Open AccessBiophysical Fragment Screening of the β1-Adrenergic Receptor: Identification of High Affinity Arylpiperazine Leads Using Structure-Based Drug Design
Author(s) -
J.A. Christopher,
Jason Brown,
A.S. Dore,
James C. Errey,
Markus Koglin,
Fiona H. Marshall,
David G. Myszka,
Rebecca L. Rich,
Christopher G. Tate,
Benjamin G. Tehan,
Tony Warne,
Miles Congreve
Publication year - 2013
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm400140q
Subject(s) - chemistry , ligand (biochemistry) , surface plasmon resonance , indole test , g protein coupled receptor , quinoline , fragment (logic) , receptor , stereochemistry , lead compound , combinatorial chemistry , biochemistry , nanotechnology , in vitro , organic chemistry , nanoparticle , materials science , computer science , programming language
Biophysical fragment screening of a thermostabilized β1-adrenergic receptor (β1AR) using surface plasmon resonance (SPR) enabled the identification of moderate affinity, high ligand efficiency (LE) arylpiperazine hits 7 and 8. Subsequent hit to lead follow-up confirmed the activity of the chemotype, and a structure-based design approach using protein-ligand crystal structures of the β1AR resulted in the identification of several fragments that bound with higher affinity, including indole 19 and quinoline 20. In the first example of GPCR crystallography with ligands derived from fragment screening, structures of the stabilized β1AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 Å, respectively.
Accelerating Research
Robert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom
Address
John Eccles HouseRobert Robinson Avenue,
Oxford Science Park, Oxford
OX4 4GP, United Kingdom