A virtual screening approach to finding novel and potent antagonists at the melanin-concentrating hormone 1 receptor.
Melanin-concentrating hormone (MCH) has been known to be an appetite-stimulating peptide for a number of years. However, it is only recently that MCH has been discovered to be the natural ligand for a previously "orphan" G-protein-coupled receptor, now designated MCH-1R. This receptor has been shown to mediate the effects of MCH on appetite and body weight, and consequently, drug discovery programs have begun to exploit this information in the search for MCH-1R antagonists for the treatment of obesity. In this paper, we report the rapid discovery of multiple, structurally distinct series of MCH-1R antagonists using a variety of virtual screening techniques. The most potent of these compounds (12) demonstrated an IC(50) value of 55 nM in the primary screen and exhibited antagonist properties in a functional cellular assay measuring Ca(2+) release. More potent compounds were identified by follow-up searches around the initial hit. A proposed binding mode for compound 12 in a homology model of the MCH-1R is also presented.
Clark
David E
DE
Argenta Discovery Ltd., 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex, CM19 5TR, UK. david.clark @argentadiscovery.com
Higgs
Christopher
C
Wren
Stephen P
SP
Dyke
Hazel J
HJ
Wong
Melanie
M
Norman
Dennis
D
Lockey
Peter M
PM
Roach
Alan G
AG
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D016208:Databases, Factual; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C103263:MCHR1 protein, human; D010879:Piperazines; D011804:Quinolines; D017481:Receptors, Somatostatin; D002118:Calcium