title: Molecular modeling aided design of nicotinic acid receptor GPR109A agonists.
abstract: A homology model of the nicotinic acid receptor GPR109A was constructed based on the X-ray crystal structure of bovine rhodopsin. An HTS hit was docked into the homology model. Characterization of the binding pocket by a grid-based surface calculation of the docking model suggested that a larger hydrophobic body plus a polar tail would improve interaction between the ligand and the receptor. The designed compounds were synthesized, and showed significantly improved binding affinity and activation of GPR109A.
authors.affiliation: Department of Molecular Systems, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. qiaolin_deng@merck.com
authors.forename: Qiaolin
authors.initials: Q
authors.lastname: Deng
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Frie
authors.forename: Daria M
authors.initials: DM
authors.lastname: Marley
authors.forename: Richard T
authors.initials: RT
authors.lastname: Beresis
authors.forename: Ning
authors.initials: N
authors.lastname: Ren
authors.forename: Tian-Quan
authors.initials: TQ
authors.lastname: Cai
authors.forename: Andrew K P
authors.initials: AK
authors.lastname: Taggart
authors.forename: Kang
authors.initials: K
authors.lastname: Cheng
authors.forename: Ester
authors.initials: E
authors.lastname: Carballo-Jane
authors.forename: Junying
authors.initials: J
authors.lastname: Wang
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: M Gerard
authors.initials: MG
authors.lastname: Waters
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
authors.forename: Steven L
authors.initials: SL
authors.lastname: Colletti