{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:35:21Z","timestamp":1788975321720,"version":"build-2803163510"},"reference-count":55,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,3,5]],"date-time":"2023-03-05T00:00:00Z","timestamp":1677974400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council","doi-asserted-by":"publisher","award":["RGPIN\/2018-03878"],"award-info":[{"award-number":["RGPIN\/2018-03878"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Tubulin isotypes are known to regulate microtubule stability and dynamics, as well as to play a role in the development of resistance to microtubule-targeted cancer drugs. Griseofulvin is known to disrupt cell microtubule dynamics and cause cell death in cancer cells through binding to tubulin protein at the taxol site. However, the detailed binding mode involved molecular interactions, and binding affinities with different human \u03b2-tubulin isotypes are not well understood. Here, the binding affinities of human \u03b2-tubulin isotypes with griseofulvin and its derivatives were investigated using molecular docking, molecular dynamics simulation, and binding energy calculations. Multiple sequence analysis shows that the amino acid sequences are different in the griseofulvin binding pocket of \u03b2I isotypes. However, no differences were observed at the griseofulvin binding pocket of other \u03b2-tubulin isotypes. Our molecular docking results show the favorable interaction and significant affinity of griseofulvin and its derivatives toward human \u03b2-tubulin isotypes. Further, molecular dynamics simulation results show the structural stability of most \u03b2-tubulin isotypes upon binding to the G1 derivative. Taxol is an effective drug in breast cancer, but resistance to it is known. Modern anticancer treatments use a combination of multiple drugs to alleviate the problem of cancer cells resistance to chemotherapy. Our study provides a significant understanding of the involved molecular interactions of griseofulvin and its derivatives with \u03b2-tubulin isotypes, which may help to design potent griseofulvin analogues for specific tubulin isotypes in multidrug-resistance cancer cells in future.<\/jats:p>","DOI":"10.3390\/molecules28052384","type":"journal-article","created":{"date-parts":[[2023,3,6]],"date-time":"2023-03-06T02:06:43Z","timestamp":1678068403000},"page":"2384","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["In Silico Exploration of Microtubule Agent Griseofulvin and Its Derivatives Interactions with Different Human \u03b2-Tubulin Isotypes"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2774-7035","authenticated-orcid":false,"given":"Parisa","family":"Aris","sequence":"first","affiliation":[{"name":"Department of Biology, University of Ottawa, 30 Marie Curie, Station A, P.O. Box 450, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5054-5602","authenticated-orcid":false,"given":"Masoud","family":"Mohamadzadeh","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences, University of Hormozgan, Bandar Abbas 71961, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6074-8764","authenticated-orcid":false,"given":"Alibek","family":"Kruglikov","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, 30 Marie Curie, Station A, P.O. Box 450, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahbubeh","family":"Askari Rad","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, 30 Marie Curie, Station A, P.O. Box 450, Ottawa, ON K1N 6N5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3092-7566","authenticated-orcid":false,"given":"Xuhua","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Ottawa, 30 Marie Curie, Station A, P.O. Box 450, Ottawa, ON K1N 6N5, Canada"},{"name":"Ottawa Institute of Systems Biology, Ottawa, ON K1H 8M5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1042\/bj0330240","article-title":"Studies in the Biochemistry of Micro-Organisms: Griseofulvin, C17h17o6cl, a Metabolic Product of Penicillium griseo-fulvum Dierckx","volume":"33","author":"Oxford","year":"1939","journal-title":"Biochem. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/j.1365-4362.1989.tb01348.x","article-title":"Griseofulvin and Ketoconazole in the Treatment of Dermatophyte Infections","volume":"28","author":"Lambert","year":"1989","journal-title":"Int. J. