Robust classification-based molecular modelling of diverse chemical entities as potential SARS-CoV-2 3CL^pro inhibitors: theoretical justification in light of experimental evidences

ABSTRACT

COVID-19 is the most unanticipated incidence of 2020 affecting the human population worldwide. Currently, it is utmost important to produce novel small molecule anti-SARS-CoV-2 drugs urgently that can save human lives globally. Based on the earlier SARS-CoV and MERS-CoV infection along with the general characters of coronaviral replication, a number of drug molecules have been proposed. However, one of the major limitations is the lack of experimental observations with different drug molecules. In this article, 70 diverse chemicals having experimental SARS-CoV-2 3CL^proinhibitory activity were accounted for robust classification-based QSAR analysis statistically validated with 4 different methodologies to recognize the crucial structural features responsible for imparting the activity. Results obtained from all these methodologies supported and validated each other. Important observations obtained from these analyses were also justified with the ligand-bound crystal structure of SARS-CoV-2 3CL^pro enzyme. Our results suggest that molecules should contain a 2-oxopyrrolidine scaffold as well as a methylene (hydroxy) sulphonic acid warhead in proper orientation to achieve higher inhibitory potency against SARS-CoV-2 3CL^pro. Outcomes of our study may be able to design and discover highly effective SARS-CoV-2 3CL^pro inhibitors as potential anticoronaviral therapy to crusade against COVID-19.

KEYWORDS:

• SARS-CoV-2 3CL^pro inhibitors
• classification-based QSAR
• LDA
• Bayesian classification
• SARpy
• recursive partitioning

Acknowledgements

Nilanjan Adhikari is grateful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India for providing research associateship (RA) [FILE NO.: 09/096(0966)/2019-EMR-I, Dated: 28-03-2019]. Suvankar Banerjee and Tarun Jha are thankful for the financial assistance from RUSA 2.0 of UGC, New Delhi, India to Jadavpur University, Kolkata, India. Sandip Kumar Baidya is thankful to the Indian Council of Medical Research (ICMR), New Delhi, India for awarding the senior research fellowship (SRF) [FILE NO.: 45/29/2019-PHA, dated: 21-06-2019]. The research has been supported by the research fund provided by the Council of Scientific and Industrial Research (CSIR-37(1722)/19/EMR-II) to Dr Balaram Ghosh and DST-SERB, New Delhi, India. The authors thank the Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India and the Department of Pharmacy, BITS-Pilani, Hyderabad, India for providing the research facilities.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed at: https://doi.org/10.1080/1062936X.2021.1914721

Additional information

Funding

This work was supported by the Indian Council of Medical Research [45/29/2019-PHA]; Council of Scientific and Industrial Research, India [09/096(0966)/2019-EMR-I, CSIR-37(1722)/19/EMR-II].