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Is there a common allosteric binding site for all GPCRs?

Is there a common allosteric binding site for all GPCRs?
所有 GPCR 是否都有一个共同的变构结合位点?
批准号:
10690270
负责人:
Zhijun Li
金额:
$10.0万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-15 至 2024-08-31

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中文摘要
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英文摘要
Project Summary G-protein coupled receptors (GPCRs) represent the largest superfamily of human proteome with more than 800 members. Given the key role of GPCRs in signal transduction across membranes, GPCRs are the number one drug target, accounting for approximately 25% of the current drugs in the market. Despite significant progresses in drug discovery targeting GPCRs, many pharmaceutically important GPCRs remain elusive. In recent years, a novel venue has been reported to exploit the allosteric sites on them for the development of drugs to treat various diseases. Identifying the allosteric sites on GPCRs, however, remains a challenge. This proposal aims to explore the existence of a common allosteric site below the middle of the transmembrane domain that spatially overlaps with the G-protein binding site for all human GPCRs. The long- term objective of this project is to understand the mechanism of allosteric regulations in GPCRs. For this proposal, proposed works will include two specific Aims. Aim I is to identify allosteric antagonists and agonists of eight representative GPCRs from Class A, B, C and F that bind to the proposed common allosteric site on these GPCRs through in silico screening and in vitro test. For this aim, two GPCRs with known structure, one in its inactive conformation and one in its active conformation, will be chosen from each of the four non-sensory GPCR Classes, A, B, C and F. Then in silico screening against ZINC database will be performed using each structure. For top-ranked compounds, their binding stability and binding affinity in the binding site will be computationally studied using molecular dynamics simulations. Finally, for those top-ranked antagonists and agonists, in vitro activity studies and site-specific mutagenesis studies will be carried out. Aim II is to improve the selectivity and potency of the identified GLP-1R allosteric agonist through structure-based molecule design and experimental test. This aim will be carried out by: 1) obtain the active structure of both GLP-1R and GCGR and run molecular dynamics simulations; 2) compare the conformation snapshots from GLP-1R simulations with those of GCGR and identify one conformation of GLP-1R that have the largest structural difference at the proposed allosteric site from all GCGR conformations; 3) dock the GLP-1R allosteric agonist to the allosteric site in the identified GLP-1R conformation from las step and perform in virtual combinatorial library design to generate optimized compounds; 4) re-dock the top-ranked compounds from last step to the same allosteric site on the GCGR conformation most similar to GLP-1R conformation; and 5) in vitro assay test the lowest ranked compounds from last step. Given the strategic location of this common binding site, the success of this proposal could provide a useful venue for biological studies and therapeutic discovery targeting various GPCRs.
期刊论文(3)
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会议论文
DOI: 10.1007/s10822-022-00454-5
发表时间: 2022-06
期刊: Journal of computer-aided molecular design
影响因子: 3.5
作者: []
通讯作者:
DOI: 10.1111/cbdd.14039
发表时间: 2022-06
期刊: Chemical biology & drug design
影响因子: 3
作者: []
通讯作者:
Is there a common allosteric binding site for all GPCRs?
  • 批准号:
    10630589
  • 项目类别:
  • 资助金额:
    $22.83万
  • 财政年份:
    2020
  • 负责人:
    Zhijun Li
  • 依托单位:
海外基金