Peloruside, laulimalide, and noscapine interactions with beta-tubulin.
This article reviews the recent findings regarding the binding sites, binding modes and binding affinities of three novel antimitotic drugs peloruside, laulimalide and noscapine with respect to tubulin as the target of their action. These natural compounds are shown to bind to β-tubulin and stabilize microtubules for the cases of peloruside A and laulimalide, and prolong the time spent in pause for noscapine. Particular attention is focused on β-tubulin isotypes as targets for new cancer chemotherapy agents and the amino acid differences in the binding site for these compounds between isotypes. We propose a new strategy for antimitotic drug design that exploits differential distributions of tubulin isotypes between normal and cancer cells and corresponding differential affinities between various drug molecules and tubulin isotypes.
Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
Melissa M
MM
Gajewski
Laleh
L
Alisaraie
Jack A
JA
Tuszynski
D000818:Animals; D001665:Binding Sites; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology*; D009665:Noscapine / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism*; D050257:Tubulin Modulators / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D007783:Lactones; D018942:Macrolides; D014404:Tubulin; D050257:Tubulin Modulators; C117305:laulimalide; C414085:peloruside A; D009665:Noscapine