title: Interaction of epothilone analogs with the paclitaxel binding site: relationship between binding affinity, microtubule stabilization, and cytotoxicity.
abstract: The interactions of epothilone analogs with the paclitaxel binding site of microtubules were studied. The influence of chemical modifications in the C15 side chain and in C12 on binding affinity and microtubule elongation was characterized. Modifications favorable for binding affinity are (1). a thiomethyl group at C21 of the thiazole side chain, (2). a methyl group at C12 in S configuration, (3). a pyridine side chain with C15 in S configuration, and (4). a cyclopropyl moiety between C12 and C13. The same modification in different ligands has similar effect on affinity, allowing good structure-affinity characterization. The correlation between binding, microtubule stabilization, and cytotoxicity of the compounds has been determined, showing differential effects of the modifications. The binding constants correlate well with IC(50) values, demonstrating that affinity measurements are a useful tool for drug design.
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain.
authors.forename: Rubén M
authors.initials: RM
authors.lastname: Buey
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Díaz
authors.forename: José M
authors.initials: JM
authors.lastname: Andreu
authors.forename: Aurora
authors.initials: A
authors.lastname: O'Brate
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Giannakakou
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Sasmal
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritzén
authors.forename: Kenji
authors.initials: K
authors.lastname: Namoto
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D001665:Binding Sites; D045744:Cell Line, Tumor; D015195:Drug Design; D034261:Epothilones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000187:drug effects*; D008968:Molecular Conformation; D017239:Paclitaxel / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D034261:Epothilones; D017239:Paclitaxel