Modelling topoisomerase I inhibition by minor groove binders.

Topoisomerase inhibition is an extremely useful target for anticancer and antimicrobial drugs, and an undesirable side effect of some drugs targeting other proteins. Published modelling studies are sparse, and have used small data sets with relatively low molecular diversity. Given the important role of minor groove binding in the mechanism of topoisomerase I inhibition, we have conducted the first 3D QSAR study of topoisomerase I inhibition of a large, diverse set of minor groove binders using the minor groove binding conformation as the alignment template. The highly significant QSAR models resulting from this alignment identify the roles played by molecular features, most importantly the hydrogen bond donor properties.