐马尔可夫模型（HMM）的预测方法对地衣芽孢杆菌、施氏假单胞菌、化脓性链球菌和金黄色葡萄球菌的 2 型 IDI 结构进行了建模。根据 Q-mean 和 Prosa 评分对预测模型进行了评估。使用 Molegro Virtual Docker 及其 MolDock 评分函数来测量发现的抑制剂与模型活性部位的结合亲和力。此外，还对结晶解决的 Sulfolobus shibatae 和 Thermus thermophilus 2 型 IDI 以及大肠杆菌 1 型 IDI 的结构进行了化合物的虚拟抑制作用测试。最后，对发现的抑制剂对人 1 型 IDI 的抑制作用进行了虚拟测试。有趣的是，结果表明该抑制剂能有效地结合并抑制细菌 IDI，特别是病原体中的 2 型 IDI，而不会抑制人类 IDI。
