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Brief Article

NMR Structure of a Potent Small Molecule Inhibitor Bound to Human Keratinocyte Fatty Acid-Binding Protein^†

Supporting Info

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, and Bennett T. Farmer, II^‡

Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543

J. Med. Chem., 2006, 49 (16), pp 5013–5017

DOI: 10.1021/jm060360i

Publication Date (Web): July 11, 2006

†

The resonance assignments for kFABP−1 have been deposited in the BMRB databank, access code 7107.

To whom correspondence should be addressed. Phone: 609-252-4286. Fax: 609-252-6012. E-mail: patricia.mcdonnell@bms.com.

‡

Present address: Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877.

Abstract

The NMR structure is presented for compound 1 (BMS-480404) (K_i = 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.

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