{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T05:51:08Z","timestamp":1790142668794,"version":"4.0.1"},"reference-count":48,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T00:00:00Z","timestamp":1720051200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deanship of Graduate Studies Scientific Research","award":["G00004400"],"award-info":[{"award-number":["G00004400"]}]},{"name":"Middle East University, MEU","award":["G00004400"],"award-info":[{"award-number":["G00004400"]}]},{"name":"Department of Pharmacy","award":["G00004400"],"award-info":[{"award-number":["G00004400"]}]},{"DOI":"10.13039\/501100014733","name":"UAEU","doi-asserted-by":"publisher","award":["G00004400"],"award-info":[{"award-number":["G00004400"]}],"id":[{"id":"10.13039\/501100014733","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Candida albicans and Aspergillus fumigatus are recognized as significant fungal pathogens, responsible for various human infections. The rapid emergence of drug-resistant strains among these fungi requires the identification and development of innovative antifungal therapies. We undertook a comprehensive screening of 297 naturally occurring compounds to address this challenge. Using computational docking techniques, we systematically analyzed the binding affinity of each compound to key proteins from Candida albicans (PDB ID: 1EAG) and Aspergillus fumigatus (PDB ID: 3DJE). This rigorous in silico examination aimed to unveil compounds that could potentially inhibit the activity of these fungal infections. This was followed by an ADMET analysis of the top-ranked compound, providing valuable insights into the pharmacokinetic properties and potential toxicological profiles. To further validate our findings, the molecular reactivity and stability were computed using the DFT calculation and molecular dynamics simulation, providing a deeper understanding of the stability and behavior of the top-ranking compounds in a biological environment. The outcomes of our study identified a subset of natural compounds that, based on our analysis, demonstrate notable potential as antifungal candidates. With further experimental validation, these compounds could pave the way for new therapeutic strategies against drug-resistant fungal pathogens.<\/jats:p>","DOI":"10.3390\/ph17070886","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T14:40:50Z","timestamp":1720449650000},"page":"886","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Unveiling Moroccan Nature\u2019s Arsenal: A Computational Molecular Docking, Density Functional Theory, and Molecular Dynamics Study of Natural Compounds against Drug-Resistant Fungal Infections"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8406-8533","authenticated-orcid":false,"given":"Imane","family":"Yamari","sequence":"first","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9183-6951","authenticated-orcid":false,"given":"Oussama","family":"Abchir","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hassan","family":"Nour","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meriem","family":"Khedraoui","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bouchra","family":"Rossafi","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9972-7522","authenticated-orcid":false,"given":"Abdelkbir","family":"Errougui","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Talbi","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1766-4471","authenticated-orcid":false,"given":"Abdelouahid","family":"Samadi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MHammed El","family":"Kouali","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. Box 7955, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2344-5101","authenticated-orcid":false,"given":"Samir","family":"Chtita","sequence":"additional","affiliation":[{"name":"Faculty of Sciences Ben M\u2019Sik, Hassan II University of Casablanca, Sidi Othman, Casablanca P.O. 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Clinical Mycology, Elsevier.","DOI":"10.1016\/B978-1-4160-5680-5.00007-4"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.tim.2021.12.013","article-title":"Emergence and evolution of virulence in human pathogenic fungi","volume":"30","author":"Hube","year":"2022","journal-title":"Trends Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4161\/viru.22913","article-title":"Candida albicans pathogenicity mechanisms","volume":"4","author":"Mayer","year":"2013","journal-title":"Virulence"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Brown, R., Priest, E., Naglik, J.R., and Richardson, J.P. (2021). Fungal Toxins and Host Immune Responses. Front. Microbiol., 12.","DOI":"10.3389\/fmicb.2021.643639"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Liu, S., Le Mauff, F., Sheppard, D.C., and Zhang, S. (2022). Filamentous fungal biofilms: Conserved and unique aspects of extracellular matrix composition, mechanisms of drug resistance and regulatory networks in Aspergillus fumigatus. NPJ Biofilm. Microbiomes, 