Discovery of 3CLpro Inhibitor of SARS-CoV-2 Main Protease

Abstract

Coronavirus main protease (3CLpro), a special cysteine protease in coronavirus family, is highly desirable in the life cycle of coronavirus. Here, molecular docking, ADMET pharmacokinetic profiles and molecular dynamics (MD) simulation were performed to develop specific 3CLpro inhibitor. The results showed that the 137 compounds originated from Chinese herbal have good binding affinity to 3CLpro. Among these, Cleomiscosin C, (+)-Norchelidonine, Protopine, Turkiyenine, Isochelidonine and Mallotucin A possessed prominent drug-likeness properties. Cleomiscosin C and Turkiyenine exhibited excellent pharmacokinetic profiles. Furthermore, the complex of Cleomiscosin C with SARS-CoV-2 main protease presented high stability. The findings in this work indicated that Cleomiscosin C is highly promising as a potential 3CLpro inhibitor, thus facilitating the development of effective drugs for COVID-19.

Plain Language Summary

In this work, computer aided drug design technology was used to study the main protease 3CLpro of novel coronavirus, and functional small molecules with inhibitory effects on novel coronavirus were screened from the compound library of natural products. The results showed that Cleomiscosin C is highly promising as a potential 3CLpro inhibitor with prominent binding affinity, pharmacokinetic profiles and stability.

Keywords:

• 3CLpro
• ADMET prediction
• molecular docking
• molecular dynamics simulation
• SARS-CoV-2

Author contributions

Conceptualization: Qingqing Rao and Shengxiang Yang; Data curation: Wenjing Shen; Investigation, Yi Kuang; Methodology: Yi Kuang and Xiaodong Ma; Resources: Xiaodong Ma, Qingqing Rao and Shengxiang Yang; Supervision: Qingqing Rao and Shengxiang Yang; Validation: Yi Kuang, Xiaodong Ma and Wenjing Shen; Writing – original draft: Yi Kuang and Xiaodong Ma; Writing – review & editing: Qingqing Rao and Shengxiang Yang.

Financial & competing interests disclosure

This work was supported by the “Pioneer” and “Leading Goose” R&D Program of Zhejiang (2022C02023); National Natural Science Foundation of China (32271527); Research Foundation of Talented Scholars of Zhejiang A&F University (2021LFR058); the Ability Establishment of Sustainable Use for Valuable Chinese Medicine resources (2060302) and the National Science & Technology Fundamental Resources Investigation Program of China (2018FY100800). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.