Rožman Kaja, Lešnik Samo, Brus Boris, Hrast Martina, Sova Matej, Patin Delphine, Barreteau Hélène, Konc Janez, Janežič Dušanka, Gobec Stanislav
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):944-949. doi: 10.1016/j.bmcl.2016.12.082. Epub 2016 Dec 31.
We report on the successful application of ProBiS-CHARMMing web server in the discovery of new inhibitors of MurA, an enzyme that catalyzes the first committed cytoplasmic step of bacterial peptidoglycan synthesis. The available crystal structures of Escherichia coli MurA in the Protein Data Bank have binding sites whose small volume does not permit the docking of drug-like molecules. To prepare the binding site for docking, the ProBiS-CHARMMing web server was used to simulate the induced-fit effect upon ligand binding to MurA, resulting in a larger, more holo-like binding site. The docking of a filtered ZINC compound library to this enlarged binding site was then performed and resulted in three compounds with promising inhibitory potencies against MurA. Compound 1 displayed significant inhibitory potency with IC value of 1μM. All three compounds have novel chemical structures, which could be used for further optimization of small-molecule MurA inhibitors.
我们报告了ProBiS-CHARMMing网络服务器在发现MurA新抑制剂方面的成功应用，MurA是一种催化细菌肽聚糖合成首个关键细胞质步骤的酶。蛋白质数据库中大肠杆菌MurA的现有晶体结构具有结合位点，其体积较小，不允许类药物分子对接。为了准备用于对接的结合位点，使用ProBiS-CHARMMing网络服务器模拟配体与MurA结合时的诱导契合效应，从而产生一个更大、更类似全酶的结合位点。然后将经过筛选的ZINC化合物库对接至这个扩大的结合位点，结果得到了三种对MurA具有良好抑制活性的化合物。化合物1表现出显著的抑制活性，IC值为1μM。所有三种化合物都具有新颖的化学结构，可用于进一步优化小分子MurA抑制剂。
