A predictive pharmacophore model of human melanocortin-4 receptor as derived from the solution structures of cyclic peptides.
Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the solution structures for a series of potent agonists for the human melanocortin-4 receptor (hMC4R), based on the cyclic peptide MT-II [Ac-Nle-cyclo-(Asp-Lys) (Asp-His-(D)Phe-Arg-Trp-Lys)-NH2]. Members of this series were designed to improve selectivity for MC4R versus the other melanocortin receptors, and to reduce the flexibility of the side chains. The most selective and rigid analog [penta-cyclo(D-K)-Asp-Apc-(D)Phe-Arg-(2S,3S)-beta-methylTrp-Lys-NH2] was found to be a full agonist of hMC4R with an EC50 of 11nM against hMC4R, and to exhibit 65-fold selectivity against hMC1R. This compound represents the most constrained hMC4R peptide agonist described to date. A beta-turn structure was conserved among all of the cyclic peptides studied. The rigidity of the analogs allowed an exceptionally well-defined pharmacophore model to be derived. This model was used to perform a virtual screen using a library of 1000 drug-like compounds, to which a small set of known potent ligands had been intentionally added. The utility of the model was validated by its ability to identify the known ligands from among this large library.
Sun
Hongmao
H
Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. hongmao.sun@roche.com
Greeley
David N
DN
Chu
Xin-Jie
XJ
Cheung
Adrian
A
Danho
Waleed
W
Swistok
Joseph
J
Wang
Yao
Y
Zhao
Chunlin
C
Chen
Li
L
Fry
David C
DC
D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D044105:Receptor, Melanocortin, Type 4 / Q000819:agonists*; D012996:Solutions; D013329:Structure-Activity Relationship
D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; D012996:Solutions