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. 2021 Jun;39(9):3387-3395.
doi: 10.1080/07391102.2020.1764392. Epub 2020 May 15.

Using integrated computational approaches to identify safe and rapid treatment for SARS-CoV-2

Khattab Al-Khafaji  1 , Dunya Al-Duhaidahawi  2 , Tugba Taskin Tok  1   3
Affiliations

Using integrated computational approaches to identify safe and rapid treatment for SARS-CoV-2

Khattab Al-Khafaji et al. J Biomol Struct Dyn. 2021 Jun.

Abstract

SARS-CoV-2 is a new generation of coronavirus, which was first determined in Wuhan, China, in December 2019. So far, however, there no effective treatment has been found to stop this new generation of coronavirus but discovering of the crystal structure of SARS-CoV-2 main protease (SARS-CoV-2 Mpro) may facilitate searching for new therapies for SARS-COV-2. The aim was to assess the effectiveness of available FDA approved drugs which can construct a covalent bond with Cys145 inside binding site SARS-CoV-2 main protease by using covalent docking screening. We conducted the covdock module MMGBSA module in the Schrodinger suite 2020-1, to examine the covalent bonding utilizing. Besides, we submitted the top three drugs to molecular dynamics simulations via Gromacs 2018.1. The covalent docking showed that saquinavir, ritonavir, remdesivir, delavirdine, cefuroxime axetil, oseltamivir and prevacid have the highest binding energies MMGBSA of -72.17, -72.02, -65.19, -57.65, -54.25, -51.8, and -51.14 kcal/mol, respectively. The 50 ns molecular dynamics simulation was conducted for saquinavir, ritonavir and remdesivir to evaluate the stability of these drugs inside the binding pocket of SARS-CoV-2 main protease. The current study provides a powerful in silico results, means for rapid screening of drugs as anti-protease medications and recommend that the above-mentioned drugs can be used in the treatment of SARS-CoV-2 in combined or sole therapy.Communicated by Ramaswamy H. Sarma.

Keywords: MD simulation; Mpro; PCA; SARS-CoV-2; covalent docking; drug repurposing.

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Figures

Figure 1.
Figure 1.
The correlation between MMGBSA binding energies and docking score.
Figure 2.
Figure 2.
Effect of molecular weight upon the MMGBSA binding energy.
Figure 3.
Figure 3.
Covalent docking analysis of saquinavir inside the SARS-CoV-2 Mpro.
Figure 4.
Figure 4.
Covalent docking analysis of ritonavir inside the SARS-CoV-2 Mpro.
Figure 5.
Figure 5.
Covalent docking analysis of remdesivir inside the SARS-CoV-2 Mpro.
Figure 6.
Figure 6.
Analysis of RMSD, RMSF, Rg and Hydrogen bonding of saquinvir-SARS-CoV-2 Mpro, ritonavir- SARS-CoV-2 Mpro and remdesivir- SARS-CoV-2 Mpro. (a)The protein’s backbone RMSD values with respect to time. (b) RMSF of the protein’s backbone with respect to position of residue in the protein. (c) Rg of the protein backbone over the entire time of MD simulation. (d) The number of hydrogen bonds through all the time of MD simulation.
Figure 7.
Figure 7.
Two-dimensional projection of motion of trajectory of SARS-CoV-2 Mpro bound with drugs over the PC1 and PC2.
See this image and copyright information in PMC

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