Identifying conformational changes of the β2 adrenoceptor that enable accurate prediction of ligand/receptor interactions and screening for GPCR modulators

Kimberly A. Reynolds, Vsevolod Katritch, Ruben Abagyan

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

The new β2 Adrenoceptor (β2AR) crystal structures provide a high-resolution snapshot of receptor interactions with two particular partial inverse agonists, (-)-carazolol and timolol. However, both experimental and computational studies of GPCR structure are significantly complicated by the existence of multiple conformational states coupled to ligand type and receptor activity. Agonists and antagonists induce or stabilize distinct changes in receptor structure that mediate a range of pharmacological activities. In this work, we (1) established that the existing β2AR crystallographic conformers can be extended to describe ligand/receptor interactions for additional antagonist types, (2) generated agonist-bound receptor conformations, and (3) validated these models for agonist and antagonist virtual ligand screening (VLS). Using a ligand directed refinement protocol, we derived a single agonist-bound receptor conformation that selectively retrieved a diverse set of full and partial β2AR agonists in VLS trials. Additionally, the impact of extracellular loop two conformation on VLS was assessed by docking studies with rhodopsin-based β2AR homology models, and loop-deleted receptor models. A general strategy for constructing and selecting agonist-bound receptor pocket conformations is presented, which may prove broadly useful in creating agonist and antagonist bound models for other GPCRs.

Original languageEnglish (US)
Pages (from-to)273-288
Number of pages16
JournalJournal of Computer-Aided Molecular Design
Volume23
Issue number5
DOIs
StatePublished - 2009

Fingerprint

Adrenergic Receptors
Modulators
modulators
Screening
screening
Ligands
ligands
Conformations
predictions
interactions
Timolol
Rhodopsin
homology
activity (biology)
Crystal structure
Pharmacology
crystal structure
high resolution

Keywords

  • β Adrenoceptor
  • Agonist
  • G-protein coupled receptor
  • GPCR
  • Homology model
  • MMFF
  • Virtual ligand screening

ASJC Scopus subject areas

  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Computer Science Applications

Cite this

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abstract = "The new β2 Adrenoceptor (β2AR) crystal structures provide a high-resolution snapshot of receptor interactions with two particular partial inverse agonists, (-)-carazolol and timolol. However, both experimental and computational studies of GPCR structure are significantly complicated by the existence of multiple conformational states coupled to ligand type and receptor activity. Agonists and antagonists induce or stabilize distinct changes in receptor structure that mediate a range of pharmacological activities. In this work, we (1) established that the existing β2AR crystallographic conformers can be extended to describe ligand/receptor interactions for additional antagonist types, (2) generated agonist-bound receptor conformations, and (3) validated these models for agonist and antagonist virtual ligand screening (VLS). Using a ligand directed refinement protocol, we derived a single agonist-bound receptor conformation that selectively retrieved a diverse set of full and partial β2AR agonists in VLS trials. Additionally, the impact of extracellular loop two conformation on VLS was assessed by docking studies with rhodopsin-based β2AR homology models, and loop-deleted receptor models. A general strategy for constructing and selecting agonist-bound receptor pocket conformations is presented, which may prove broadly useful in creating agonist and antagonist bound models for other GPCRs.",
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