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

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, which 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 explored, 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 ∼7,000 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.