title: Fighting obesity with a sugar-based library: discovery of novel MCH-1R antagonists by a new computational-VAST approach for exploration of GPCR binding sites.
abstract: Obesity is an increasingly common disease. While antagonism of the melanin-concentrating hormone-1 receptor (MCH-1R) has been widely reported as a promising therapeutic avenue for obesity treatment, no MCH-1R antagonists have reached the market. Discovery and optimization of new chemical matter targeting MCH-1R is hindered by reduced HTS success rates and a lack of structural information about the MCH-1R binding site. X-ray crystallography and NMR, the major experimental sources of structural information, are very slow processes for membrane proteins and are not currently feasible for every GPCR or GPCR-ligand complex. This situation significantly limits the ability of these methods to impact the drug discovery process for GPCR targets in "real-time", and hence, there is an urgent need for other practical and cost-efficient alternatives. We present here a conceptually pioneering approach that integrates GPCR modeling with design, synthesis, and screening of a diverse library of sugar-based compounds from the VAST technology (versatile assembly on stable templates) to provide structural insights on the MCH-1R binding site. This approach creates a cost-efficient new avenue for structure-based drug discovery (SBDD) against GPCR targets. In our work, a primary VAST hit was used to construct a high-quality MCH-1R model. Following model validation, a structure-based virtual screen yielded a 14% hit rate and 10 novel chemotypes of potent MCH-1R antagonists, including EOAI3367472 (IC50 = 131 nM) and EOAI3367474 (IC50 = 213 nM).
authors.affiliation: Evotec (UK), Ltd., Milton Park, Abingdon, Oxfordshire, United Kingdom. Alexander.Heifetz@Evotec.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Heifetz
authors.forename: Oliver
authors.initials: O
authors.lastname: Barker
authors.forename: Geraldine
authors.initials: G
authors.lastname: Verquin
authors.forename: Norbert
authors.initials: N
authors.lastname: Wimmer
authors.forename: Wim
authors.initials: W
authors.lastname: Meutermans
authors.forename: Sandeep
authors.initials: S
authors.lastname: Pal
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Law
authors.forename: Mark
authors.initials: M
authors.lastname: Whittaker
mesh_terms: D000595:Amino Acid Sequence; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001665:Binding Sites; D002241:Carbohydrates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009765:Obesity / Q000188:drug therapy*; D011487:Protein Conformation; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D014584:User-Computer Interface
chemical_list: D019440:Anti-Obesity Agents; D002241:Carbohydrates; C103263:MCHR1 protein, human; D017481:Receptors, Somatostatin; D054852:Small Molecule Libraries