NMR structure of a potent small molecule inhibitor bound to human keratinocyte fatty acid-binding protein.
The NMR structure is presented for compound 1 (BMS-480404) (Ki = 33 (+/-2) nM) bound to keratinocyte fatty acid-binding protein. This article describes interactions between a high affinity drug-like compound and a member of the fatty acid-binding protein family. A benzyl group ortho to the mandelic acid in 1 occupies an area of the protein that fatty acids do not normally contact. Similar to that in the kFABP-palmitic acid structure, the acid moiety in 1 is proximal to R129 and Y131. Computational modeling indicates that the acid moiety in 1 interacts indirectly via a modeled water molecule to R109.
McDonnell
Patricia A
PA
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, USA. patricia.mcdonnell@bms.com
Constantine
Keith L
KL
Goldfarb
Valentina
V
Johnson
Stephen R
SR
Sulsky
Richard
R
Magnin
David R
DR
Robl
Jeffrey A
JA
Caulfield
Thomas J
TJ
Parker
Rex A
RA
Taylor
David S
DS
Adam
Leonard P
LP
Metzler
William J
WJ
Mueller
Luciano
L
Farmer
Bennett T
BT
D001665:Binding Sites; D003198:Computer Simulation; D050556:Fatty Acid-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure
D050556:Fatty Acid-Binding Proteins; D008024:Ligands