Aliebrahimi Shima, Montasser Kouhsari Shideh, Ostad Seyed Nasser, Arab Seyed Shahriar, Karami Leila
Department of Cellular and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
Department of Toxicology and Pharmacology, Faculty of Pharmacy and Poisoning Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Cell Biochem Biophys. 2018 Jun;76(1-2):135-145. doi: 10.1007/s12013-017-0821-6. Epub 2017 Aug 29.
c-Met receptor tyrosine kinase is a proto-oncogene whose aberrant activation is attributed to a lower rate of survival in most cancers. Natural product-derived inhibitors known as "fourth generation inhibitors" constitute more than 60% of anticancer drugs. Furthermore, consensus docking approach has recently been introduced to augment docking accuracy and reduce false positives during a virtual screening. In order to obtain novel small-molecule Met inhibitors, consensus docking approach was performed using Autodock Vina and Autodock 4.2 to virtual screen Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target database against active and inactive conformation of c-Met kinase domain structure. Two hit molecules that were in line with drug-likeness criteria, desired docking score, and binding pose were subjected to molecular dynamics simulations to elucidate intermolecular contacts in protein-ligand complexes. Analysis of molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area studies showed that ZINC08234189 is a plausible inhibitor for the active state of c-Met, whereas ZINC03871891 may be more effective toward active c-Met kinase domain compared to the inactive form due to higher binding energy. Our analysis showed that both the hit molecules formed hydrogen bonds with key residues of the hinge region (P1158, M1160) in the active form, which is a hallmark of kinase domain inhibitors. Considering the pivotal role of HGF/c-Met signaling in carcinogenesis, our results propose ZINC08234189 and ZINC03871891 as the therapeutic options to surmount Met-dependent cancers.
c-Met受体酪氨酸激酶是一种原癌基因,其异常激活与大多数癌症患者较低的生存率有关。被称为“第四代抑制剂”的天然产物衍生抑制剂占抗癌药物的60%以上。此外,最近引入了一致性对接方法,以提高对接准确性并减少虚拟筛选过程中的假阳性。为了获得新型小分子Met抑制剂,使用Autodock Vina和Autodock 4.2进行一致性对接,以针对c-Met激酶结构域的活性和非活性构象虚拟筛选天然植物来源的抗癌化合物-活性-靶点数据库。对两个符合类药性标准、理想对接分数和结合姿势的命中分子进行分子动力学模拟,以阐明蛋白质-配体复合物中的分子间相互作用。分子动力学模拟和分子力学泊松-玻尔兹曼表面积研究分析表明,ZINC08234189是c-Met活性状态的一种可能抑制剂,而ZINC03871891由于具有更高的结合能,可能对活性c-Met激酶结构域比非活性形式更有效。我们的分析表明,这两个命中分子在活性形式下均与铰链区的关键残基(P1158、M1160)形成氢键,这是激酶结构域抑制剂的一个标志。考虑到HGF/c-Met信号在致癌过程中的关键作用,我们的结果提出ZINC08234189和ZINC03871891作为克服Met依赖性癌症的治疗选择。