tetano
Editor, Senior Moderator
J Pharm Anal
. 2020 Aug 28.
doi: 10.1016/j.jpha.2020.08.012. Online ahead of print.
Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches
Mubarak A Alamri[SUP] 1 [/SUP], Muhammad Tahir Ul Qamar[SUP] 2 [/SUP], Muhammad Usman Mirza[SUP] 3 [/SUP], Safar M Alqahtani[SUP] 1 [/SUP], Matheus Froeyen[SUP] 3 [/SUP], Ling-Ling Chen[SUP] 2 4 [/SUP]
Affiliations
Abstract
The papain-like protease (PL[SUP]pro[/SUP]) 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[SUP]pro[/SUP], that can be further developed as potential pan-PL[SUP]pro[/SUP] based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL[SUP]pro[/SUP] 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[SUP]pro[/SUP] and showed consistent interaction profile with SARS-CoV PL[SUP]pro[/SUP] and MERS-CoV PL[SUP]pro[/SUP] as well. Conclusively, the reported SARS-CoV-2 PL[SUP]pro[/SUP] specific compounds could serve as seeds for developing potent pan-PL[SUP]pro[/SUP] 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.
Keywords: COVID-19; MERS-CoV; Molecular dynamic simulation; Pan-inhibitors; Papain-like protease; SARS-CoV; SARS-CoV-2; Virtual screening.
.
. 2020 Aug 28.
doi: 10.1016/j.jpha.2020.08.012. Online ahead of print.
Discovery of human coronaviruses pan-papain-like protease inhibitors using computational approaches
Mubarak A Alamri[SUP] 1 [/SUP], Muhammad Tahir Ul Qamar[SUP] 2 [/SUP], Muhammad Usman Mirza[SUP] 3 [/SUP], Safar M Alqahtani[SUP] 1 [/SUP], Matheus Froeyen[SUP] 3 [/SUP], Ling-Ling Chen[SUP] 2 4 [/SUP]
Affiliations
- PMID: 32874702
- PMCID: PMC7453225
- DOI: 10.1016/j.jpha.2020.08.012
Abstract
The papain-like protease (PL[SUP]pro[/SUP]) 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[SUP]pro[/SUP], that can be further developed as potential pan-PL[SUP]pro[/SUP] based broad-spectrum antiviral drugs. The sequence, structure, and functional conserveness of most deadly human CoVs PL[SUP]pro[/SUP] 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[SUP]pro[/SUP] and showed consistent interaction profile with SARS-CoV PL[SUP]pro[/SUP] and MERS-CoV PL[SUP]pro[/SUP] as well. Conclusively, the reported SARS-CoV-2 PL[SUP]pro[/SUP] specific compounds could serve as seeds for developing potent pan-PL[SUP]pro[/SUP] 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.
Keywords: COVID-19; MERS-CoV; Molecular dynamic simulation; Pan-inhibitors; Papain-like protease; SARS-CoV; SARS-CoV-2; Virtual screening.
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