Journal of Computer-Aided Molecular Design

, Volume 23, Issue 5, pp 273–288 | Cite as

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


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.


β2 Adrenoceptor Homology model G-protein coupled receptor Agonist Virtual ligand screening GPCR MMFF 



K.A.R. and R.A. gratefully acknowledge support from the National Institutes of Health (GM074832).

Supplementary material


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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Kimberly A. Reynolds
    • 1
  • Vsevolod Katritch
    • 2
  • Ruben Abagyan
    • 1
  1. 1.Department of Molecular BiologyThe Scripps Research InstituteLa JollaUSA
  2. 2.Molsoft, LLCLa JollaUSA

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