ABSTRACT
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 ß-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 ß-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.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Lactones/pharmacology , Macrolides/pharmacology , Noscapine/pharmacology , Tubulin Modulators/pharmacology , Tubulin/metabolism , Animals , Binding Sites , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Drug Evaluation, Preclinical , HumansABSTRACT
Base excision repair (BER) is the fundamental pathway responsible for the elimination of damaged DNA bases and repair of DNA single-strand breaks generated spontaneously or produced by DNA-damaging agents. Among the essential enzymes that are required to achieve the BER reaction is DNA polymerase beta (pol ß), which has been regarded as a potential therapeutic target. More than 60 pol ß-inhibitors have been identified so far; however, most of them are either not potent or not specific enough to become a drug. In this article we compile an essential knowledge base regarding the structures, the modes of inhibition and the activities of these pharmacologically interesting molecules.
