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. 2020 Jul 24;15(7):e0235030.
doi: 10.1371/journal.pone.0235030. eCollection 2020.

In silico identification of potential inhibitors of key SARS-CoV-2 3CL hydrolase (Mpro) via molecular docking, MMGBSA predictive binding energy calculations, and molecular dynamics simulation

M Iqbal Choudhary  1   2 , Muniza Shaikh  1 , Atia- Tul-Wahab  1 , Atta- Ur-Rahman  1   2
Affiliations

In silico identification of potential inhibitors of key SARS-CoV-2 3CL hydrolase (Mpro) via molecular docking, MMGBSA predictive binding energy calculations, and molecular dynamics simulation

M Iqbal Choudhary et al. PLoS One. .

Abstract

The incidence of 2019 novel corona virus (SARS-CoV-2) has created a medical emergency throughout the world. Various efforts have been made to develop the vaccine or effective treatments against the disease. The discovery of crystal structure of SARS-CoV-2 main protease has made the in silico identification of its inhibitors possible. Based on its critical role in viral replication, the viral protease can prove to be a promising "target" for antiviral drug therapy. We have systematically screened an in-house library of 15,754 natural and synthetic compounds, established at International Center for Chemical and Biological Sciences, University of Karachi. The in silico search for potential viral protease inhibitors resulted in nine top ranked ligands (compounds 1-9) against SARS-CoV-2 main protease (PDB ID: 6LU7) based on docking scores, and predictive binding energies. The in silico studies were updated via carrying out the docking, and predictive binding energy estimation, with a recently reported crystal structure of main protease (PDB ID: 6Y2F) at a better resolution i.e., 1.95 Å. Compound 2 (molecular bank code AAA396) was found to have highest negative binding energy of -71.63 kcal/mol for 6LU7. While compound 3 (molecular bank code AAD146) exhibited highest negative binding energy of -81.92 kcal/mol for 6Y2F. The stability of the compounds- in complex with viral protease was analyzed by Molecular Dynamics simulation studies, and was found to be stable over the course of 20 ns simulation time. Compound 2, and 3 were predicted to be the significant inhibitors of SARS-CoV-2 3CL hydrolase (Mpro) among the nine short listed compounds.

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Conflict of interest statement

The study has financial support of the Searle Company, Pakistan through a research project funding. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. 3CL pro hydrolase prepared via Protein Preparation Wizard, Maestro.
H-bond network optimized and geometry minimized structures of 2019-nCOV 3CL hydrolase (Mpro) PDB ID: (a), and (b) 6LU7, (c), and (d) 6Y2F represented as 3D molecular surface and ribbon structure.
Fig 2
Fig 2. Ligands identified against SARS-CoV-2 3CL protease (6LU7 and 6Y2F) from in-house chemical library via in silico screening.
Fig 3
Fig 3. Molecular interactions of 3CL pro hydrolase with co-crystallized inhibitors.
(a) 3D-Ligand interaction and (b) 3D molecular surface diagrams of co-crystallized peptide inhibitor in the binding site of 6LU7. (c) 3D-Ligand interaction and (d) 3D molecular surface diagrams of co-crystallized α-ketoamide inhibitor in the binding site of 6Y2F. The hydrogen bonds are represented as yellow dotted lines.
Fig 4
Fig 4. Docked poses and molecular interactions of compound 1, 2, and 3 in binding site of 6LU7.
3D-Ligand interaction and 3D molecular surface diagrams of compounds 1 (a) and (b), compound 2 (c) and (d) compound 3 (e) and (f), showing the docked pose in the binding site of 2019-nCOV 3CL hydrolase (Mpro). The hydrogen bonds are represented as yellow dotted lines.
Fig 5
Fig 5. Docked poses and molecular interactions of compound 1, 2, and 3 in binding site of 6Y2F.
3D-Ligand interaction and 3D molecular surface diagrams of compounds 1 (a) and (b), compound 2 (c) and (d) compound 3 (e) and (f), showing the docked pose in the binding site of 2019-nCOV 3CL hydrolase (Mpro). The hydrogen bonds, and π-π interaction are represented as yellow and blue dotted lines.
Fig 6
Fig 6. RMSD analysis of MD simulation trajectory.
The RMSD plot obtained for (a) compound 2-SARS-CoV-2 main protease complex (PDB ID 6LU7), and (b) compound 3-SARS-CoV-2 main protease complex (PDB ID 6Y2F). The simulation time of 20 ns showing the formation of stable complex without any significant conformational changes in protein structure.
Fig 7
Fig 7. Analysis of molecular interaction and type of contacts with 3CL pro hydrolase after MD simulation.
Detailed schematic interaction of (a) compound 2 (AAA396), and (c) compound 3 atoms with binding site residue of hydrolase crystal structures 6LU7, and 6Y2F, respectively. Interaction happening more than 30% of the simulation time are shown. Normalized stacked bar chart of viral protease binding site residues interacting with (b) compound 2 and (d) compound 3 via hydrogen bond, hydrophobic and ionic interactions, and water bridges.
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References

    1. WHO. Novel coronavirus–China. Jan 12, 2020. http://www.who.int/csr/doon/12-january-2020-novel-coronavirus-china/en/ (accessed Jan 19, 2020).
    1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med. 2020; 382: 727–733. 10.1056/NEJMoa2001017 - DOI - PMC - PubMed
    1. Lu H, Stratton CW, Tang YW. Outbreak of Pneumonia of Unknown Etiology in Wuhan China: the Mystery and the Miracle. J Med Virol. 2020; 92: 401–402. 10.1002/jmv.25678 - DOI - PMC - PubMed
    1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020. February 15; 395(10223): 497–506. - PMC - PubMed
    1. Hui DS, I Azhar E, Madani TA, Ntoumi F, Kock R, Dar O, et al. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health—the latest 2019 novel coronavirus outbreak in Wuhan, China. Int J Infect Dis. 2020; 91: 264–6. 10.1016/j.ijid.2020.01.009 - DOI - PMC - PubMed

Publication types

Grants and funding

The study has financial support of the Searle Company, Pakistan through a research project funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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