title: Hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site microtubule inhibitors with anti-leukemic activity.
abstract: The crucial role of the microtubule in cell division has identified tubulin as a target for the development of therapeutics for cancer; in particular, tubulin is a target for antineoplastic agents that act by interfering with the dynamic stability of microtubules. A molecular modeling study was carried out to accurately represent the complex structure and the binding mode of a new class of stilbene-based tubulin inhibitors that bind at the alphabeta-tubulin colchicine site. Computational docking along with HINT (Hydropathic INTeractions) score analysis fitted these inhibitors into the colchicine site and revealed detailed structure-activity information useful for inhibitor design. Quantitative analysis of the results was in good agreement with the in vitro antiproliferative activity of these derivatives (ranging from 3 nM to 100 muM) such that calculated and measured free energies of binding correlate with an r(2) of 0.89 (standard error +/- 0.85 kcal mol(-1)). This correlation suggests that the activity of unknown compounds may be predicted.
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathi
authors.forename: David
authors.initials: D
authors.lastname: Durrant
authors.forename: Ray M
authors.initials: RM
authors.lastname: Lee
authors.forename: Riccardo
authors.initials: R
authors.lastname: Baruchello
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Daniele
authors.initials: D
authors.lastname: Simoni
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013267:Stilbenes; D050257:Tubulin Modulators; D003078:Colchicine