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. 2021 Aug;39(13):4671-4685.
doi: 10.1080/07391102.2020.1779131. Epub 2020 Jun 22.

Promising inhibitors of main protease of novel corona virus to prevent the spread of COVID-19 using docking and molecular dynamics simulation

Durgesh Kumar  1   2 , Kamlesh Kumari  3 , Vijay Kumar Vishvakarma  1   2 , Abhilash Jayaraj  4 , Dhiraj Kumar  5 , Venkatesh Kumar Ramappa  6 , Rajan Patel  7 , Vinod Kumar  8 , Sujata K Dass  9 , Ramesh Chandra  2 , Prashant Singh  9
Affiliations

Promising inhibitors of main protease of novel corona virus to prevent the spread of COVID-19 using docking and molecular dynamics simulation

Durgesh Kumar et al. J Biomol Struct Dyn. 2021 Aug.

Abstract

Coronavirus disease-2019 (COVID-19) is a global health emergency and the matter of serious concern, which has been declared a pandemic by WHO. Till date, no potential medicine/ drug is available to cure the infected persons from SARS-CoV-2. This deadly virus is named as novel 2019-nCoV coronavirus and caused coronavirus disease, that is, COVID-19. The first case of SARS-CoV-2 infection in human was confirmed in the Wuhan city of the China. COVID-19 is an infectious disease and spread from man to man as well as surface to man . In the present work, in silico approach was followed to find potential molecule to control this infection. Authors have screened more than one million molecules available in the ZINC database and taken the best two compounds based on binding energy score. These lead molecules were further studied through docking against the main protease of SARS-CoV-2. Then, molecular dynamics simulations of the main protease with and without screened compounds were performed at room temperature to determine the thermodynamic parameters to understand the inhibition. Further, molecular dynamics simulations at different temperatures were performed to understand the efficiency of the inhibition of the main protease in the presence of the screened compounds. Change in energy for the formation of the complexes between the main protease of novel coronavirus and ZINC20601870 as well ZINC00793735 at room temperature was determined on applying MM-GBSA calculations. Docking and molecular dynamics simulations showed their antiviral potential and may inhibit viral replication experimentally. Communicated by Ramaswamy H. Sarma.

Keywords: MD simulations; MM-GBSA; SARS-CoV-2; ZINC database; docking; inhibitors.

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Figures

None
Graphical abstract
Figure 1.
Figure 1.
(a) General structure of coronavirus and (b) prefusion CoVs spikes.
Figure 2.
Figure 2.
Spread of the infection from BAT to humans in SARS, MERS and COVID-19.
Figure 3.
Figure 3.
A brief understanding of the attack of the virus to make the person sick.
Figure 4.
Figure 4.
Interactions between the main protease of novel coronavirus with ZINC20601870, ZINC00793735 and N3.
Figure 5.
Figure 5.
Pictorial view for the superimposition of (a) ZINC20601870 with ZINC00793735; (b) ZINC20601870, ZINC00793735 with N3 on interaction with the main protease of the novel coronavirus.
Figure 6.
Figure 6.
RMSD plots of main protease of novel coronavirus-2 with and without ZINC20601870 and ZINC00793735 at 300 K for simulations time of 100 ns.
Figure 7.
Figure 7.
RMSF plots for residue number of main protease of novel coronavirus-2 with ZINC20601870 and ZINC00793735 at 300 K for simulations time of 100 ns.
Figure 8.
Figure 8.
Relative changes in enthalpy for the formation of complexes of main protease of SARS-CoV-2 with ZINC20601870 and ZINC00793735 for simulation time of 100 ns.
Figure 9.
Figure 9.
Hydrogen bonding (HB) plot for interacted residue of main protease of novel coronavirus with ZINC20601870 at 300 K for simulations time of 100 ns.
Figure 10.
Figure 10.
Hydrogen bonding (HB) plot for interacted residue of main protease of novel coronavirus with ZINC00793735 at 300 K for simulations time of 100 ns.
Figure 11.
Figure 11.
RMSD plot of main protease of new-coronavirus with ZINC20601870 at 325, 350, 375 and 400 K for simulations time of 10 ns.
Figure 12.
Figure 12.
RMSD plot of main protease of new-coronavirus with ZINC00793735 at 325, 350, 375 and 400 K for simulations time of 10 ns.
Figure 13.
Figure 13.
RMSF plots for residue number of main protease of new-coronavirus with ZINC20601870 at 325, 350, 375 and 400 K for 10 ns simulations time.
Figure 14.
Figure 14.
RMSF plot for residue number of main protease of new-coronavirus with ZINC00793735 at 325, 350, 375 and 400 K for 10 ns simulations time.
Figure 15.
Figure 15.
HBs plot for interacted residue of main protease of new-coronavirus with ZINC20601870 at 325, 350, 375 and 400 K for simulations time of 10 ns.
Figure 16.
Figure 16.
HBs plot for interacted residue of main protease of new-coronavirus with ZINC00793735 at 325, 350, 375 and 400 K for simulations time of 10 ns.
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