Abstract：
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (https://epimedlab.org/sars-cov-2-proteome/). Many of these proteins contain potential targetable sites for the development of antivirals. Despite the widespread use of vaccinations, the emergence of variants necessitates the investigation of new therapeutics and antivirals. Here, the EpiMed Coronabank Chemical Collection (https://epimedlab.org/crl/) was utilized to investigate potential antivirals against the nsp14 exoribonuclease (ExoN) domain. Molecular docking was performed to evaluate the binding characteristics of our chemical library against the nsp14 ExoN site. Based on the initial screen, trisjuglone, ararobinol, corilagin, and naphthofluorescein were identified as potential lead compounds. Molecular dynamics (MD) simulations were subsequently performed, with the results highlighting the stability of the lead compounds in the nsp14 ExoN site. Protein-RNA docking revealed the potential for the lead compounds to disrupt the interaction with RNA when bound to the ExoN site. Moreover, hypericin, cyanidin-3-O-glucoside, and rutin were previously identified as lead compounds targeting the papain-like protease (PLpro) naphthalene binding site. Through performing MD simulations, the stability and interactions of lead compounds with PLpro were further examined. Overall, given the critical role of the exonuclease activity of nsp14 in ensuring viral fidelity and the multifunctional role of PLpro in viral pathobiology and replication, these nsps represent important targets for antiviral drug development. Our databases can be utilized for in silico studies, such as the ones performed here, and this approach can be applied to other potentially druggable SARS-CoV-2 protein targets.
摘要：
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）基因组编码29种蛋白质，包括4种结构，16个非结构（NSPS），和9种辅助蛋白（https://epimedlab.org/sars-cov-2-proteome/）。这些蛋白质中的许多含有开发抗病毒剂的潜在可靶向位点。尽管疫苗的广泛使用，变异的出现需要研究新的治疗方法和抗病毒药物。这里,EpiMedCoronabank化学收藏（https://epimedlab.org/crl/）用于研究针对nsp14外切核糖核酸酶（ExoN）域的潜在抗病毒药物。进行分子对接以评估我们的化学文库针对nspl4ExoN位点的结合特性。基于初始屏幕，Trisjuglone,ararobinol,corilagin,和萘荧光素被确定为潜在的先导化合物。随后进行了分子动力学（MD）模拟，结果突出了nsp14ExoN位点中先导化合物的稳定性。蛋白质-RNA对接揭示了先导化合物在与ExoN位点结合时破坏与RNA相互作用的潜力。此外，金丝桃素,花青素-3-O-葡萄糖苷，和芦丁先前被鉴定为靶向木瓜蛋白酶样蛋白酶（PLpro）萘结合位点的先导化合物。通过进行MD模拟，进一步检查了先导化合物与PLpro的稳定性和相互作用。总的来说,鉴于nsp14的核酸外切酶活性在确保病毒保真度方面的关键作用以及PLpro在病毒病理学和复制中的多功能作用，这些nsps是抗病毒药物开发的重要靶点。我们的数据库可用于计算机模拟研究，比如在这里表演的，这种方法可以应用于其他潜在的药物SARS-CoV-2蛋白靶标。
