On-column ligand exchange for structure-based drug design: a case study with human 11β-hydroxysteroid dehydrogenase type 1.
Successfully forming ligand-protein complexes with specific compounds can be a significant challenge in supporting structure-based drug design for a given protein target. In this respect, an on-column ligand- and detergent-exchange method was developed to obtain ligand-protein complexes of an adamantane series of compounds with 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) after a variety of other complexation methods had failed. This report describes the on-column exchange method and an unexpected byproduct of the method in which artificial trimers were observed in the structures.
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA.
Wenying
W
Qin
Russell A
RA
Judge
Kenton L
KL
Longenecker
Larry R
LR
Solomon
John E
JE
Harlan
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000295:instrumentation / Q000379:methods*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D020836:Protein Structure, Quaternary
D004791:Enzyme Inhibitors; D008024:Ligands; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human