{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T18:57:32Z","timestamp":1770231452306,"version":"3.49.0"},"reference-count":50,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T00:00:00Z","timestamp":1678752000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u2019s 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\u2019 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 \u221249.37 \u00b1 0.15 kcal\/mol, followed by compound 7 (\u221239.83 \u00b1 0.19 kcal\/mol), while compound 17 showed the lowest binding free energy (\u221223.54 \u00b1 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\u2019s ability to bind better at the active site of the SARS-CoV-2 Mpro.<\/jats:p>","DOI":"10.3390\/molecules28062641","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T05:22:59Z","timestamp":1678857779000},"page":"2641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Unveiling the Inhibitory Potentials of Peptidomimetic Azanitriles and Pyridyl Esters towards SARS-CoV-2 Main Protease: A Molecular Modelling Investigation"],"prefix":"10.3390","volume":"28","author":[{"given":"Aganze G.","family":"Mushebenge","sequence":"first","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel C.","family":"Ugbaja","sequence":"additional","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3444-7073","authenticated-orcid":false,"given":"Sphamandla E.","family":"Mtambo","sequence":"additional","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thandokuhle","family":"Ntombela","sequence":"additional","affiliation":[{"name":"Catalysis and Peptide Research Unit, School of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joy I.","family":"Metu","sequence":"additional","affiliation":[{"name":"National Institute for Nigerian Languages, Aba 453106, Nigeria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oludotun","family":"Babayemi","sequence":"additional","affiliation":[{"name":"Cloneshouse Nigeria, 6th Floor, Left Wing, NICON Plaza, Plot 242, Muhammadu Buhari Way, Central Business District, Abuja 900103, Nigeria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joy I.","family":"Chima","sequence":"additional","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Appiah-Kubi","sequence":"additional","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3074-1574","authenticated-orcid":false,"given":"Adeshina I.","family":"Odugbemi","sequence":"additional","affiliation":[{"name":"South African National Bioinformatics Institute, Faculty of Natural Sciences, University of the Western Cape, Cape Town 7535, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1802-3185","authenticated-orcid":false,"given":"Mthobisi L.","family":"Ntuli","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Faculty of Applied Science, Durban University of Technology, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3589-6869","authenticated-orcid":false,"given":"Rene","family":"Khan","sequence":"additional","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hezekiel M.","family":"Kumalo","sequence":"additional","affiliation":[{"name":"Drug Research and Innovation Unit, Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Science, University of KwaZulu-Natal, Durban 4000, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10423","DOI":"10.1002\/anie.202016961","article-title":"Targeting the Main Protease of SARS-CoV-2: From the Establishment of High Throughput Screening to the Design of Tailored Inhibitors","volume":"60","author":"Breidenbach","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/jmv.25695","article-title":"Updates on Wuhan 2019 novel coronavirus epidemic","volume":"92","author":"Dzuvor","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101608","DOI":"10.1016\/j.tmaid.2020.101608","article-title":"Asymptomatic coronavirus infection: MERS-CoV and SARS-CoV-2 (COVID-19)","volume":"35","year":"2020","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.tmaid.2018.12.003","article-title":"Asymptomatic Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: Extent and implications for infection control: A systematic review","volume":"27","author":"Gautret","year":"2019","journal-title":"Travel Med. Infect. Dis."},{"key":"ref_5","unstructured":"Aleem, A., AB, A.S., and Slenker, A.K. (2021). Emerging Variants of SARS-CoV-2 and Novel Therapeutics against Coronavirus (COVID-19), StatPearls Publishing."},{"key":"ref_6","unstructured":"World Health Organization (2022). Enhancing Response to Omicron SARS-CoV-2 Variant: Technical Brief and Priority Actions for Member States, World Health Organization."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108270","DOI":"10.1016\/j.asoc.2021.108270","article-title":"Self-Organizing Migrating Algorithm with narrowing search space strategy for robot path planning","volume":"116","author":"Diep","year":"2022","journal-title":"Appl. Soft Comput."