Molecular modeling aided design of nicotinic acid receptor GPR109A agonists

被引：22

作者：

Deng, Qiaolin ^{[1
]}

Frie, Jessica L. ^{[2
]}

Marley, Daria M. ^{[2
]}

Beresis, Richard T. ^{[2
]}

Ren, Ning ^{[3
]}

Cai, Tian-Quan ^{[3
]}

Taggart, Andrew K. P. ^{[3
]}

Cheng, Kang ^{[3
]}

Carballo-Jane, Ester ^{[4
]}

Wang, Junying ^{[5
]}

Tong, Xinchun ^{[5
]}

Waters, M. Gerard ^{[3
]}

Tata, James R. ^{[2
]}

Colletti, Steven L. ^{[2
]}

机构：

[1] Merck Res Labs, Dept Mol Syst, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Med Chem, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Cardiovasc Dis, Rahway, NJ 07065 USA

[4] Merck Res Labs, Dept Pharmacol, Rahway, NJ 07065 USA

[5] Merck Res Labs, Dept Drug Metab, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 18期

关键词：

GPR109A agonists; homology modeling;

D O I：

10.1016/j.bmcl.2008.08.030

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：4963 / 4967

页数：5

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