Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation
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 molecule...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/6/2641 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Aganze G. Mushebenge |
| collection | DOAJ |
| description | 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 <b>8</b> exhibited the highest binding free energy of −49.37 ± 0.15 kcal/mol, followed by compound <b>7</b> (−39.83 ± 0.19 kcal/mol), while compound <b>17</b> 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 <b>17</b> 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 <b>8</b> as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound <b>7</b> with an aromatic benzene ring in compound <b>8</b> significantly enhanced the drug’s ability to bind better at the active site of the SARS-CoV-2 Mpro. |
| first_indexed | 2024-03-11T06:07:03Z |
| format | Article |
| id | doaj.art-18bf8222e4344f97b15aa0942eb9202d |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T06:07:03Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-18bf8222e4344f97b15aa0942eb9202d2023-11-17T12:53:10ZengMDPI AGMolecules1420-30492023-03-01286264110.3390/molecules28062641Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling InvestigationAganze G. Mushebenge0Samuel C. Ugbaja1Sphamandla E. Mtambo2Thandokuhle Ntombela3Joy I. Metu4Oludotun Babayemi5Joy I. Chima6Patrick Appiah-Kubi7Adeshina I. Odugbemi8Mthobisi L. Ntuli9Rene Khan10Hezekiel M. Kumalo11Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaCatalysis and Peptide Research Unit, School of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South AfricaNational Institute for Nigerian Languages, Aba 453106, NigeriaCloneshouse Nigeria, 6th Floor, Left Wing, NICON Plaza, Plot 242, Muhammadu Buhari Way, Central Business District, Abuja 900103, NigeriaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaSouth African National Bioinformatics Institute, Faculty of Natural Sciences, University of the Western Cape, Cape Town 7535, South AfricaDepartment of Mathematics, Faculty of Applied Science, Durban University of Technology, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaDrug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South AfricaThe 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 <b>8</b> exhibited the highest binding free energy of −49.37 ± 0.15 kcal/mol, followed by compound <b>7</b> (−39.83 ± 0.19 kcal/mol), while compound <b>17</b> 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 <b>17</b> 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 <b>8</b> as a promising drug candidate for inhibiting SARS-CoV-2 Mpro. The substitution of isopropane in compound <b>7</b> with an aromatic benzene ring in compound <b>8</b> significantly enhanced the drug’s ability to bind better at the active site of the SARS-CoV-2 Mpro.https://www.mdpi.com/1420-3049/28/6/2641SARS-CoV-2 main proteaseADMEbinding free energymolecular dynamics simulations |
| spellingShingle | 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 Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation Molecules SARS-CoV-2 main protease ADME binding free energy molecular dynamics simulations |
| title | Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation |
| title_full | Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation |
| title_fullStr | Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation |
| title_full_unstemmed | Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation |
| title_short | Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation |
| title_sort | unveiling the inhibitory potentials of peptidomimetic azanitriles and pyridyl esters towards sars cov 2 main protease a molecular modelling investigation |
| topic | SARS-CoV-2 main protease ADME binding free energy molecular dynamics simulations |
| url | https://www.mdpi.com/1420-3049/28/6/2641 |
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