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6335","DOI":"10.3748\/wjg.v26.i41.6335","article-title":"Origin and genomic characteristics of SARS-CoV-2 and its interaction with angiotensin converting enzyme type 2 receptors, focusing on the gastrointestinal tract","volume":"26","author":"Galanopoulos","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhou, L., Ayeh, S.K., Chidambaram, V., and Karakousis, P.C. (2021). Modes of transmission of SARS-CoV-2 and evidence for preventive behavioral interventions. BMC Infect. Dis., 21.","DOI":"10.1186\/s12879-021-06222-4"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e20210583","DOI":"10.1084\/jem.20210583","article-title":"Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics","volume":"218","author":"Cheemarla","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4334","DOI":"10.1080\/07391102.2020.1776157","article-title":"Identification of potential natural inhibitors of SARS-CoV2 main protease by molecular docking and simulation studies","volume":"39","author":"Gupta","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104315","DOI":"10.1016\/j.bioorg.2020.104315","article-title":"Role of heterocyclic compounds in SARS and SARS CoV-2 pandemic","volume":"104","author":"Negi","year":"2020","journal-title":"Bioorg. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3058","DOI":"10.1016\/j.bmcl.2005.04.027","article-title":"Synthesis and evaluation of isatin derivatives as effective SARS coronavirus 3CL protease inhibitors","volume":"15","author":"Chen","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1021\/jm0602357","article-title":"Isatin compounds as noncovalent SARS coronavirus 3C-like protease inhibitors","volume":"49","author":"Zhou","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.bmc.2013.11.028","article-title":"Synthesis, modification and docking studies of 5-sulfonyl isatin derivatives as SARS-CoV 3C-like protease inhibitors","volume":"22","author":"Liu","year":"2014","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1038\/s41594-020-0440-6","article-title":"Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug carmofur","volume":"27","author":"Jin","year":"2020","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"4433","DOI":"10.1080\/07391102.2020.1778536","article-title":"Virtual screening and dynamics of potential inhibitors targeting RNA binding domain of nucleocapsid phosphoprotein from SARS-CoV-2","volume":"39","author":"Yadav","year":"2021","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_18","unstructured":"Accelrys, S.I. (2013). Discovery Studio Visualizer, 3DS. Release 4.0."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"132712","DOI":"10.1016\/j.molstruc.2022.132712","article-title":"An overview on applications of SwissADME web tool in the design and development of anticancer, antitubercular and antimicrobial agents: A medicinal chemist\u2019s perspective","volume":"1259","author":"Bakchi","year":"2022","journal-title":"J. Mol. Struct."},{"key":"ref_20","first-page":"1","article-title":"Computational Approach for Designing, Swiss ADME, Molecular Docking and Biological Implication of Nickel Based Transition Metal Complex","volume":"1","author":"Khan","year":"2021","journal-title":"Rev. Pharm. Pharm. Sci."},{"key":"ref_21","first-page":"34","article-title":"Mutations on RBD of SARS-CoV-2 Omicron variant result in stronger binding to human ACE2 receptor. Biochem. Biophys","volume":"590","author":"Lupala","year":"2022","journal-title":"Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129390","DOI":"10.1016\/j.molstruc.2020.129390","article-title":"Screening of potential drug from Azadirachta Indica (Neem) extracts for SARS-CoV-2: An insight from molecular docking and MD-simulation studies","volume":"1227","author":"Baildya","year":"2021","journal-title":"J. Mol. Struct."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"119094","DOI":"10.1016\/j.saa.2020.119094","article-title":"How important are the intermolecular hydrogen bonding interactions in methanol solvent for interpreting the chiroptical properties?","volume":"247","author":"Polavarapu","year":"2021","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1021\/acs.jpclett.0c03797","article-title":"Switching Hydrogen Bonding to \u03c0-Stacking: The Thiophenol Dimer and Trimer","volume":"12","author":"Saragi","year":"2021","journal-title":"J. Phys. Chem. Lett."},{"key":"ref_25","first-page":"366","article-title":"Dietary patterns derived from principal component analysis (PCA) and risk of colorectal cancer: A systematic review and meta-analysis","volume":"73","author":"Morton","year":"2018","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1109\/TPAMI.2004.1261097","article-title":"Two-Dimensional PCA: A New Approach to Appearance-Based Face Representation and Recognition","volume":"26","author":"Yang","year":"2004","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1002\/jcc.20084","article-title":"UCSF Chimera\u2014A visualisation system for exploratory research and analysis","volume":"25","author":"Pettersen","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1021\/ci040123t","article-title":"ChemDraw 8 ultra, windows and macintosh versions","volume":"44","author":"Mendelsohn","year":"2004","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An advanced semantic chemical editor, visualisation, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimisation, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1021\/acs.jctc.9b01139","article-title":"Alchemical Hydration Free-Energy Calculations Using Molecular Dynamics with Explicit Polarization and Induced Polarity Decoupling: An On-the-Fly Polarization Approach","volume":"16","author":"Kelly","year":"2020","journal-title":"J. Chem. Theory Comput."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0010-4655(95)00041-D","article-title":"AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules","volume":"91","author":"Pearlman","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7366","DOI":"10.1021\/acs.jctc.1c00867","article-title":"Fast Equilibration of Water between Buried Sites and the Bulk by Molecular Dynamics with Parallel Monte Carlo Water Moves on Graphical Processing Units","volume":"17","author":"Lin","year":"2021","journal-title":"J. Chem. Theory Comput."