Molecular modeling aided design of nicotinic acid receptor GPR109A agonists.
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.
Deng
Qiaolin
Q
Department of Molecular Systems, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. qiaolin_deng@merck.com
Frie
Jessica L
JL
Marley
Daria M
DM
Beresis
Richard T
RT
Ren
Ning
N
Cai
Tian-Quan
TQ
Taggart
Andrew K P
AK
Cheng
Kang
K
Carballo-Jane
Ester
E
Wang
Junying
J
Tong
Xinchun
X
Waters
M Gerard
MG
Tata
James R
JR
Colletti
Steven L
SL