Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 23, Issue 5, Pages 273-288Publisher
SPRINGER
DOI: 10.1007/s10822-008-9257-9
Keywords
beta(2) Adrenoceptor; Homology model; G-protein coupled receptor; Agonist; Virtual ligand screening; GPCR; MMFF
Categories
Funding
- National Institutes of Health [GM074832]
Ask authors/readers for more resources
The new beta(2) Adrenoceptor (beta(2)AR) 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 beta(2)AR 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 beta(2)AR agonists in VLS trials. Additionally, the impact of extracellular loop two conformation on VLS was assessed by docking studies with rhodopsin-based beta(2)AR 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available