Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach

Srikanth Jupudi; Kalirajan Rajagopal; Sankaranarayanan Murugesan; Banoth Karan Kumar; Kannan Raman; Gowramma Byran; Jayakuamar Chennaiah; Velayutham Pillai Muthiah; Bharathi Dasan P; Sathianarayanan Sankaran

doi:10.1016/j.sajb.2021.11.033

Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach

S Afr J Bot. 2022 Dec:151:82-91. doi: 10.1016/j.sajb.2021.11.033. Epub 2021 Dec 3.

Affiliations

¹ Department of Pharmaceutical Chemistry, JSS College of Pharmacy, (A Constituent college of JSS Academy of higher education & Research- deemed University), Ooty 643001, The Nilgiris, Tamilnadu, India.
² Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science-Pilani, Pilani Campus, Pilani 333031 Rajasthan India.
³ Department of Chemistry, School of Advanced Sciences, Kalasalingam Academy of Research and Education, Krishnankovil 626 126, Tamil Nadu, India.
⁴ Bio Pharma Laboratories Pvt. Limited., Hyderabad 502 325, Telangana, India.
⁵ Faculty of Pharmacy, Karpagam Academy of Higher Education, Karpagam University Pollachi Main Road, Eachanari Post, Coimbatore 641021, Tamil Nadu, India.

Abstract

Coronaviruses (CoVs) are a large group of enveloped positive sense single-stranded RNA viruses that can cause disease to humans. These are zoonotic having potential to cause large-scale outbreaks of infections widely causing morbidity and mortality. Papain-Like Protease (PLpro) is a cysteine protease, essential for viral replication and proliferation, as a highly conserved enzyme it cleaves peptide linkage between Nsp1, Nsp2, Nsp3, and Nsp4. As a valid therapeutic target, it stops viral reproduction and boosts host immune response thereby halting further spread of infection. In the purpose of identifying inhibitors targeting Papain-Like Proteases (PLpro) we initiated a high throughput virtual screening (HTVS) protocol using a SuperNatural Database. The XP docking results revealed that two compounds SN00334175 and SN00162745 exhibited docking scores of -10.58 kcal/mol and -9.93 kcal/mol respectively. The Further PRIME MMGB-SA studies revealed Van der Waal energy and hydrophobic energy terms as major contributors for total binding free energy. The 100 ns molecular dynamics simulation of SN00334175/7JN2 and SN00162745/7JN2 revealed that these complexes were stabilized with ligand binding forming interactions with Gly266, Asn267, Tyr268, Tyr273, Thr301 and Asp302, Lys157, Leu162, Asp164, Arg166, Glu167, Pro248 and Tyr264.

Keywords: COVID-19, Coronavirus disease; Drug likeness; Molecular docking; Molecular dynamics; OPLS, Optimized Potentials for Liquid Simulations; PLpro; PLpro, Papain-Like Proteases; RMSD, Root-Mean-Square Deviation; RTC, Replicase-Transcriptase Complex; SARS CoV-2; SuperNatural Database.