Nature and Life Sciences Department, Benyoucef Benkhedda University, 16000, Didouche Mourad, Algiers, Algeria.
Faculty of Biological Sciences, Cellular and Molecular Biology, University of Science and Technology Houari Boumediene, BP 32, El Alia Bab Ezzouar, 16111, Algiers, Algeria.
J Mol Graph Model. 2020 Dec;101:107758. doi: 10.1016/j.jmgm.2020.107758. Epub 2020 Sep 21.
A novel strain of coronavirus, namely, SARS-CoV-2 identified in Wuhan city of China in December 2019, continues to spread at a rapid rate worldwide. There are no specific therapies available and investigations regarding the treatment of this disease are still lacking. In order to identify a novel potent inhibitor, we performed blind docking studies on the main virus protease M with eight approved drugs belonging to four pharmacological classes such as: anti-malarial, anti-bacterial, anti-infective and anti-histamine. Among the eight studied compounds, Lymecycline and Mizolastine appear as potential inhibitors of this protease. When docked against M crystal structure, these two compounds revealed a minimum binding energy of -8.87 and -8.71 kcal/mol with 168 and 256 binding modes detected in the binding substrate pocket, respectively. Further, to study the interaction mechanism and conformational dynamics of protein-ligand complexes, Molecular dynamic simulation and MM/PBSA binding free calculations were performed. Our results showed that both Lymecycline and Mizolastine bind in the active site. And exhibited good binding affinities towards target protein. Moreover, the ADMET analysis also indicated drug-likeness properties. Thus it is suggested that the identified compounds can inhibit Chymotrypsin-like protease (3CL) of SARS-CoV-2.
一种新型冠状病毒，即 2019 年 12 月在中国武汉市发现的 SARS-CoV-2，继续在全球范围内迅速传播。目前尚无特效疗法，针对该疾病的治疗研究仍在进行中。为了寻找新型有效的抑制剂，我们对主要病毒蛋白酶 M 进行了盲法对接研究，共涉及 8 种已批准的药物，分为四类：抗疟药、抗菌药、抗感染药和抗组胺药。在研究的 8 种化合物中，盐酸林可霉素和咪唑斯汀似乎是该蛋白酶的潜在抑制剂。当与 M 晶体结构对接时，这两种化合物的最低结合能分别为-8.87 和-8.71 kcal/mol，在结合底物口袋中分别检测到 168 和 256 种结合模式。此外，为了研究蛋白质-配体复合物的相互作用机制和构象动力学，进行了分子动力学模拟和 MM/PBSA 结合自由能计算。结果表明，盐酸林可霉素和咪唑斯汀都结合在活性位点上，并对靶蛋白表现出良好的结合亲和力。此外，ADMET 分析也表明了这些化合物具有类药性。因此，我们认为鉴定出的化合物可以抑制 SARS-CoV-2 的胰凝乳蛋白酶样蛋白酶（3CL）。
