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PMID: 23517028 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Biophysical fragment screening of the β1-adrenergic receptor: identification of high affinity arylpiperazine leads using structure-based drug design.

Journal of medicinal chemistry ·Vol. 56 ·No. 9 ·2013-05-09 ·Pages 3446-55

Christopher JA, Brown J, Doré AS, Errey JC, Koglin M, Marshall FH, Myszka DG, Rich RL, Tate CG, Tehan B, Warne T, Congreve M

Abstract

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.

MeSH Terms
Biophysical Phenomena Drug Design Drug Evaluation, Preclinical HEK293 Cells Humans Molecular Docking Simulation Piperazine Piperazines/chemistry,metabolism Protein Binding Protein Conformation Receptors, Adrenergic, beta-1/chemistry,metabolism Surface Plasmon Resonance
Chemicals
Piperazines Receptors, Adrenergic, beta-1 Piperazine
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Christopher John A
Heptares Therapeutics Ltd. , BioPark, Welwyn Garden City, Hertfordshire, AL7 3AX, U.K. john.christopher@heptares.com
Brown Jason
Doré Andrew S
Errey James C
Koglin Markus
Marshall Fiona H
Myszka David G
Rich Rebecca L
Tate Christopher G
Tehan Benjamin
Warne Tony
Congreve Miles
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Article Info
Journal
Journal of medicinal chemistry
Abbr.
J Med Chem
ISSN
1520-4804
DOI
10.1021/jm400140q
Email
john.christopher@heptares.com
Published
2013-05-09
Epub
2013-00-09
Pages
3446-55
Language
English
Region
United States
NLM ID
9716531
PMCID
PMC3654563
Subset
IM
Grants
Medical Research Council · MC_U105197215 · United Kingdom
Biotechnology and Biological Sciences Research Council · BB/G003653/1 · United Kingdom
Medical Research Council · U105197215 · United Kingdom
Databases
PDB
3ZPQ, 3ZPR
External Links
PubMed source DOI: 10.1021/jm400140q PMC Full Text View journal details
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