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.