BACKGROUND The coronavirus 3 chymotrypsin-like protease (3CL(pro)) is a validated target in the design of potential anticoronavirus inhibitors. The high degree of homology within the protease's active site and substrate conservation supports the identification of broad spectrum lead compounds. A previous study identified the compound ML188, also termed 16R, as an inhibitor of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) 3CL(pro). This study will detail the generation of a homology model of the 3CL(pro) of the human coronavirus OC43 and determine the potential of 16R to form a broad-spectrum lead compound. MODELLER was used to generate a suitable three-dimensional model of the OC43 3CL(pro) and the Prime module of Schrӧdinger predicted the binding conformation and free energy of binding of 16R within the 3CL(pro) active site. Molecular dynamics further confirmed ligand stability and hydrogen bonding networks. RESULTS A high quality homology model of the OC43 3CL(pro) was successfully generated in an active conformation. Further studies reproduced the binding pose of 16R within the active site of the generated model, where its free energy of binding was shown to equal that of the 3CL(pro) of SARS-CoV, a receptor it is experimentally proven to inhibit. The stability of the ligand was subsequently confirmed by molecular dynamics. CONCLUSION The lead compound 16R may represent a broad-spectrum inhibitor of the 3CL(pro) of OC43 and potentially other coronaviruses. This study provides an atomistic structure of the 3CL(pro) of OC43 and supports further experimental validation of the inhibitory effects of 16R. These findings further confirm that the 3CL(pro) of coronaviruses can be inhibited by broad spectrum lead compounds.

中文翻译：

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人冠状病毒OC43 3CL蛋白酶和ML188作为广谱先导化合物的潜力：同源性建模和分子动力学研究。

背景冠状病毒3胰凝乳蛋白酶样蛋白酶（3CL（pro））是潜在抗冠状病毒抑制剂设计中的有效靶标。蛋白酶活性位点和底物保守性之间的高度同源性支持了广谱先导化合物的鉴定。先前的研究将化合物ML188（也称为16R）鉴定为严重急性呼吸系统综合症冠状病毒（SARS-CoV）3CL（pro）的抑制剂。这项研究将详细介绍人类冠状病毒OC43的3CL（pro）同源模型的产生，并确定16R形成广谱先导化合物的潜力。使用MODELLER生成OC43 3CL（pro）的合适三维模型，Schrӧdinger的Prime模块预测3R（pro）活性位点内16R的结合构象和结合​​自由能。分子动力学进一步证实了配体稳定性和氢键网络。结果成功创建了一个活性构象的OC43 3CL（pro）高质量同源性模型。进一步的研究在生成的模型的活性位点重现了16R的结合姿势，在该模型中，其结合自由能被证明与SARS-CoV的3CL（pro）相等，该受体已被实验证明可以抑制。随后通过分子动力学证实了配体的稳定性。结论铅化合物16R可能代表OC43和潜在的其他冠状病毒的3CL（pro）的广谱抑制剂。这项研究提供了OC43的3CL（pro）的原子结构，并支持16R抑制作用的进一步实验验证。