title: Computational design and biological testing of highly cytotoxic colchicine ring A modifications.
abstract: Microtubules are the primary target for many anti-cancer drugs, the majority of which bind specifically to beta-tubulin. The existence of several beta-tubulin isotypes, coupled with their varied expression in normal and cancerous cells provides a platform upon which to construct selective chemotherapeutic agents. We have examined five prevalent human beta-tubulin isotypes and identified the colchicine-binding site as the most promising for drug design based on specificity. Using this binding site as a template, we have designed several colchicine derivatives and computationally probed them for affinity to the beta-tubulin isotypes. These compounds were synthesized and subjected to cytotoxicity assays to determine their effectiveness against several cancerous cell lines. We observed a correlation between computational-binding predictions and experimentally determined IC(50) values, demonstrating the utility of computational screening in the design of more effective colchicine derivatives. The most promising derivative exhibited an IC(50) approximately threefold lower than values previously reported for either colchicine or paclitaxel, demonstrating the utility of computational design and assessment of binding to tubulin.
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta T6G1Z2, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Torin Huzil
authors.forename: Philip
authors.initials: P
authors.lastname: Winter
authors.forename: Lorelei
authors.initials: L
authors.lastname: Johnson
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Weis
authors.forename: Tamas
authors.initials: T
authors.lastname: Bakos
authors.forename: Asok
authors.initials: A
authors.lastname: Banerjee
authors.forename: Richard F
authors.initials: RF
authors.lastname: Luduena
authors.forename: Sambasivarao
authors.initials: S
authors.lastname: Damaraju
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D003078:Colchicine / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D003198:Computer Simulation; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D020033:Protein Isoforms; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine