title: Docking and hydropathic scoring of polysubstituted pyrrole compounds with antitubulin activity.
abstract: Compounds that bind at the colchicine site of tubulin have drawn considerable attention with studies indicating that these agents suppress microtubule dynamics and inhibit tubulin polymerization. Data for 18 polysubstituted pyrrole compounds are reported, including antiproliferative activity against human MDA-MB-435 cells and calculated free energies of binding following docking the compounds into models of alphabeta-tubulin. These docking calculations coupled with HINT interaction analyses are able to represent the complex structures and the binding modes of inhibitors such that calculated and measured free energies of binding correlate with an r(2) of 0.76. Structural analysis of the binding pocket identifies important intermolecular contacts that mediate binding. As seen experimentally, the complex with JG-03-14 (3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester) is the most stable. These results illuminate the binding process and should be valuable in the design of new pyrrole-based colchicine site inhibitors as these compounds have very accessible syntheses.
authors: Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
authors: Ashutosh
authors: A
authors: Tripathi
authors: Micaela
authors: M
authors: Fornabaio
authors: Glen E
authors: GE
authors: Kellogg
authors: John T
authors: JT
authors: Gupton
authors: David A
authors: DA
authors: Gewirtz
authors: W Andrew
authors: WA
authors: Yeudall
authors: Nina E
authors: NE
authors: Vega
authors: Susan L
authors: SL
authors: Mooberry
mesh_terms: D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000031:analogs & derivatives / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D021122:Protein Subunits; D011758:Pyrroles; D014404:Tubulin; C012852:colchiceine; D003078:Colchicine