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7114","DOI":"10.1080\/07391102.2021.1894987","article-title":"Discovery of novel heterocyclic amide-based inhibitors: An integrative in-silico approach to targeting soluble epoxide hydrolase","volume":"40","author":"Fakhar","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jin, T., Patel, S.J., and Lehn, R.C. (2021). Van Molecular simulations of lipid membrane partitioning and translocation by bacterial quorum sensing modulators. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0246187"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1007\/s10822-017-0040-7","article-title":"Binding mode prediction and MD\/MMPBSA-based free energy ranking for agonists of REV-ERB\u03b1\/NCoR","volume":"31","author":"Westermaier","year":"2017","journal-title":"J. Comput. Mol. Des."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5253","DOI":"10.1080\/07391102.2020.1869099","article-title":"Unravelling the molecular basis of AM-6494 high potency at BACE1 in Alzheimer\u2019s disease: An integrated dynamic interaction investigation","volume":"40","author":"Ugbaja","year":"2022","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4344","DOI":"10.1080\/07391102.2019.1677501","article-title":"Exploring the impact of H5N1 neuraminidase (H274Y) mutation on Peramivir: A bio-computational study from a molecular perspective","volume":"38","author":"Buthelezi","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2659","DOI":"10.1080\/07391102.2020.1752310","article-title":"Understanding the binding affinity of noscapines with protease of SARS-CoV-2 for COVID-19 using MD simulations at different temperatures","volume":"39","author":"Kumar","year":"2020","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Bultinck, P., Winter, H., Langenaeker, W., and Tollenaere, J. (2004). Computational Medicinal Chemistry for Drug Discovery, CRC Press.","DOI":"10.1201\/9780203913390"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3084","DOI":"10.1021\/ct400341p","article-title":"PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data","volume":"9","author":"Roe","year":"2013","journal-title":"J. Chem. Theory Comput."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1093\/bioinformatics\/btaa018","article-title":"LigRMSD: A web server for automatic structure matching and RMSD calculations among identical and similar compounds in protein-ligand docking","volume":"36","author":"Caballero","year":"2020","journal-title":"Bioinformatics"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Ugbaja, S.C., Lawal, I.A., Abubakar, B.H., Mushebenge, A.G., Lawal, M.M., and Kumalo, H.M. (2022). Allostery Inhibition of BACE1 by Psychotic and Meroterpenoid Drugs in Alzheimer\u2019s Disease Therapy. Molecules, 27.","DOI":"10.3390\/molecules27144372"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1134\/S0026893308040195","article-title":"Radius of gyration as an indicator of protein structure compactness","volume":"42","author":"Lobanov","year":"2008","journal-title":"Mol. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"36003","DOI":"10.1209\/0295-5075\/133\/36003","article-title":"Molecular-shape- and size-independent power-law dependence of percolation thresholds on radius of gyration in ideal molecular systems","volume":"133","author":"Norizoe","year":"2021","journal-title":"Europhys. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"244111","DOI":"10.1063\/1.2746330","article-title":"Dihedral angle principal component analysis of molecular dynamics simulations","volume":"126","author":"Altis","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Cocco, S., Monasson, R., and Weigt, M. (2013). From Principal Component to Direct Coupling Analysis of Coevolution in Proteins: Low-Eigenvalue Modes are Needed for Structure Prediction. PLoS Comput. Biol., 9.","DOI":"10.1371\/journal.pcbi.1003176"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Mohammad, A., Al-Mulla, F., Wei, D.Q., and Abubaker, J. (2021). Remdesivir md simulations suggest a more favourable binding to sars-cov-2 rna dependent rna polymerase mutant p323l than wild-type. Biomolecules, 11.","DOI":"10.3390\/biom11070919"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1080\/1062936X.2020.1777584","article-title":"Probing molecular mechanism of inhibitor bindings to bromodomain-containing protein 4 based on molecular dynamics simulations and principal component analysis","volume":"31","author":"Wu","year":"2020","journal-title":"SAR QSAR Environ. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10849","DOI":"10.1039\/C4RA13494J","article-title":"Single H5N1 influenza A neuraminidase mutation develops resistance to oseltamivir due to distorted conformational and drug binding landscape: Multiple molecular dynamics analyses","volume":"5","author":"Mhlongo","year":"2015","journal-title":"RSC Adv."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/6\/2641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:55:01Z","timestamp":1760122501000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/6\/2641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,14]]},"references-count":50,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["molecules28062641"],"URL":"https:\/\/doi.org\/10.3390\/molecules28062641","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,14]]}}}