Multiple flexible alignment with SEAL: a study of molecules acting on the colchicine binding site.
An extension of the steric and electrostatic alignment alignment (SEAL) method (MultiSEAL) is described that allows the overlay of multiple molecules and conformations. The method is well-suited for the systematic study of possible alignments, also revealing information about the conformational energies associated with a given overlay. It has been tested on three examples: angiotensin II antagonists, 5-HT3 antagonists, and dopaminergic compounds. The utility of the method is further demonstrated in an analysis of molecules that putatively bind to the colchicine site of tubulin. On the basis of its overlay with colchicine, allocolchicine, 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone, and combretastatin A-4, it appears that 2-methoxyestradiol (2-ME) is unlikely to fit the colchine site properly. The weak antimitotic activity of 2-ME may be explained by its partial fit in the site.
Feher
M
M
Nanodesign Inc., Guelph, Ontario, Canada.
Schmidt
J M
JM
D000077584:2-Methoxyestradiol; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D001665:Binding Sites; D003078:Colchicine / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D015195:Drug Design; D004958:Estradiol / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D012702:Serotonin Antagonists / Q000494:pharmacology; D055672:Static Electricity; D013816:Thermodynamics
D015259:Dopamine Agents; D012702:Serotonin Antagonists; D000804:Angiotensin II; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003078:Colchicine