title: Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure-activity relationships and molecular docking.
abstract: One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r (2) = 0.878, q (2) = 0.630, and r (pred) (2) = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities.
authors.affiliation: Department of Medicinal Chemistry, University of Mississippi, University, MS 38677-1848, USA.
authors.forename: Aihua
authors.initials: A
authors.lastname: Xie
authors.forename: Srinivas
authors.initials: S
authors.lastname: Odde
authors.forename: Sivaprakasam
authors.initials: S
authors.lastname: Prasanna
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; C029899:imidazole; D051231:Farnesyltranstransferase