Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches
- Author:
A.Alamri MUBARAK
1
;
Muhammad Tahir ul Qamar
;
Mirza Usman MUHAMMAD
;
M.Alqahtani SAFAR
;
Froeyen MATHEUS
;
Chen LING-LING
Author Information
1. Department of Pharmaceutical Chemistry
- Keywords:
COVID-19;
MERS-CoV;
Molecular dynamic simulation;
Pan-inhibitors;
Papain-like protease;
SARS-CoV;
SARS-CoV-2;
Virtual screening
- From:
Journal of Pharmaceutical Analysis
2020;10(6):546-559
- CountryChina
- Language:Chinese
-
Abstract:
The papain-like protease (PLpro) 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) PLpro, which can be further developed as potential pan-PLpro based broad-spectrum antiviral drugs. The sequence, structure, and functional con-serveness of most deadly human CoVs PLpro 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 in-hibitors 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 PLpro, and showed consistent interaction profile with SARS-CoV PLpro and MERS-CoV PLpro as well. Conclusively, the re-ported SARS-CoV-2 PLpro specific compounds could serve as seeds for developing potent pan-PLpro based broad-spectrum antiviral drugs against deadly human coronaviruses. Moreover, the presented infor-mation related to binding site residual energy contribution could lead to further optimization of these compounds.
