tetano
Editor, Senior Moderator
Life Sci
. 2020 Jul 9;118080.
doi: 10.1016/j.lfs.2020.118080. Online ahead of print.
Computational Insights Into Tetracyclines as Inhibitors Against SARS-CoV-2 M [SUP]pro[/SUP] via Combinatorial Molecular Simulation Calculations
Shiv Bharadwaj[SUP] 1 [/SUP], Kyung Eun Lee[SUP] 1 [/SUP], Vivek Dhar Dwivedi[SUP] 2 [/SUP], Sang Gu Kang[SUP] 3 [/SUP]
Affiliations
Abstract
The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (M[SUP]pro[/SUP]). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 M[SUP]pro[/SUP] crystal structure. Molecular docking simulation predicted the docking score >-7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 M[SUP]pro[/SUP]. The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 M[SUP]pro[/SUP] which can used in combinational therapy against SARS-CoV-2 infection.
Keywords: COVID-19; Drug repurposing; Molecular simulation calculations; SARS-CoV-2 M(pro); Tetracyclines.
. 2020 Jul 9;118080.
doi: 10.1016/j.lfs.2020.118080. Online ahead of print.
Computational Insights Into Tetracyclines as Inhibitors Against SARS-CoV-2 M [SUP]pro[/SUP] via Combinatorial Molecular Simulation Calculations
Shiv Bharadwaj[SUP] 1 [/SUP], Kyung Eun Lee[SUP] 1 [/SUP], Vivek Dhar Dwivedi[SUP] 2 [/SUP], Sang Gu Kang[SUP] 3 [/SUP]
Affiliations
- PMID: 32653520
- DOI: 10.1016/j.lfs.2020.118080
Abstract
The COVID-19 pandemic raised by SARS-CoV-2 is a public health emergency. However, lack of antiviral drugs and vaccine against human coronaviruses demands a concerted approach to challenge the SARS-CoV-2 infection. Under limited resource and urgency, combinatorial computational approaches to identify the potential inhibitor from known drugs could be applied against risen COVID-19 pandemic. Thereof, this study attempted to purpose the potent inhibitors from the approved drug pool against SARS-CoV-2 main protease (M[SUP]pro[/SUP]). To circumvent the issue of lead compound from available drugs as antivirals, antibiotics with broad spectrum of viral activity, i.e. doxycycline, tetracycline, demeclocycline, and minocycline were chosen for molecular simulation analysis against native ligand N3 inhibitor in SARS-CoV-2 M[SUP]pro[/SUP] crystal structure. Molecular docking simulation predicted the docking score >-7 kcal/mol with significant intermolecular interaction at the catalytic dyad (His41 and Cys145) and other essential substrate binding residues of SARS-CoV-2 M[SUP]pro[/SUP]. The best ligand conformations were further studied for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamics simulation, established the significant stability and interactions of selected antibiotics by comparison to N3 inhibitor. Based on combinatorial molecular simulation analysis, doxycycline and minocycline were selected as potent inhibitor against SARS-CoV-2 M[SUP]pro[/SUP] which can used in combinational therapy against SARS-CoV-2 infection.
Keywords: COVID-19; Drug repurposing; Molecular simulation calculations; SARS-CoV-2 M(pro); Tetracyclines.