Biophysical Fragment Screening of the β1-Adrenergic Receptor: Identification of High Affinity Arylpiperazine Leads Using Structure-Based Drug Design

被引：121

作者：

Christopher, John A. ^{[1
]}

Brown, Jason ^{[1
]}

Dore, Andrew S. ^{[1
]}

Errey, James C. ^{[1
]}

Koglin, Markus ^{[1
]}

Marshall, Fiona H. ^{[1
]}

Myszka, David G. ^{[2
]}

Rich, Rebecca L. ^{[2
]}

Tate, Christopher G. ^{[3
]}

Tehan, Benjamin ^{[1
]}

Warne, Tony ^{[3
]}

Congreve, Miles ^{[1
]}

机构：

[1] Heptares Therapeut Ltd, Welwyn Garden City AL7 3AX, Herts, England

[2] Biosensor Tools LLC, Salt Lake City, UT 84103 USA

[3] MRC, Mol Biol Lab, Cambridge CB2 0QH, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2013年 / 56卷 / 09期

基金：

英国生物技术与生命科学研究理事会; 英国医学研究理事会;

关键词：

PROTEIN-COUPLED RECEPTORS; RESOLUTION CRYSTAL-STRUCTURE; OPIOID RECEPTOR; DISCOVERY; COMPLEX; DOPAMINE; AGONISTS; THERMOSTABILIZATION; INHIBITOR; PROGRESS;

D O I：

10.1021/jm400140q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Biophysical fragment screening of a thermostabilized beta(1)-adrenergic receptor (beta(1)AR) 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 beta(1)AR 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 beta(1)AR complexed with 19 and 20 were determined at resolutions of 2.8 and 2.7 angstrom, respectively.

引用

页码：3446 / 3455

页数：10

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