Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches

Abstract

The papain-like protease (PL pro ) is vital for the replication of coronaviruses (CoVs), as well as for escaping innate-immune responses of the host. Hence, it has emerged as an attractive antiviral drug-target. In this study, computational approaches were employed, mainly the structure-based virtual screening coupled with all-atom molecular dynamics (MD) simulations to computationally identify specific inhibitors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PL pro , that can be further developed as potential pan-PL pro based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL pro were exploited, and it was revealed that functionally important catalytic triad residues are well conserved among SARS-CoV, SARS-CoV-2, and middle east respiratory syndrome coronavirus (MERS-CoV). The subsequent screening of a focused protease inhibitors database composed of ∼7000 compounds resulted in the identification of three candidate compounds, ADM_13083841, LMG_15521745, and SYN_15517940. These three compounds established conserved interactions which were further explored through MD simulations, free energy calculations, and residual energy contribution estimated by MM-PB(GB)SA method. All these compounds showed stable conformation and interacted well with the active residues of SARS-CoV-2 PL pro and showed consistent interaction profile with SARS-CoV PL pro and MERS-CoV PL pro as well. Conclusively, the reported SARS-CoV-2 PL pro specific compounds could serve as seeds for developing potent pan-PL pro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented information related to binding site residual energy contribution could lead to further optimization of these compounds.

Designing of a next generation multiepitope based vaccine (MEV) against SARS-COV-2: Immunoinformatics and in silico approaches

“…MD simulation is an important approach to analyse the stability of the receptor-ligand complex [ 48 , 70 ]. Complexes of MEV with TLR3 and TLR8 were simulated at 20 ns using GROMACS 5.1.4 [ 71 ] by following the same protocol of our previously published studies [ 5 , 7 , 20 , 72 , 73 ]. The trajectories were saved for each complex after every 2 fs and root mean square deviation (RMSD) and root mean square fluctuations (RMSF) analysis were performed using GROMCAS tools.…”

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

“…The PLpro enzyme is vital in processing the polypeptide to produce a functional replicase complex and aids in viral spreading [ 22 ]. PLpro also plays a role in evading host antiviral immune responses by cleaving proteinaceous modification on the host protein after the post-translation phase [ 34 ]. Thus, targeting this enzyme is useful in highlighting therapeutic strategies that can suppress the virus infection and prompt antiviral immunity.…”

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

“…Although molecules obtained from virtual screens have previously been deposited in the literature for prospective testing against PL pro [ 84 , 85 , 86 , 87 , 88 ], these were mainly docking studies, and we could not find any paper where a ligand-based virtual screen of such scale had been performed against GRL-0617 before docking. Additionally, and in contrast to our work, the docking had commonly been performed against the PL pro catalytic site and not the GRL-0617 binding site, which is distinctly different.…”