One microsecond MD simulations of the SARS-CoV-2 main protease and hydroxychloroquine complex reveal the intricate nature of binding

Abstract

Currently, several vaccines and antivirals across the globe are in clinical trials. Hydroxychloroquine (HCQ) was reported to inhibit the SARS-CoV-2 virus in antiviral assays. Here, it raises the curiosity about the molecular target of HCQ inside the cell. It may inhibit some of the viral targets, or some other complex mechanisms must be at disposal towards action mechanisms. In some of the viruses, proteases are experimentally reported to be a potential target of HCQ. However, no in-depth investigations are available in the literature yet. Henceforth, we have carried out extensive, one-microsecond long molecular dynamics simulations of the bound complex of hydroxychloroquine with main protease (Mpro) of SARS-CoV-2. Our analysis found that HCQ binds within the catalytic pocket of Mpro and remains stable upto one-third of simulation time but further causes increased fluctuations in simulation parameters. In the end, the HCQ does not possess any pre-formed hydrogen bond, other non-covalent interactions with Mpro, ultimately showing the unsteadiness in binding at catalytic binding pocket and may suggest that HCQ may not inhibit the Mpro. In the future, this study would require experimental validation on enzyme assays against Mpro, and that may be the final say.

Communicated by Ramaswamy H. Sarma

Keywords:

• COVID-19
• SARS-CoV-2
• Mpro
• hydroxychloroquine
• molecular dynamics simulations

Acknowledgements

All the authors would like to thank IIT Mandi and HPC utility for providing facilities. RG would like to acknowledge the Department of Biotechnology, Govt of India (BT/11/IYBA/2018/06). PK and AK are supported by MHRD for funding. TB is grateful to the Department of Science and Technology for her INSPIRE fellowship for Funding.

Disclosure statement

No potential conflict of interest was reported by the authors.

Authors’ contribution

RG & NG: Conception, design, and review of the manuscript. PK, TB, and AK: acquisition and interpretation of data, writing of the manuscript.

Additional information

Funding

All the authors would like to thank IIT Mandi and HPC utility for providing facilities. RG would like to acknowledge the Department of Biotechnology, Govt of India (BT/11/IYBA/2018/06). PK and AK are supported by MHRD for funding. TB is grateful to the Department of Science and Technology for her INSPIRE fellowship for Funding.