8.","DOI":"10.1038\/s41522-022-00347-3"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Costa-Orlandi, C.B., Sardi, J.C.O., Pitangui, N.S., de Oliveira, H.C., Scorzoni, L., Galeane, M.C., Medina-Alarc\u00f3n, K.P., Melo, W.C.M., Marcelino, M.Y., and Braz, J.D. (2017). Fungal Biofilms and Polymicrobial Diseases. J. Fungi, 3.","DOI":"10.3390\/jof3020022"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41579-022-00720-1","article-title":"Tackling the emerging threat of antifungal resistance to human health","volume":"20","author":"Fisher","year":"2022","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/21505594.2021.2019950","article-title":"Pathogenesis and virulence of Candida albicans","volume":"13","author":"Lopes","year":"2022","journal-title":"Virulence"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Shinu, P., Gupta, G.L., Sharma, M., Khan, S., Goyal, M., Nair, A.B., Kumar, M., Soliman, W.E., Rahman, A., and Attimarad, M. (2023). Pharmacological Features of 18\u03b2-Glycyrrhetinic Acid: A Pentacyclic Triterpenoid of Therapeutic Potential. Plants, 12.","DOI":"10.3390\/plants12051086"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100115","DOI":"10.1016\/j.simyco.2021.100115","article-title":"Aspergillus fumigatus and aspergillosis: From basics to clinics","volume":"100","author":"Arastehfar","year":"2021","journal-title":"Stud. Mycol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Dzobo, K. (2022). The Role of Natural Products as Sources of Therapeutic Agents for Innovative Drug Discovery. Comprehensive Pharmacology, Elsevier.","DOI":"10.1016\/B978-0-12-820472-6.00041-4"},{"key":"ref_13","first-page":"e01986","article-title":"The anticoagulant potential of Lippia alba extract in inhibiting SARS-CoV-2 Mpro: Density functional calculation, molecular docking analysis, and molecular dynamics simulations","volume":"23","author":"Yamari","year":"2024","journal-title":"Sci. Afr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"100372","DOI":"10.1016\/j.chphi.2023.100372","article-title":"Oxidative functionalization of triterpenes isolated from Euphorbia resinifera latex: Semisynthesis, ADME-Tox, molecular docking, and molecular dynamics simulations","volume":"7","author":"Yamari","year":"2023","journal-title":"Chem. Phys. Impact"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e202301092","DOI":"10.1002\/slct.202301092","article-title":"Structure-Based Virtual Screening, ADMET analysis, and Molecular Dynamics Simulation of Moroccan Natural Compounds as Candidates \u03b1-Amylase Inhibitors","volume":"8","author":"Abchir","year":"2023","journal-title":"ChemistrySelect"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"100262","DOI":"10.1016\/j.prmcm.2023.100262","article-title":"Antifungal natural products and their derivatives: A review of their activity and mechanism of actions","volume":"7","author":"Zhang","year":"2023","journal-title":"Pharmacol. Res.-Mod. Chin. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"90","DOI":"10.2174\/1389557520666200628032116","article-title":"Herbal Extracts with Antifungal Activity against Candida albicans: A Systematic Review","volume":"21","author":"Hsu","year":"2021","journal-title":"Mini-Rev. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"379","DOI":"10.2174\/1570163817666200518074629","article-title":"Anti-Candida Activity of Curcumin: A Systematic Review","volume":"18","author":"Cheraghipour","year":"2021","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.copbio.2021.02.001","article-title":"Antifungal natural products","volume":"69","author":"Heard","year":"2021","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.ijantimicag.2005.09.002","article-title":"Antimicrobial activity of flavonoids","volume":"26","author":"Cushnie","year":"2005","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hewlings, S.J., and Kalman, D.S. (2017). Curcumin: A review of its effects on human health. Foods, 6.","DOI":"10.3390\/foods6100092"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"841315","DOI":"10.1155\/2012\/841315","article-title":"Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial","volume":"2012","author":"Jawad","year":"2012","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e11991","DOI":"10.1016\/j.heliyon.2022.e11991","article-title":"Combined computational approaches for developing new anti-Alzheimer drug candidates: 3D-QSAR, molecular docking and molecular dynamics studies of liquiritigenin derivatives","volume":"8","author":"Nour","year":"2022","journal-title":"Heliyon"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3127","DOI":"10.3889\/oamjms.2019.793","article-title":"Antimicrobial Activity of Terpenoids Extracted from Annona muricata Seeds and its Endophytic Aspergillus niger Strain SH3 Either Singly or in Combination","volume":"7","author":"Hussein","year":"2019","journal-title":"Open Access Maced. J. Med. