QSAR and molecular docking studies on designing potent inhibitors of SARS-CoVs main protease

Fucheng Song; Haoyang Sun; Xiaofang Ma; Wei Wang; Mingyuan Luan; Honglin Zhai; Guanmin Su; Yantao Liu

doi:10.3389/fphar.2023.1185004

QSAR and molecular docking studies on designing potent inhibitors of SARS-CoVs main protease

Front Pharmacol. 2023 May 5:14:1185004. doi: 10.3389/fphar.2023.1185004. eCollection 2023.

Authors

Fucheng Song¹, Haoyang Sun², Xiaofang Ma¹, Wei Wang¹, Mingyuan Luan³, Honglin Zhai⁴, Guanmin Su⁵, Yantao Liu¹

Affiliations

¹ Qingdao Municipal Center for Disease Control and Prevention, Qingdao, China.
² Department of Traditional Chinese Medicine, Songshan Hospital of Qingdao University, Qingdao, China.
³ Qingdao University Medical College, Qingdao, China.
⁴ Department of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, China.
⁵ Shandong Provincial Center for Disease Control and Prevention, Jinan, China.

Abstract

Background: Severe acute respiratory syndrome coronavirus (SARS-CoVs) have emerged as a global health threat, which had caused a high rate of mortality. There is an urgent need to find effective drugs against these viruses. Objective: This study aims to predict the activity of unsymmetrical aromatic disulfides by constructing a QSAR model, and to design new compounds according to the structural and physicochemical attributes responsible for higher activity towards SARS-CoVs main protease. Methods: All molecules were constructed in ChemOffice software and molecular descriptors were calculated by CODESSA software. A regression-based linear heuristic method was established by changing descriptors datasets and calculating predicted IC₅₀ values of compounds. Then, some new compounds were designed according to molecular descriptors from the heuristic method model. The compounds with predicted values smaller than a set point were constantly screened out. Finally, the properties analysis and molecular docking were conducted to further understand the structure-activity relationships of these finalized compounds. Results: The heuristic method explored the various descriptors responsible for bioactivity and gained the best linear model with R² 0.87. The success of the model fully passed the testing set validation, proving that the model has both high statistical significance and excellent predictive ability. A total of 5 compounds with ideal predicted IC₅₀ were found from the 96 newly designed derivatives and their properties analyze was carried out. Molecular docking experiments were conducted for the optimal compound 31a, which has the best compound activity with good target protein binding capability. Conclusion: The heuristic method was quite reliable for predicting IC₅₀ values of unsymmetrical aromatic disulfides. The present research provides meaningful guidance for further exploration of the highly active inhibitors for SARS-CoVs.

Keywords: QSAR; SARS-CoVs; drugs design; molecular docking; unsymmetrical aromatic disulfides.