NMR structural characterization of oligo-N-substituted glycine lead compounds from a combinatorial library
Erin K. Bradley, Janice M. Kerr, Lutz S. Richter, Gianine M.
Figliozzi, Dane A. Goff,
Ronald N. Zuckermann,
David C. Spellmeyer,
Jeffrey M. Blaney
Small Molecule Drug Discovery, Chiron Corporation, 4560 Horton Street,
Emeryville, CA 94608, U.S.A.
Abstract
Synthesis and screening of combinatorial libraries for pharmaceutical lead
discovery is a rapidly expanding field. Oligo-N-substituted glycines
(NSGs) were one of the earliest sources of molecular diversity in
combinatorial libraries. In one of the first demonstrations of the power
of combinatorial chemistry, two NSG trimers, CHIR-2279 and CHIR-4531, were
identified as nM ligands for two 7-transmembrane G-protein-coupled
receptors. The NMR characterization of these two lead compounds was
undertaken to verify covalent connectivity and to determine solution
conformations, if any. The sequential chemical shift assignments were
performed using a new strategy for assigning 1H and 13C resonances of
NSGs. The conformational preferences were then determined in both an
aqueous co-solvent system and an organic solvent to probe the effects of
hydrophobic collapse. NSGs are expected to be more flexible than peptides
due to the tertiary amide, with both cis and trans amide bond
conformations being accessible. Solution NMR studies indicate that
although CHIR-2279 and CHIR-4531 have identical backbones and termini, and
very similar side chains, they do not display the same solution
conformational characteristics.
Keywords
combinatorial library, hydrophobic collapse, NMR, n-substituted glycines,
structure
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