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.chembiol.2010.03.015","article-title":"Identification of the Viridicatumtoxin and Griseofulvin Gene Clusters from Penicillium aethiopicum","volume":"17","author":"Chooi","year":"2010","journal-title":"Chem. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"749","DOI":"10.5248\/131.749","article-title":"Abieticola koreana Gen. Et Sp. Nov., a Griseofulvin-Producing Endophytic Xylariaceous ascomycete from Korea","volume":"131","author":"Lee","year":"2016","journal-title":"Mycotaxon"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7627","DOI":"10.1021\/acs.jafc.7b04197","article-title":"Biological and Chemical Control of Sclerotinia Sclerotiorum Using Stachybotrys Levispora and Its Secondary Metabolite Griseofulvin","volume":"66","author":"Ribeiro","year":"2018","journal-title":"J. Agric. Food Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e00890-19","DOI":"10.1128\/MRA.00890-19","article-title":"Draft Genome Sequence of the Griseofulvin-Producing Fungus Xylaria flabelliformis Strain G536","volume":"8","author":"Mead","year":"2019","journal-title":"Microbiol. Resour. Announc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"jkab399","DOI":"10.1093\/g3journal\/jkab399","article-title":"Conservation of Griseofulvin Genes in the Gsf Gene Cluster among Fungal Genomes","volume":"12","author":"Aris","year":"2021","journal-title":"G3"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6342","DOI":"10.1158\/0008-5472.CAN-07-0663","article-title":"Identification of Griseofulvin as an Inhibitor of Centrosomal Clustering in a Phenotype-Based Screen","volume":"67","author":"Rebacz","year":"2007","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Rathinasamy, K., Jindal, B., Asthana, J., Singh, P., Balaji, P.V., and Panda, D. (2010). Griseofulvin Stabilizes Microtubule Dynamics, Activates P53 and Inhibits the Proliferation of Mcf-7 Cells Synergistically with Vinblastine. BMC Cancer, 10.","DOI":"10.1186\/1471-2407-10-213"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Aris, P., Wei, Y., Mohamadzadeh, M., and Xia, X. (2022). Griseofulvin: An Updated Overview of Old and Current Knowledge. Molecules, 27.","DOI":"10.3390\/molecules27207034"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"495","DOI":"10.3109\/10408449709078444","article-title":"Toxic Effects of Griseofulvin: Disease Models, Mechanisms, and Risk Assessment","volume":"27","author":"Parzefall","year":"1997","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_12","unstructured":"Zimmerman, H.J. (1999). Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver, Wolters Kluwer."},{"key":"ref_13","unstructured":"Moseley, R.H. (2013). Drug-Induced Liver Disease, Elsevier."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1111\/j.1872-034X.2008.00352.x","article-title":"Griseofulvin, an Oral Antifungal Agent, Suppresses Hepatitis C Virus Replication in Vitro","volume":"38","author":"Jin","year":"2008","journal-title":"Hepatol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Aris, P., Mohamadzadeh, M., Wei, Y., and Xia, X. (2022). In Silico Molecular Dynamics of Griseofulvin and Its Derivatives Revealed Potential Therapeutic Applications for COVID-19. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23136889"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1158\/1535-7163.MCT-09-0366","article-title":"Microtubule Inhibitors: Differentiating Tubulin-Inhibiting Agents Based on Mechanisms of Action, Clinical Activity, and Resistance","volume":"8","author":"Perez","year":"2009","journal-title":"Mol. Cancer Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7167","DOI":"10.1158\/1078-0432.CCR-08-0169","article-title":"Microtubule Active Agents: Beyond the Taxane Frontier","volume":"14","author":"Morris","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.ab.2008.09.020","article-title":"Tubulin Proteomics: Towards Breaking the Code","volume":"384","author":"Pasquier","year":"2009","journal-title":"Anal. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1083\/jcb.201406055","article-title":"The Tubulin Code: Molecular Components, Readout Mechanisms, and Functions","volume":"206","author":"Janke","year":"2014","journal-title":"J. