title: Combretastatin-like chalcones as inhibitors of microtubule polymerisation. Part 2: Structure-based discovery of alpha-aryl chalcones.
abstract: Tubulin is an important molecular target in cancer chemotherapy. Antimitotic agents able to bind to the protein are currently under study, commonly used in the clinic to treat a variety of cancers and/or exploited as probes to investigate the protein's structure and function. Here we report the binding modes for a series of colchicinoids, combretastatin A4 and chalcones established from docking studies carried out on the structure of tubulin in complex with colchicine. The proposed models, in agreement with published biochemical data, show that combretastatin A4 binds to the colchicine site of beta-tubulin and that chalcones assume an orientation similar to that of podophyllotoxin. The models can be used to design a new class of podophyllotoxin mimics, the alpha-aryl chalcones, capable of binding to the colchicine-binding site of beta-tubulin with higher affinity.
authors.affiliation: Department of Chemistry, UMIST, Manchester M60 1QD, UK. Sylvie.DUCKI@univ-bpclermont.fr
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ducki
authors.forename: Grant
authors.initials: G
authors.lastname: Mackenzie
authors.forename: Ben
authors.initials: B
authors.lastname: Greedy
authors.forename: Simon
authors.initials: S
authors.lastname: Armitage
authors.forename: Jérémie Fournier Dit
authors.initials: JF
authors.lastname: Chabert
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bennett
authors.forename: Jim
authors.initials: J
authors.lastname: Nettles
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lawrence
mesh_terms: D000465:Algorithms; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D003078:Colchicine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D006844:Hydrocarbons, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001632:Bibenzyls; D047188:Chalcones; D006844:Hydrocarbons, Cyclic; D050257:Tubulin Modulators; C040105:combretastatin; D003078:Colchicine