title: Pyrrole-Based Antitubulin Agents: Two Distinct Binding Modalities are Predicted for C-2 Analogs in the Colchicine Site.
abstract: 3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester is a promising antitubulin lead agent that targets the colchicine site of tubulin. C-2 analogs were synthesized and tested for microtubule depolymerizing and antiproliferative activity. Molecular modeling studies using both GOLD docking and HINT (Hydropathic INTeraction) scoring revealed two distinct binding modes that explain the structural-activity relationships and are in accord with the structural basis of colchicine binding to tubulin. The binding mode of higher activity compounds is buried deeper in the site and overlaps well with rings A and C of colchicine, while the lower activity binding mode shows fewer critical contacts with tubulin. The model distinguishes highly active compounds from those with weaker activities and provides novel insights into the colchicine site and compound design.
authors.affiliation: Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, USA 23298-0540.
authors.forename: Chenxiao
authors.initials: C
authors.lastname: Da
authors.forename: Nakul
authors.initials: N
authors.lastname: Telang
authors.forename: Peter
authors.initials: P
authors.lastname: Barelli
authors.forename: Xin
authors.initials: X
authors.lastname: Jia
authors.forename: John T
authors.initials: JT
authors.lastname: Gupton
authors.forename: Susan L
authors.initials: SL
authors.lastname: Mooberry
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg