In silico approach identified benzoylguanidines as SARS-CoV-2 main protease (M^pro) potential inhibitors

Abstract

The coronavirus disease-2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), became the highest public health crisis nowadays. Although the use of approved vaccines for emergency immunization and the reuse of FDA-approved drugs remains at the forefront, the search for new, more selective, and potent drug candidates from synthetic compounds is also a viable alternative to combat this viral disease. In this context, the present study employed a computational virtual screening approach based on molecular docking and molecular dynamics (MD) simulation to identify possible inhibitors for SARS-CoV-2 M^pro (main protease), an important molecular target required for the maturation of the various polyproteins involved in viral replication. The virtual screening approach selected four potential inhibitors against SARS-CoV-2 M^pro. In addition, MD simulation studies revealed changes in the positions of the ligands during the simulations compared to the complex obtained in the molecular docking studies, showing the benzoylguanidines LMed-110 and LMed-136 have a higher affinity for the active site compared to the other structures that tended to leave the active site. Besides, there was a better understanding of the formation and stability of the existing H-bonds in the formed complexes and the energetic contributions to the stability of the target-ligand molecular complexes. Finally, the in silico prediction of the ADME profile suggested that LMed-136 has drug-like characteristics and good pharmacokinetic properties. Therefore, from the present study, it can be suggested that these structures can inhibit SARS-CoV-2 M^pro. Nevertheless, further studies are needed in vitro assays to investigate the antiviral properties of these structures against SARS-CoV-2.

Communicated by Ramaswamy H. Sarma

Keywords:

• 3CL^pro
• ADME
• Coronavirus
• COVID-19
• molecular docking
• molecular dynamics

Acknowledgments

The Molecular Dynamics simulations were realized using resources of the “Centro Nacional de Processamento de Alto Desempenho em São Paulo (CENAPAD-SP).”

Disclosure statement

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

Additional information

Funding

This study was supported by Coordenadoria de Aperfeiçoamento Pessoal de Nível Superior (CAPES, Brazil), Finance Code 23038.013866/2020-19 and scholarship financing (Code 001); Conselho Nacional de Desenvolvimento Científico e Tecnológico - CNPq.