Application of a novel design paradigm to generate general nonpeptide combinatorial templates mimicking beta-turns: synthesis of ligands for melanocortin receptors.
We report the further application of a novel approach to template and ligand design by the synthesis of agonists of the melanocortin receptor. This design method uses the conserved structural data from the three-dimensional conformations of beta-turn peptides to design rigid nonpeptide templates that mimic the orientation of the main chain C-alpha atoms in a peptide beta-turn. We report details on a new synthesis of derivatives of template 1 that are useful for the synthesis of exploratory libraries. The utility of this technique is further exemplified by several iterative rounds of high-throughput synthesis and screening, which result in new partially optimized nonpeptide agonists for several melanocortin receptors.
Webb
Thomas R
TR
ChemBridge Research Labs, Inc., ChemBridge Corporation, 16981 Via Tazon, San Diego, California 92127, USA. thomas.webb@stjude.org
Jiang
Luyong
L
Sviridov
Sergey
S
Venegas
Ruben E
RE
Vlaskina
Anna V
AV
McGrath
Douglas
D
Tucker
John
J
Wang
Jian
J
Deschenes
Alain
A
Li
Rongshi
R
D000818:Animals; D040761:Biomimetic Materials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D020650:Combinatorial Chemistry Techniques; D006224:Cricetinae; D003412:Cricetulus; D030562:Databases, Protein; D015195:Drug Design; D008024:Ligands; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry; D044101:Receptors, Melanocortin / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D010455:Peptides; D044101:Receptors, Melanocortin