Hydropathic analysis and biological evaluation of stilbene derivatives as colchicine site microtubule inhibitors with anti-leukemic activity.
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.
Tripathi
Ashutosh
A
Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
Durrant
David
D
Lee
Ray M
RM
Baruchello
Riccardo
R
Romagnoli
Romeo
R
Simoni
Daniele
D
Kellogg
Glen E
GE
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*
D000970:Antineoplastic Agents; D013267:Stilbenes; D050257:Tubulin Modulators; D003078:Colchicine