Discovery of Novel and Highly Potent Inhibitors of SARS CoV-2 Papain-Like Protease Through Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, Molecular Dynamics Simulations, and Biological Evaluation

Frontiers in Pharmacology

卷:13

Xiaoyan Tian¹  Zhe Peng¹  Xiaodan Tan¹  Lin Chen¹  Yang Yang¹  Xiaohong Chen¹  Qin Wang²  Quanfeng Zhao³ 

[1] Department of Pharmacology, Chongqing Health Center for Women and Children, Chongqing, China;

[2] Department of Pharmacology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China;

[3] Department of Pharmacy, Southwest Hospital, First Affiliated Hospital to TMMU, Third Military Medical University (Army Medical University), Chongqing, China;

关键词: SARS CoV-2;    papain-like protease;    pharmacophore modeling;    molecular docking;    inhibitor;   

DOI  :  10.3389/fphar.2022.817715

来源: DOAJ

【 摘 要 】

Background and Objective: COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19.Methods: We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking.Results: We found that four hit compounds showed excellent inhibitory activities against PLpro with IC50 values ranging from 0.6 to 2.4 μM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site.Conclusion: Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19.

【 授权许可】

Unknown