{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T18:58:56Z","timestamp":1790276336980,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1014804","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000}}],"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"\n Microtubules are dynamic cytoskeletal polymers assembled from\n \n \n \n \n \n \u03b1<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n \/\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin heterodimers. Microtubules are validated targets for novel therapeutic drugs, yet therapeutic efficacy targeting them is often compromised by multidrug resistance (MDR). 5-(3-chlorophenyl)-N-(3-pyridinyl)-2-furamide (CPPF) is a novel microtubule-targeting anticancer agent which was found to disrupt microtubule growth in cells and inhibit tubulin polymerization in vitro. CPPF could suppress the growth of multidrug-resistant cell lines and demonstrate anti-tumor efficacy in animal models. However, the fundamental mechanism of how CPPF disrupts microtubule assembly remains unclear. To investigate this, we performed structure prediction using Protenix, RoseTTAFold All-Atom (RFAA) and Umol, as well as molecular dynamics (MD) simulations, using the human\n \n \n \n \n \n \u03b1<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n \/\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin heterodimer (PDB ID: 5IJ0) for analyzing the interaction between CPPF and tubulin. Our results showed that CPPF binds at the\n \n \n \n \n \n \u03b1<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n \/\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n interface with dominant contributions from\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin residues, particularly VAL236 and LEU253. In isolated-monomer comparisons,\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin exhibited more favorable binding energetics and deeper, broader free-energy minima than\n \n \n \n \n \n \u03b1<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin. Supplementary simulations on the alternative\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin conformational state (PDB: 6E7B; straight microtubule-lattice) indicated that CPPF binding is preserved across the two major\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin conformations, with comparable MM-PBSA binding free energies. Taken together, these findings establish a plausible binding mode for CPPF at the\n \n \n \n \n \n \u03b1<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n \/\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -tubulin interface, providing a structural hypothesis for understanding its anticancer potential against multidrug-resistant cancers. Experimental validation through binding assays or crystallography is warranted to further substantiate these computational insights.\n <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014804","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:59:54Z","timestamp":1789754394000},"page":"e1014804","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative AI-assisted modeling suggests CPPF binding at a composite \u03b1\/\u03b2-tubulin interface pocket dominated by \u03b2-tubulin contacts"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5489-0593","authenticated-orcid":true,"given":"Jixin","family":"Yang","sequence":"first","affiliation":[{"name":"The Hong Kong University of Science and Technology (Guangzhou)","place":["Guangzhou, China"],"department":["Data Science and Analytics Thrust, Information 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Hub"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhuo","family":"Feng","sequence":"additional","affiliation":[{"name":"The Hong Kong University of Science and Technology (Guangzhou)","place":["Guangzhou, China"],"department":["Bioscience and Biomedical Engineering Thrust, Systems Hub"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5141-0515","authenticated-orcid":true,"given":"Shaojun","family":"Tang","sequence":"additional","affiliation":[{"name":"Virginia Commonwealth University","place":["Richmond, Virginia, United States of America"],"department":["Department of Biostatistics"]},{"name":"Virginia Commonwealth University","place":["Richmond, Virginia, United States of America"],"department":["Massey Comprehensive Cancer 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