Ali Dahhas Mohammed, M Alkahtani Hamad, Malik Ajamaluddin, Almehizia Abdulrahman A, Bakheit Ahmed H, Akber Ansar Siddique, AlAbdulkarim Abdullah S, S Alrasheed Lamees, Alsenaidy Mohammad A
Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pharmaceutical Chemistry, Department Chairman, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Saudi Pharm J. 2023 Feb;31(2):228-244. doi: 10.1016/j.jsps.2022.12.007. Epub 2022 Dec 16.
MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds , and , showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.
中东呼吸综合征冠状病毒（MERS-CoV）属于冠状病毒群。近年来，冠状病毒疫情频发。2012年6月，MERS-CoV在沙特阿拉伯王国被发现，截至2022年8月底，实验室检测确诊的中东呼吸综合征（MERS）病例达2591例，全球记录的死亡病例为894例，病死率为34.5%。沙特阿拉伯报告了大多数此类病例，有2184例病例和813例死亡（病死率：37.2%），因此有必要深入了解MERS-CoV的分子机制。为了开发抗病毒药物，需要对冠状病毒亚基中的蛋白质进行说明性研究，以增进我们对该主题的理解。在本研究中，使用基于片段的文库结合基于结构的虚拟筛选的高通量筛选方法，完成了作为22种新抑制剂开发主要目标的MERS-CoV木瓜蛋白酶样蛋白酶（PLpro）的重组表达和纯化。化合物、和显示出显著的生物活性。此外，对接分析表明这三种化合物具有良好的结合模式和结合自由能。分子动力学模拟证明了化合物（2-（（苯并咪唑-2-基）硫代）-1-芳基乙-1-酮）对PLpro酶的抑制活性最强。此外，间位和对位的双取代是唯一可能增强对PLpro抑制作用的取代。化合物在通过吸收、分布、代谢和排泄研究后被选为MERS-CoV PLpro抑制剂；然而，还需要进一步研究。
