Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2Main Protease: A MolecularModelling Investigation
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Date
2023
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for
COVID-19, which was declared a global pandemic in March 2020 by the World Health Organization
(WHO). Since SARS-CoV-2 main protease plays an essential role in the virus’s life cycle, the design of
small drug molecules with lower molecular weight has been a promising development targeting its
inhibition. Herein, we evaluated the novel peptidomimetic azatripeptide and azatetrapeptide nitriles
against SARS-CoV-2 main protease. We employed molecular dynamics (MD) simulations to elucidate
the selected compounds’ binding free energy profiles against SARS-CoV-2 and further unveil the
residues responsible for the drug-binding properties. Compound 8 exhibited the highest binding
free energy of 49.37 0.15 kcal/mol, followed by compound 7 (39.83 0.19 kcal/mol), while
compound 17 showed the lowest binding free energy (23.54 0.19 kcal/mol). In addition, the
absorption, distribution, metabolism, and excretion (ADME) assessment was performed and revealed
that only compound 17 met the drug-likeness parameters and exhibited high pharmacokinetics to
inhibit CYP1A2, CYP2C19, and CYP2C9 with better absorption potential and blood-brain barrier
permeability (BBB) index. The additional intermolecular evaluations suggested compound 8 as
a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in
compound 7 with an aromatic benzene ring in compound 8 significantly enhanced the drug’s ability
to bind better at the active site of the SARS-CoV-2 Mpro.
Description
Keywords
SARS-CoV-2 main protease, ADME, Binding free energy, Molecular dynamics simulations
Citation
Mushebenge, A.G, et al . (2023). Unveiling the inhibitory potentials of peptidomimetic azanitriles and pyridyl esters towards SARS-CoV-2 main protease: A molecular modelling investigation. Molecules, 28(6) doi:10.3390/molecules28062641