Quantum biochemistry, molecular docking, and dynamics simulation revealed synthetic peptides induced conformational changes affecting the topology of the catalytic site of SARS-CoV-2 main protease

Abstract

The recent outbreak caused by SARS-CoV-2 continues to threat and take many lives all over the world. The lack of an efficient pharmacological treatments are serious problems to be faced by scientists and medical staffs worldwide. In this work, an in silico approach based on the combination of molecular docking, dynamics simulations, and quantum biochemistry revealed that the synthetic peptides RcAlb-PepI, PepGAT, and PepKAA, strongly interact with the main protease (Mpro) a pivotal protein for SARS-CoV-2 replication. Although not binding to the proteolytic site of SARS-CoV-2 Mpro, RcAlb-PepI, PepGAT, and PepKAA interact with other protein domain and allosterically altered the protease topology. Indeed, such peptide-SARS-CoV-2 Mpro complexes provoked dramatic alterations in the three-dimensional structure of Mpro leading to area and volume shrinkage of the proteolytic site, which could affect the protease activity and thus the virus replication. Based on these findings, it is suggested that RcAlb-PepI, PepGAT, and PepKAA could interfere with SARS-CoV-2 Mpro role in vivo. Also, unlike other antiviral drugs, these peptides have no toxicity to human cells. This pioneering in silico investigation opens up opportunity for further in vivo research on these peptides, towards discovering new drugs and entirely new perspectives to treat COVID-19.

Communicated by Ramaswamy H. Sarma

Keywords:

• SARS-CoV-2 main protease
• COVID-19
• synthetic peptides

Acknowledgements

The authors are also grateful to the support received from the National Center for High Performance Processing - Federal University of Ceara and Center for Permanent Education in Health Care-CEATS/School of Public Health of Ceara (ESP-CE). V.N.F. also acknowledges support from PRONEX FUNCAP/CNPq (PR2-0101-00006.01.00/15).

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

Conceptualization: Pedro F. N. Souza, Jackson L. Amaral. Francisco E. S. Lopes, and Jose T. A. Oliveira. Data curation: Pedro F. N. Souza, Jackson L. Amaral, Francisco E. S. Lopes, Cleverson D. T. Freitas, and Valder N. Freire. Formal analysis: Pedro F. N. Souza, Jackson L. Amaral, and Francisco E. S. Lopes. Funding acquisition: Jose T. A. Oliveira, Cleverson D. T. Freitas, and Valder N. Freire. Methodology: Jackson L. Amaral and Francisco E. S. Lopes. Resources: Jose T. A. Oliveira, Cleverson D. T. Freitas, and Valder N. Freire. Supervision: Pedro F. N. Souza. Writing–original draft: Pedro F. N. Souza, Jackson L. Amaral, Francisco E. S. Lopes, and Leonardo V. Abreu. Writing–review and editing: Pedro F. N. Souza, Jackson L. Amaral, Francisco E. S. Lopes, Leonardo V. Abreu, and Jose T. A. Oliveira.

Additional information

Funding

This work was supported by grants from the following Brazilian agencies: The National Council for Scientific and Technological Development (CNPq) with a doctoral grant to J.L.A. and research grant (codes 431511/2016-0 and 306202/2017-4) to J.T.A.O.; the Council for Advanced Professional Training (CAPES) sponsored PFNS with a Postdoctoral Fellowships.