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

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Christopher JA, Brown J, Doré AS, Errey JC, Koglin M, Marshall FH, Myszka DG, Rich RL, Tate CG, Tehan B, Warne T, Congreve M
OpenAccess logo J Med Chem 56 3446-55 (2013)
Cited: 79 times
EuropePMC logo PMID: 23517028

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.

Reviews - 3zpq mentioned but not cited (4)

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  22. Allosteric modulation of G protein-coupled receptors by amiloride and its derivatives. Perspectives for drug discovery? Massink A, Amelia T, Karamychev A, IJzerman AP. Med Res Rev 40 683-708 (2020)
  23. Allosteric Modulation of Adenosine A2A Receptors as a New Therapeutic Avenue. Korkutata M, Agrawal L, Lazarus M. Int J Mol Sci 23 2101 (2022)
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