Discovery of novel chemotypes to a G-protein-coupled receptor through ligand-steered homology modeling and structure-based virtual screening.
Melanin-concentrating hormone receptor 1 (MCH-R1) is a G-protein-coupled receptor (GPCR) and a target for the development of therapeutics for obesity. The structure-based development of MCH-R1 and other GPCR antagonists is hampered by the lack of an available experimentally determined atomic structure. A ligand-steered homology modeling approach has been developed (where information about existing ligands is used explicitly to shape and optimize the binding site) followed by docking-based virtual screening. Top scoring compounds identified virtually were tested experimentally in an MCH-R1 competitive binding assay, and six novel chemotypes as low micromolar affinity antagonist "hits" were identified. This success rate is more than a 10-fold improvement over random high-throughput screening, which supports our ligand-steered method. Clearly, the ligand-steered homology modeling method reduces the uncertainty of structure modeling for difficult targets like GPCRs.
Cavasotto
Claudio N
CN
MolSoft LLC, La Jolla, CA 92037, USA. Claudio.N.Cavasotto@uth.tmc.edu
Orry
Andrew J W
AJ
Murgolo
Nicholas J
NJ
Czarniecki
Michael F
MF
Kocsi
Sue Ann
SA
Hawes
Brian E
BE
O'Neill
Kim A
KA
Hine
Heather
H
Burton
Marybeth S
MS
Voigt
Johannes H
JH
Abagyan
Ruben A
RA
Bayne
Marvin L
ML
Monsma
Frederick J
FJ
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002417:Cattle; D006224:Cricetinae; D003412:Cricetulus; D016208:Databases, Factual; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D012243:Rhodopsin / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013269:Stochastic Processes; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D008024:Ligands; C103263:MCHR1 protein, human; D011979:Receptors, Pituitary Hormone; D017481:Receptors, Somatostatin; C092274:melanin-concentrating hormone receptor; D012243:Rhodopsin