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/30288","article-title":"Erratum: Structure of the A\u03b2 Tubulin Dimer by Electron Crystallography","volume":"393","author":"Nogales","year":"1998","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.lungcan.2011.08.016","article-title":"Rt-Pcr Versus Immunohistochemistry for Correlation and Quantification of Ercc1, Brca1, Tubb3 and Rrm1 in Nsclc","volume":"75","author":"Vilmar","year":"2012","journal-title":"Lung Cancer"},{"key":"ref_22","first-page":"2992","article-title":"Prediction of Response to Docetaxel by Quantitative Analysis of Class I and Iii \u0392-Tubulin Isotype Mrna Expression in Human Breast Cancers","volume":"9","author":"Hasegawa","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2582","DOI":"10.1002\/cncr.28017","article-title":"Tubulin-\u0392-Iii Overexpression by Uterine Serous Carcinomas Is a Marker for Poor Overall Survival after Platinum\/Taxane Chemotherapy and Sensitivity to Epothilones","volume":"119","author":"Roque","year":"2013","journal-title":"Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3554","DOI":"10.1021\/bi962724m","article-title":"Taxol Differentially Modulates the Dynamics of Microtubules Assembled from Unfractionated and Purified \u0392-Tubulin Isotypes","volume":"36","author":"Derry","year":"1997","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"13335","DOI":"10.1016\/S0021-9258(18)42215-6","article-title":"Kinetics of Colchicine Binding to Purified Beta-Tubulin Isotypes from Bovine Brain","volume":"267","author":"Banerjee","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/ddr.10023","article-title":"Interaction of Nocodazole with Tubulin Isotypes","volume":"55","author":"Xu","year":"2002","journal-title":"Drug Dev. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1001\/archderm.1963.01590140038006","article-title":"Effective Use of Griseofulvin","volume":"87","author":"Crounse","year":"1963","journal-title":"Arch. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1016\/j.bmcl.2015.03.081","article-title":"Synthesis and Activities towards Resistant Cancer Cells of Sulfone and Sulfoxide Griseofulvin Derivatives","volume":"25","author":"Grisoni","year":"2015","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3342","DOI":"10.1021\/jm801517j","article-title":"Synthesis and Structure\u2212Activity Relationship of Griseofulvin Analogues as Inhibitors of Centrosomal Clustering in Cancer Cells","volume":"52","author":"Rebacz","year":"2009","journal-title":"J. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/prot.20149","article-title":"Comparative Evaluation of Eight Docking Tools for Docking and Virtual Screening Accuracy","volume":"57","author":"Kellenberger","year":"2004","journal-title":"Proteins: Struct. Funct. Bioinform."},{"key":"ref_31","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":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1248\/cpb.40.127","article-title":"Simple Method of Calculating Octanol\/Water Partition Coefficient","volume":"40","author":"Moriguchi","year":"1992","journal-title":"Chem. Pharm. Bull."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2547","DOI":"10.1002\/jps.20875","article-title":"Role of Nanotechnology in Pharmaceutical Product Development","volume":"96","author":"Devalapally","year":"2007","journal-title":"J. Pharm. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"652","DOI":"10.1021\/jm200835c","article-title":"Disparate Sar Data of Griseofulvin Analogues for the Dermatophytes Trichophyton Mentagrophytes, T. Rubrum, and Mda-Mb-231 Cancer Cells","volume":"55","author":"Raab","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1021\/ar000033j","article-title":"Calculating Structures and Free Energies of Complex Molecules: Combining Molecular Mechanics and Continuum Models","volume":"33","author":"Kollman","year":"2000","journal-title":"Acc. Chem. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1172\/JCI119642","article-title":"Taxol-Resistant Epithelial Ovarian Tumors Are Associated with Altered Expression of Specific Beta-Tubulin Isotypes","volume":"100","author":"Kavallaris","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1002\/cm.20109","article-title":"Comparison of \u0392-Tubulin Mrna and Protein Levels in 12 Human Cancer Cell Lines","volume":"63","author":"Hiser","year":"2006","journal-title":"Cell Motil. Cytoskelet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/nbt1210-1248","article-title":"Towards a Knowledge-Based Human Protein Atlas","volume":"28","author":"Uhlen","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1016\/j.ygyno.2007.01.044","article-title":"Expression of Beta-Tubulin Isotypes in Human Primary Ovarian Carcinoma","volume":"105","author":"Ohishi","year":"2007","journal-title":"Gynecol. