In silico evaluation of S-adenosyl-L-homocysteine analogs as inhibitors of nsp14-viral cap N7 methyltranferase and PLpro of SARS-CoV-2: synthesis, molecular docking, physicochemical data, ADMET and molecular dynamics simulations studies

Abstract

A series of S-adenosyl-L-homosysteine (SAH) analogs, with modification in the base and sugar moiety, have been designed, synthesized and screened as nsp14 and PLpro inhibitors of severe acute respiratory syndrome corona virus (SARS-CoV-2). The outcomes of ADMET (Adsorption, Distribution, Metabolism, Excretion, and Toxicity) studies demonstrated that the physicochemical properties of all analogs were permissible for development of these SAH analogs as antiviral agents. All molecules were screened against different SARS-CoV-2 targets using molecular docking. The docking results revealed that the SAH analogs interacted well in the active site of nsp14 protein having H-bond interactions with the amino acid residues Arg289, Val290, Asn388, Arg400, Phe401 and π-alkyl interactions with Arg289, Val290 and Phe426 of Nsp14-MTase site. These analogs also formed stable H-bonds with Leu163, Asp165, Arg167, Ser246, Gln270, Tyr274 and Asp303 residues of PLpro proteins and found to be quite stable complexes therefore behaved as probable nsp14 and PLpro inhibitors. Interestingly, analog 3 showed significant in silico activity against the nsp14 N7 methyltransferase of SARS-CoV-2. The molecular dynamics (MD) and post-MD results of analog 3 unambiguously established the higher stability of the nsp14 (N7 MTase):3 complex and also indicated its behavior as probable nsp14 inhibitor like the reference sinefungin. The docking and MD simulations studies also suggested that sinefungin did act as SARS-CoV-2 PLpro inhibitor as well. This study’s findings not only underscore the efficacy of the designed SAH analogs as potent inhibitors against crucial SARS-CoV-2 proteins but also pinpoint analog 3 as a particularly promising candidate. All the study provides valuable insights, paving the way for potential advancements in antiviral drug development against SARS-CoV-2.

Communicated by Ramaswamy H. Sarma

Highlights

• SAH analogs bearing modified bases and sugar moiety have been synthesized as antivirals against SARS-CoV-2.

• Molecular dynamics simulation established the stability of ligand-protein complex of analog 3 with nsp14 (N7-MTase) protein of SARS-CoV-2.

• Molecular docking studies of SAH analogs indicated them as nsp14 N7 methyltranferase as well as the PLpro inhibitors of SARS-CoV-2.

• The in silico antiviral activity of SAH analogs has been found comparable to the reference drug Sinefungin.

Keywords:

• SARS-CoV-2
• nsp 14 N7 MTase
• PLpro
• docking
• MD simulation

Author contributions

R. Srivastava, R. K. Singh and Richa Srivastava conceived and planned the experiments. S. K. Panda, P. S. S. Gupta, M. K. Rana planned and carried out the docking and MD simulation studies. A. Chaudhary, A. K. Yadav, N. K. Ram performed physicochemical data, ADMET studies. F. Naaz edited the manuscript. All authors contributed to the interpretation of the results. R. Srivastava, P. S. S. Gupta and Richa Srivastava took the lead in writing the manuscript. All authors provided critical feedback and helped shape the research, analysis and manuscript.

Disclosure statement

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

Additional information

Funding

The author Ritika Srivastava received the financial support in the form of a postdoctoral research fellowship to IISER Berhampur, Odisha, India.