{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T15:09:37Z","timestamp":1769267377651,"version":"3.49.0"},"reference-count":69,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,6,21]],"date-time":"2019-06-21T00:00:00Z","timestamp":1561075200000},"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>Buruli ulcer is a neglected tropical disease caused by the bacterium Mycobacterium ulcerans. Its virulence is attributed to the dermo-necrotic polyketide toxin mycolactone, whose synthesis is regressed when its iron acquisition system regulated by the iron-dependent regulator (ideR) is deactivated. Interfering with the activation mechanism of ideR to inhibit the toxin\u2019s synthesis could serve as a possible cure for Buruli ulcer. The three-dimensional structure of the ideR for Mycobacterium ulcerans was generated using homology modeling. A library of 832 African natural products (AfroDB), as well as five known anti-mycobacterial compounds were docked against the metal binding site of the ideR. The area under the curve (AUC) values greater than 0.7 were obtained for the computed Receiver Operating Characteristics (ROC) curves, validating the docking protocol. The identified top hits were pharmacologically profiled using Absorption, Distribution, Metabolism, Elimination and Toxicity (ADMET) predictions and their binding mechanisms were characterized. Four compounds with ZINC IDs ZINC000018185774, ZINC000095485921, ZINC000014417338 and ZINC000005357841 emerged as leads with binding energies of \u22127.7 kcal\/mol, \u22127.6 kcal\/mol, \u22128.0 kcal\/mol and \u22127.4 kcal\/mol, respectively. Induced Fit Docking (IFD) was also performed to account for the protein\u2019s flexibility upon ligand binding and to estimate the best plausible conformation of the complexes. Results obtained from the IFD were consistent with that of the molecular docking with the lead compounds forming interactions with known essential residues and some novel critical residues Thr14, Arg33 and Asp17. A hundred nanoseconds molecular dynamic simulations of the unbound ideR and its complexes with the respective lead compounds revealed changes in the ideR\u2019s conformations induced by ZINC000018185774. Comparison of the lead compounds to reported potent inhibitors by docking them against the DNA-binding domain of the protein also showed the lead compounds to have very close binding affinities to those of the potent inhibitors. Interestingly, structurally similar compounds to ZINC000018185774 and ZINC000014417338, as well as analogues of ZINC000095485921, including quercetin are reported to possess anti-mycobacterial activity. Also, ZINC000005357841 was predicted to possess anti-inflammatory and anti-oxidative activities, which are relevant in Buruli ulcer and iron acquisition mechanisms, respectively. The leads are molecular templates which may serve as essential scaffolds for the design of future anti-mycobacterium ulcerans agents.<\/jats:p>","DOI":"10.3390\/molecules24122299","type":"journal-article","created":{"date-parts":[[2019,6,21]],"date-time":"2019-06-21T11:54:31Z","timestamp":1561118071000},"page":"2299","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Molecular Informatics Studies of the Iron-Dependent Regulator (ideR) Reveal Potential Novel Anti-Mycobacterium ulcerans Natural Product-Derived Compounds"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1093-1517","authenticated-orcid":false,"given":"Samuel K.","family":"Kwofie","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"},{"name":"West African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"},{"name":"Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kweku S.","family":"Enninful","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"},{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaleel A.","family":"Yussif","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina A.","family":"Asante","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mavis","family":"Adjei","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kwabena","family":"Kan-Dapaah","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1259-5254","authenticated-orcid":false,"given":"Elvis K.","family":"Tiburu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic and Applied Sciences, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilhelmina A.","family":"Mensah","sequence":"additional","affiliation":[{"name":"West African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-7940","authenticated-orcid":false,"suffix":"III","given":"Whelton A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA"},{"name":"Department of Chemical and Biomolecular Engineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Chemistry &amp; Physics, College of Science and Technology, Lincoln University, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Mosi","sequence":"additional","affiliation":[{"name":"West African Centre for Cell Biology of Infectious Pathogens, Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Maywood, IL 60153, USA"},{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon P.O. Box LG 54, Accra, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nyabadza, F., and Bonyah, E. (2015). On the transmission dynamics of Buruli ulcer in Ghana: Insights through a mathematical model. BMC Res. Notes, 8.","DOI":"10.1186\/s13104-015-1619-5"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Hall, B.S., Hill, K., McKenna, M., Ogbechi, J., High, S., Willis, A.E., and Simmonds, R.E. (2014). 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