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"341","DOI":"10.3816\/CBC.2002.n.037","article-title":"Microtubule-Associated Parameters as Predictive Markers of Docetaxel Activity in Advanced Breast Cancer Patients: Results of a Pilot Study","volume":"3","author":"Treilleux","year":"2002","journal-title":"Clin. Breast Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1158\/1535-7163.MCT-11-0899","article-title":"High Tubb3 Expression, an Independent Prognostic Marker in Patients with Early Non\u2013Small Cell Lung Cancer Treated by Preoperative Chemotherapy, Is Regulated by K-Ras Signaling Pathwayk-Ras and Tubb3 in Early Nsclc","volume":"11","author":"Levallet","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1158\/1078-0432.CCR-08-1274","article-title":"Overexpression of Class Iii \u0392-Tubulin Predicts Good Response to Taxane-Based Chemotherapy in Ovarian Clear Cell Adenocarcinoma","volume":"15","author":"Aoki","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.ajpath.2013.11.007","article-title":"\u0392iii-Tubulin Overexpression Is an Independent Predictor of Prostate Cancer Progression Tightly Linked to Erg Fusion Status and Pten Deletion","volume":"184","author":"Tsourlakis","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/bjc.2012.324","article-title":"\u0392v-Tubulin Expression Is Associated with Outcome Following Taxane-Based Chemotherapy in Non-Small Cell Lung Cancer","volume":"107","author":"Christoph","year":"2012","journal-title":"Br. J. Cancer"},{"key":"ref_45","unstructured":"Eswar, N., Eramian, D., Webb, B., Shen, M.Y., and Sali, A. (2008). Structural Proteomics: High-throughput Methods, Humana Press."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","article-title":"Procheck: A Program to Check the Stereochemical Quality of Protein Structures","volume":"26","author":"Laskowski","year":"1993","journal-title":"J. Appl. Crystallogr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein Structure Prediction with Alphafold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1007\/978-1-59745-251-9_3","article-title":"Bioinformatics for DNA Sequence Analysis","volume":"537","author":"Katoh","year":"2009","journal-title":"Methods Mol. Biol."},{"key":"ref_49","unstructured":"Dallakyan, S., and Olson, A.J. (2015). Chemical Biology, Springer."},{"key":"ref_50","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_51","unstructured":"Bauer, P., Hess, B., and Lindahl, E. (2023, January 10). Gromacs 2022 Source Code. Available online: https:\/\/zenodo.org\/record\/6103835#.ZAHm33bMJPY."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sousa da Silva, A.W., and Vranken, W.F. (2012). Acpype-Antechamber Python Parser Interface. BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-367"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular Dynamics with Coupling to an External Bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Kumbhar, B.V., Borogaon, A., Panda, D., and Kunwar, A. (2016). Exploring the Origin of Differential Binding Affinities of Human Tubulin Isotypes A\u03b2ii, A\u03b2iii and A\u03b2iv for Dama-Colchicine Using Homology Modelling, Molecular Docking and Molecular Dynamics Simulations. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156048"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Kumbhar, B.V., Panda, D., and Kunwar, A. (2018). Interaction of Microtubule Depolymerizing Agent Indanocine with Different Human A\u03b2 Tubulin Isotypes. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194934"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/5\/2384\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:48:10Z","timestamp":1760122090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/5\/2384"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,5]]},"references-count":55,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["molecules28052384"],"URL":"https:\/\/doi.org\/10.3390\/molecules28052384","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,5]]}}}