A common pharmacophore for a diverse set of colchicine site inhibitors using a structure-based approach.
Modulating the structure and function of tubulin and microtubules is an important route to anticancer therapeutics, and therefore, small molecules that bind to tubulin and cause mitotic arrest are of immense interest. A large number of synthetic and natural compounds with diverse structures have been shown to bind at the colchicine site, one of the major binding sites on tubulin, and inhibit tubulin assembly. Using the recently determined X-ray structure of the tubulin:colchicinoid complex as the template, we employed docking studies to determine the binding modes of a set of structurally diverse colchicine site inhibitors. These binding models were subsequently used to construct a comprehensive, structure-based pharmacophore that in combination with molecular dynamics simulations confirms and extends our understanding of binding interactions at the colchicine site.
Nguyen
Tam Luong
TL
Target Structure-Based Drug Discovery Group, Developmental Therapeutics Program, National Cancer Institute, Frederick, Maryland 21702, USA. nguyent@ncifcrf.gov
McGrath
Connor
C
Hermone
Ann R
AR
Burnett
James C
JC
Zaharevitz
Daniel W
DW
Day
Billy W
BW
Wipf
Peter
P
Hamel
Ernest
E
Gussio
Rick
R
D000077584:2-Methoxyestradiol; D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000737:chemistry; D000627:Aminophenols / Q000737:chemistry; D001665:Binding Sites; D002599:Chalcone / Q000737:chemistry; D003078:Colchicine / Q000737:chemistry*; D003521:Cyclopropanes / Q000737:chemistry; D004958:Estradiol / Q000031:analogs & derivatives / Q000737:chemistry; D007189:Indans / Q000737:chemistry; D017705:Lignans / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D015739:Nocodazole / Q000737:chemistry; D011034:Podophyllotoxin / Q000737:chemistry; D011485:Protein Binding; D013267:Stilbenes / Q000737:chemistry; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D014404:Tubulin / Q000737:chemistry*; D050257:Tubulin Modulators; D000096926:Benzenesulfonamides
D000077584:2-Methoxyestradiol; D015107:4-Butyrolactone; D000627:Aminophenols; D002599:Chalcone; D003078:Colchicine; D003521:Cyclopropanes; D004958:Estradiol; D007189:Indans; D017705:Lignans; D015739:Nocodazole; D011034:Podophyllotoxin; D013267:Stilbenes; D013449:Sulfonamides; D013844:Thiazoles; D014404:Tubulin; D050257:Tubulin Modulators; C404326:indanocine; C079199:E 7010; D000096926:Benzenesulfonamides; C095843:curacin A; C002858:steganacin; C058728:fosbretabulin