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1111\/cbdd.12385","article-title":"Computational Methods to Identify New Antibacterial Targets","volume":"85","author":"McPhillie","year":"2015","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"42717","DOI":"10.1038\/srep42717","article-title":"SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules","volume":"7","author":"Daina","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Scrocco, E., and Tomasi, J. (1978). Electronic Molecular Structure, Reactivity and Intermolecular Forces: An Euristic Interpretation by Means of Electrostatic Molecular Potentials. Advances in Quantum Chemistry, Academic Press.","DOI":"10.1016\/S0065-3276(08)60236-1"},{"key":"ref_28","first-page":"117","article-title":"Diversity of medicinal plants used on oral disease in the city of Meknes, Morocco","volume":"6","author":"Harouak","year":"2018","journal-title":"J. Med. Plants Stud."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/bs.pmch.2021.01.004","article-title":"Use of molecular docking computational tools in drug discovery","volume":"60","author":"Stanzione","year":"2021","journal-title":"Prog. Med. Chem."},{"key":"ref_30","unstructured":"(2024, June 03). Fluconazol Drug. Available online: https:\/\/go.drugbank.com\/drugs\/DB00196."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"Berman RCSB protein Data Bank","volume":"28","author":"Helen","year":"2000","journal-title":"Nucleic Acids Res"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1002\/(SICI)1096-987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B","article-title":"Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function","volume":"19","author":"Morris","year":"1998","journal-title":"J. Comput. Chem."},{"key":"ref_34","unstructured":"Guex, N., Diemand, A., Peitsch, M.C., and Schwede, T. (2024, June 03). SwissPdbViewer, Available online: https:\/\/spdbv.unil.ch\/."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An advanced semantic chemical editor, visualization, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform."},{"key":"ref_36","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 optimization, and multithreading","volume":"31","author":"Trott","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_37","unstructured":"Dassault Syst\u00e9me (2021). BIOVIA Discovery Studio 2021, Dassault Syst\u00e8mes."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Palmer, M.E., Andrews, L.J., Abbey, T.C., Dahlquist, A.E., and Wenzler, E. (2022). The importance of pharmacokinetics and pharmacodynamics in antimicrobial drug development and their influence on the success of agents developed to combat resistant gram negative pathogens: A review. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.888079"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acs.jmedchem.5b00104","article-title":"pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures","volume":"58","author":"Pires","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_40","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., and Petersson, G.A. (Gaussian 09, 2013). Gaussian 09, Revision A.02."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1177\/1747519820932091","article-title":"Theoretical investigations on the HOMO\u2013LUMO gap and global reactivity descriptor studies, natural bond orbital, and nucleus-independent chemical shifts analyses of 3-phenylbenzo[d]thiazole-2(3H)-imine and its para-substituted derivatives: Solvent and substituent effects","volume":"45","author":"Miar","year":"2021","journal-title":"J. Chem. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"647","DOI":"10.17344\/acsi.2022.7522","article-title":"Electronic Structures and Reactivities of COVID-19 Drugs: A DFT Study","volume":"69","author":"Aydogdu","year":"2022","journal-title":"Acta Chim. Slov."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"116018","DOI":"10.1016\/j.molliq.2021.116018","article-title":"A DFT approach on tioguanine: Exploring tio-tiol tautomers, frontier molecular orbitals, IR and UV spectra, and quadrupole coupling constants","volume":"334","author":"Harismah","year":"2021","journal-title":"J. Mol. Liq."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Badar, M.S., Shamsi, S., Ahmed, J., and Alam, M.A. (2022). Molecular Dynamics Simulations: Concept, Methods, and Applications. Transdisciplinarity, Springer International Publishing.","DOI":"10.1007\/978-3-030-94651-7_7"},{"key":"ref_45","unstructured":"Schr\u00f6dinger (Maestro, 2021). Maestro, Version 12.5.139."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"9954","DOI":"10.1021\/jp003020w","article-title":"Structure and Dynamics of the TIP3P, SPC, and SPC\/E Water Models at 298 K","volume":"105","author":"Mark","year":"2001","journal-title":"J. Phys. Chem. A"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.1021\/acs.jctc.8b01026","article-title":"OPLS3e: Extending Force Field Coverage for Drug-Like Small Molecules","volume":"15","author":"Roos","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"120116","DOI":"10.1016\/j.molliq.2022.120116","article-title":"Effects of thermostats\/barostats on physical properties of liquids by molecular dynamics simulations","volume":"365","author":"Ke","year":"2022","journal-title":"J. Mol. 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