Molecular insights to the binding interactions of APNS containing HIV-protease inhibitors against SARS-CoV-2 M^pro: an in silico approach towards drug repurposing

Abstract

SARS-CoV-2 M^pro is one of the most vital enzymes of the new coronavirus-2 (SARS-CoV-2) and is a crucial target for drug discovery. Unfortunately, there is not any potential drugs available to combat the action of SARS-CoV-2 M^pro. Based on the reports HIV-protease inhibitors can be applied against the SARS by targeting the SARS-CoV-1 M^pro, we have chosen few clinically trialed experimental and allophenylnorstatine (APNS) containing HIV-protease inhibitors (JE-2147, JE-533, KNI-227, KNI-272 & KNI-1931), to examine their binding affinities with SARS-CoV-2 M^pro and to assess their potential to check for a possible drug candidate against the protease. Here, we have chosen a methodology to understand the binding mechanism of these five inhibitors to SARS-CoV-2 M^pro by merging molecular docking, molecular dynamics (MD) simulation and MM-PBSA based free energy calculations. Our estimations disclose that JE-2147 is highly effective (ΔG_Bind = −28.31 kcal/mol) due to an increased favorable van der Waals (ΔE_vdw) interactions and decreased solvation (ΔG_solv) energies between the inhibitor and viral protease. JE-2147 shows a higher level of interactions as compared to JE-533 (−6.85 kcal/mol), KNI-227 (−18.36 kcal/mol), KNI-272 (−15.69 kcal/mol) and KNI-1931 (−21.59 kcal/mol) against SARS-CoV-2 M^pro. Binding contributions of important residues (His41, Met49, Cys145, His164, Met165, Glu166, Pro168, Gln189, etc.) from the active site or near the active site regions with ≥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 M^pro drugs.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coronavirus
• SARS-CoV-2 M^pro
• drug discovery
• molecular dynamics simulation
• binding free energy
• MM-PBSA

Acknowledgement

The authors sincerely acknowledge and thank Berhampur University for providing the infrastructure to study this work. All the authors thank the World Bank-OHEPEE (Odisha Higher Education Program for Excellence and Equity), Department of Higher Education, Govt. of Odisha to support the Centre of Excellence on Bioprospecting of Ethno-pharmaceuticals of Southern Odisha, Berhampur University. The authors deeply appreciate the anonymous reviewers for their constructive suggestions for improvement of the article.

Disclosure statement

The authors declare that they have no conflict of interests.

Additional information

Funding

BRM is supported through UGC-BSR Start-Up grant (F.30-484/2019(BSR)) by Govt. of India, and Science & Technology, Govt. of Odisha project (SCST-MISC-0061-2018-1288). PP is a BPRF (Biju Pattnaik Research Fellowship) awardee from Science & Technology (S&T), Govt. of Odisha, India (STBT-MISC-0007-2020-2047/ST).