Computational design and biological testing of highly cytotoxic colchicine ring A modifications.
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.
Torin Huzil
John
J
Department of Oncology, University of Alberta, Edmonton, Alberta T6G1Z2, Canada.
Winter
Philip
P
Johnson
Lorelei
L
Weis
Alexander L
AL
Bakos
Tamas
T
Banerjee
Asok
A
Luduena
Richard F
RF
Damaraju
Sambasivarao
S
Tuszynski
Jack A
JA
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
D000970:Antineoplastic Agents; D020033:Protein Isoforms; D014404:Tubulin; D050257:Tubulin Modulators; D003078:Colchicine