Drug Repurposing of Allophenylnorstatine Containing HIV-Protease Inhibitors Against SARS-CoV-2 Mpro: Insights from Molecular Dynamics Simulations and Binding Free Energy Estimations

02 June 2020, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Coronavirus-2 Main protease (SARS-CoV-2 Mpro), one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and a crucial target for drug discovery, has been battered with numerous types of drugs/inhibitors. Regrettably, till date there is no any potential drugs or effective inhibitors available to combat its action. Based on the reports of HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 Mpro, we have chosen few clinically trialed experimental HIV-protease inhibitors (JE-2147, KNI-227 and KNI-272) and a variant JE2-CH3, to examine their binding affinities with SARS-CoV-2 Mpro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the rational elucidation of the binding mechanism of these four inhibitors to SARS-CoV-2 Mpro by merging molecular docking, Molecular Dynamics (MD) simulation, and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (-14.95 kcal/mol) compared to JE2-CH3 (--11.19 kcal/mol), KNI-227 (-13.93 kcal/mol) and KNI-272 (-12.84 kcal/mol) against SARS-CoV-2 Mpro. The increase in binding affinity for JE-2147 comparative to other three inhibitors arises due to an increased favorable van der Waals interactions and decreased solvation energies between the inhibitor and viral protease. Residue decomposition analysis and hydrogen bonding pattern confirms binding affinities of the inhibitors crucial for the interactions. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Pro168, Gln189 etc.) from the active site or near the active site regions with more than 1.0 kcal/mol suggest a potent binding of the inhibitors. It is anticipated that the current study of binding interactions of these APNS containing inhibitors can pitch some valuable insights to design the significantly effective anti-SARS-CoV-2 Mpro drugs.


COVID-19 virus (SARS-CoV-2)
SARS-CoV-2 Mpro
Drug Discovery
Molecular Docking
Molecular Dynamics simulation
Binding Free energy

Supplementary materials

Supplementary Information


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.