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Article

Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2

1
Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, Shaanxi Normal University, Xi’an 710062, China
2
School of Life Sciences, Shaanxi Normal University, Xi’an 710062, China
3
Department of Medical Laboratory Techniques, School of Life Sciences, Dijlah University College, Baghdad 00964, Iraq
4
Department of Biotechnology, College of Science, University of Diyala, Baqubah 32001, Iraq
5
Foundation University Medical College, Foundation University Islamabad, Islamabad 44000, Pakistan
*
Author to whom correspondence should be addressed.
Academic Editor: Marco Tutone
Molecules 2021, 26(3), 674; https://doi.org/10.3390/molecules26030674
Received: 6 December 2020 / Revised: 18 January 2021 / Accepted: 21 January 2021 / Published: 28 January 2021
SARS-CoV-2 caused the current COVID-19 pandemic and there is an urgent need to explore effective therapeutics that can inhibit enzymes that are imperative in virus reproduction. To this end, we computationally investigated the MPD3 phytochemical database along with the pool of reported natural antiviral compounds with potential to be used as anti-SARS-CoV-2. The docking results demonstrated glycyrrhizin followed by azadirachtanin, mycophenolic acid, kushenol-w and 6-azauridine, as potential candidates. Glycyrrhizin depicted very stable binding mode to the active pocket of the Mpro (binding energy, −8.7 kcal/mol), PLpro (binding energy, −7.9 kcal/mol), and Nucleocapsid (binding energy, −7.9 kcal/mol) enzymes. This compound showed binding with several key residues that are critical to natural substrate binding and functionality to all the receptors. To test docking prediction, the compound with each receptor was subjected to molecular dynamics simulation to characterize the molecule stability and decipher its possible mechanism of binding. Each complex concludes that the receptor dynamics are stable (Mpro (mean RMSD, 0.93 Å), PLpro (mean RMSD, 0.96 Å), and Nucleocapsid (mean RMSD, 3.48 Å)). Moreover, binding free energy analyses such as MMGB/PBSA and WaterSwap were run over selected trajectory snapshots to affirm intermolecular affinity in the complexes. Glycyrrhizin was rescored to form strong affinity complexes with the virus enzymes: Mpro (MMGBSA, −24.42 kcal/mol and MMPBSA, −10.80 kcal/mol), PLpro (MMGBSA, −48.69 kcal/mol and MMPBSA, −38.17 kcal/mol) and Nucleocapsid (MMGBSA, −30.05 kcal/mol and MMPBSA, −25.95 kcal/mol), were dominated mainly by vigorous van der Waals energy. Further affirmation was achieved by WaterSwap absolute binding free energy that concluded all the complexes in good equilibrium and stability (Mpro (mean, −22.44 kcal/mol), PLpro (mean, −25.46 kcal/mol), and Nucleocapsid (mean, −23.30 kcal/mol)). These promising findings substantially advance our understanding of how natural compounds could be shaped to counter SARS-CoV-2 infection. View Full-Text
Keywords: SARS-CoV-2; COVID-19; multiprotein inhibiting natural compounds; virtual screening; MD simulation SARS-CoV-2; COVID-19; multiprotein inhibiting natural compounds; virtual screening; MD simulation
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MDPI and ACS Style

Muhseen, Z.T.; Hameed, A.R.; Al-Hasani, H.M.H.; Ahmad, S.; Li, G. Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2. Molecules 2021, 26, 674. https://doi.org/10.3390/molecules26030674

AMA Style

Muhseen ZT, Hameed AR, Al-Hasani HMH, Ahmad S, Li G. Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2. Molecules. 2021; 26(3):674. https://doi.org/10.3390/molecules26030674

Chicago/Turabian Style

Muhseen, Ziyad T., Alaa R. Hameed, Halah M.H. Al-Hasani, Sajjad Ahmad, and Guanglin Li. 2021. "Computational Determination of Potential Multiprotein Targeting Natural Compounds for Rational Drug Design Against SARS-COV-2" Molecules 26, no. 3: 674. https://doi.org/10.3390/molecules26030674

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