NMR structure of a potent small molecule inhibitor bound to human keratinocyte fatty acid-binding protein

Patricia A McDonnell; Keith L Constantine; Valentina Goldfarb; Stephen R Johnson; Richard Sulsky; David R Magnin; Jeffrey A Robl; Thomas J Caulfield; Rex A Parker; David S Taylor; Leonard P Adam; William J Metzler; Luciano Mueller; Bennett T Farmer 2nd

doi:10.1021/jm060360i

NMR structure of a potent small molecule inhibitor bound to human keratinocyte fatty acid-binding protein

J Med Chem. 2006 Aug 10;49(16):5013-7. doi: 10.1021/jm060360i.

Authors

Patricia A McDonnell¹, Keith L Constantine, Valentina Goldfarb, Stephen R Johnson, Richard Sulsky, David R Magnin, Jeffrey A Robl, Thomas J Caulfield, Rex A Parker, David S Taylor, Leonard P Adam, William J Metzler, Luciano Mueller, Bennett T Farmer 2nd

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543, USA. patricia.mcdonnell@bms.com

PMID: 16884313
DOI: 10.1021/jm060360i

Abstract

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.

MeSH terms

Binding Sites
Computer Simulation
Fatty Acid-Binding Proteins / antagonists & inhibitors*
Fatty Acid-Binding Proteins / chemistry*
Fatty Acid-Binding Proteins / metabolism
Humans
Keratinocytes / metabolism*
Ligands
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Structure

Substances

Fatty Acid-Binding Proteins
Ligands