Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation
Aganze G. Mushebenge,
Samuel C. Ugbaja,
Sphamandla E. Mtambo,
Thandokuhle Ntombela,
Joy I. Metu,
Oludotun Babayemi,
Joy I. Chima,
Patrick Appiah-Kubi,
Adeshina I. Odugbemi,
Mthobisi L. Ntuli,
Rene Khan,
Hezekiel M. Kumalo
Affiliations
Aganze G. Mushebenge
Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
Samuel C. Ugbaja
Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
Sphamandla E. Mtambo
Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
Thandokuhle Ntombela
Catalysis and Peptide Research Unit, School of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa
Joy I. Metu
National Institute for Nigerian Languages, Aba 453106, Nigeria
Oludotun Babayemi
Cloneshouse Nigeria, 6th Floor, Left Wing, NICON Plaza, Plot 242, Muhammadu Buhari Way, Central Business District, Abuja 900103, Nigeria
Joy I. Chima
Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
Patrick Appiah-Kubi
Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
Adeshina I. Odugbemi
South African National Bioinformatics Institute, Faculty of Natural Sciences, University of the Western Cape, Cape Town 7535, South Africa
Mthobisi L. Ntuli
Department of Mathematics, Faculty of Applied Science, Durban University of Technology, Durban 4000, South Africa
Rene Khan
Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
Hezekiel M. Kumalo
Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa
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.
