期刊
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
卷 23, 期 5, 页码 273-288出版社
SPRINGER
DOI: 10.1007/s10822-008-9257-9
关键词
beta(2) Adrenoceptor; Homology model; G-protein coupled receptor; Agonist; Virtual ligand screening; GPCR; MMFF
资金
- National Institutes of Health [GM074832]
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据