Abstract

SARS-CoV-2 or Coronavirus disease 19 (COVID-19) is a rapidly spreading, highly contagious, and sometimes fatal disease for which drug discovery and vaccine development are critical. SARS-CoV-2 papain-like protease (PL^pro) was used to virtually screen 1697 clinical FDA-approved drugs. Among the top results expected to bind with SARS-CoV-2 PL^pro strongly were three cell protectives and antioxidants (NAD+, quercitrin, and oxiglutatione), three antivirals (ritonavir, moroxydine, and zanamivir), two antimicrobials (doripenem and sulfaguanidine), two anticancer drugs, three benzimidazole anthelmintics, one antacid (famotidine), three anti-hypertensive ACE receptor blockers (candesartan, losartan, and valsartan) and other miscellaneous systemically or topically acting drugs. The binding patterns of these drugs were superior to the previously identified SARS CoV PL^pro inhibitor, 6-mercaptopurine (6-MP), suggesting a potential for repurposing these drugs to treat COVID-19. The objective of drug repurposing is the rapid relocation of safe and approved drugs by bypassing the lengthy pharmacokinetic, toxicity, and preclinical phases. The ten drugs with the highest estimated docking scores with favorable pharmacokinetics were subjected to molecular dynamics (MD) simulations followed by molecular mechanics/generalized Born surface area (MM/GBSA) binding energy calculations. Phenformin, quercetin, and ritonavir all demonstrated prospective binding affinities for COVID-19 PL^pro over 50 ns MD simulations, with binding energy values of −56.6, −40.9, and −37.6 kcal/mol, respectively. Energetic and structural analyses showed phenformin was more stable than quercetin and ritonavir. The list of the drugs provided herein constitutes a primer for clinical application in COVID-19 patients and guidance for further antiviral studies.

Communicated by Ramaswamy H. Sarma

摘要

SARS-CoV-2 或冠状病毒病 19 (COVID-19) 是一种传播迅速、传染性强、有时甚至是致命的疾病，因此药物发现和疫苗开发至关重要。SARS-CoV-2 类木瓜蛋白酶 (PL ^pro ) 用于虚拟筛选 1697 种经 FDA 批准的临床药物。预计与 SARS-CoV-2 PL ^pro结合的最佳结果之一强的是三种细胞保护剂和抗氧化剂（NAD+、槲皮苷和氧化谷氨酸）、三种抗病毒药（利托那韦、吗啉胍和扎那米韦）、两种抗菌剂（多利培南和磺胺嘧啶）、两种抗癌药、三种苯并咪唑驱虫药、一种抗酸剂（法莫替丁）、三种抗高血压 ACE 受体阻滞剂（坎地沙坦、氯沙坦和缬沙坦）和其他各种全身或局部作用药物。这些药物的结合模式优于先前确定的 SARS CoV PL ^pro抑制剂 6-巯基嘌呤 (6-MP)，表明这些药物有可能重新用于治疗 COVID-19。药物再利用的目的是通过绕过冗长的药代动力学、毒性和临床前阶段，快速重新定位安全和批准的药物。对具有良好药代动力学估计对接分数最高的十种药物进行分子动力学 (MD) 模拟，然后进行分子力学/广义玻恩表面积 (MM/GBSA) 结合能计算。苯乙双胍、槲皮素和利托那韦均显示出对 COVID-19 PL ^{pro 的}前瞻性结合亲和力超过 50 ns 的 MD 模拟，结合能值分别为 -56.6、-40.9 和 -37.6 kcal/mol。能量和结构分析表明，苯乙双胍比槲皮素和利托那韦更稳定。本文提供的药物清单构成了 COVID-19 患者临床应用的入门指南和进一步抗病毒研究的指导。

由 Ramaswamy H. Sarma 交流