An in silico structure-based approach to map the druggable allosteric space of membrane receptors

一种基于计算机结构的方法来绘制膜受体的可药物变构空间

• 批准号: BB/R007101/1
• 负责人: Irina Tikhonova
• 金额: $ 39.51万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR007101%2F1
• 关键词: silico; structure; based; approach; map

Membrane receptors enable cells to respond to chemical and physical signals, activate a complex chain of biological events inside the cell and ultimately lead to a change in cell biology. The G protein-coupled receptors (GPCRs), ligand- and voltage-gated ion channel receptors and tyrosine kinase receptors are effective targets of nearly 60 % of the medicines currently used in clinics. The receptor biological state can be modulated by small molecule ligands acting on spatially distinct allosteric binding sites that result in more selective and safer medicines than those targeting orthosteric sites. Recent studies point to common mechanisms of allosteric regulation and the discovery of synthetic allosteric modulators for these receptor families. However, the discovery of allosteric sites and modulators has been largely serendipitous, achieved through high-throughput screening. A recent breakthrough in structural biology disclosed the crystal structures of several GPCRs bounded to allosteric modulators providing opportunities to develop predictive computational methodologies for allosteric medicine discovery in the membrane receptors. We aim to develop a general structure-based computational methodology to search for allosteric binding sites in the membrane receptors. Since the newly available crystal structures of GPCR-allosteric modulator complexes indicate a diverse location of allosteric sites, we aim to develop computational procedures to map allosteric sites inside of the receptors; and outside of the receptor at the interface with the lipid bilayer. Our methodology will rely on the study of receptor dynamics in realistic cellular environment with the presence of carefully selected organic solvents. The organic solvents will be used as probes to search for binding sites. We will initially develop the methodology, where we predict allosteric sites for the receptors with the available crystal structures of a receptor-allosteric ligand complex (the training set) and then explore developed computational procedures predicting allosteric sites for new receptors (the test set) with further validation of the results of prediction in mutagenesis and compound screening. The bioamine, peptide and nucleotide receptors will be used to develop the methodology. We will use our receptor case studies together with sequence approaches to predict a general molecular basis of allosteric site location in GPCRs. Our computational methodology will facilitate the development of new therapies for the treatment of GPCR-related diseases such as inflammation, infertility, metabolic and neurological disorders, viral infections and cancer. The computational strategy developed for one membrane receptor family will enable its applications to other receptor families.

膜受体使细胞能够对化学和物理信号做出反应，激活细胞内复杂的生物事件链，并最终导致细胞生物学的变化。G蛋白偶联受体（GPCR）、配体和电压门控离子通道受体以及酪氨酸激酶受体是目前临床上使用的近60%的药物的有效靶点。受体生物学状态可以通过作用于空间上不同的变构结合位点的小分子配体来调节，这导致比靶向正构位点的药物更具选择性和更安全的药物。最近的研究指出了变构调节的共同机制，并发现了这些受体家族的合成变构调节剂。然而，变构位点和调节剂的发现在很大程度上是偶然的，通过高通量筛选实现。结构生物学的最新突破公开了与变构调节剂结合的几种GPCR的晶体结构，为在膜受体中发现变构药物提供了开发预测计算方法的机会。 我们的目标是发展一个通用的基于结构的计算方法来寻找膜受体的变构结合位点。由于新的GPCR-变构调节剂复合物的晶体结构表明变构位点的不同位置，我们的目标是开发计算程序来映射受体内部的变构位点;以及在与脂质双层的界面处的受体外部。我们的方法将依赖于在现实的细胞环境中仔细选择的有机溶剂的存在下，受体动力学的研究。有机溶剂将用作探针以搜索结合位点。我们将首先开发的方法，在那里我们预测变构位点的受体与可用的晶体结构的受体-变构配体复合物（训练集），然后探索开发的计算程序预测变构位点的新受体（测试集）与预测结果的进一步验证诱变和化合物筛选。生物胺、肽和核苷酸受体将用于开发方法学。我们将使用我们的受体案例研究与序列方法一起预测GPCR中变构位点位置的一般分子基础。我们的计算方法将促进新疗法的开发，用于治疗GPCR相关疾病，如炎症，不育，代谢和神经系统疾病，病毒感染和癌症。为一个膜受体家族开发的计算策略将使其应用于其他受体家族。

项目成果

Structural basis for the ligand recognition and signaling of free fatty acid receptors.

• DOI: 10.1126/sciadv.adj2384
• 发表时间: 2024-01-12
• 期刊: SCIENCE ADVANCES
• 影响因子: 13.6
• 作者: Zhang, Xuan;Guseinov, Abdul-Akim;Jenkins, Laura;Li, Kunpeng;Tikhonova, Irina G.;Milligan, Graeme;Zhang, Cheng
• 通讯作者: Zhang, Cheng

Intermolecular Interactions in G Protein-Coupled Receptor Allosteric Sites at the Membrane Interface from Molecular Dynamics Simulations and Quantum Chemical Calculations.

通过分子动力学模拟和量子化学计算，G蛋白偶联受体变构位点中的分子间相互作用。

• DOI: 10.1021/acs.jcim.2c00788
• 发表时间: 2022-10-10
• 期刊: JOURNAL OF CHEMICAL INFORMATION AND MODELING
• 影响因子: 5.6
• 作者: Ding, Tianyi;Karlov, Dmitry S.;Pino-Angeles, Almudena;Tikhonova, Irina G.
• 通讯作者: Tikhonova, Irina G.

Selective phosphorylation of threonine residues defines GPR84-arrestin interactions of biased ligands.

• DOI: 10.1016/j.jbc.2022.101932
• 发表时间: 2022-05
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Marsango, Sara;Ward, Richard J.;Jenkins, Laura;Butcher, Adrian J.;Al Mahmud, Zobaer;Dwomoh, Louis;Nagel, Falko;Schulz, Stefan;Tikhonova, Irina G.;Tobin, Andrew B.;Milligan, Graeme
• 通讯作者: Milligan, Graeme

Discovery and Characterization of Novel Antagonists of the Proinflammatory Orphan Receptor GPR84.

• DOI: 10.1021/acsptsci.1c00151
• 发表时间: 2021-10-08
• 期刊: ACS pharmacology & translational science
• 作者: Jenkins L;Marsango S;Mancini S;Mahmud ZA;Morrison A;McElroy SP;Bennett KA;Barnes M;Tobin AB;Tikhonova IG;Milligan G
• 通讯作者: Milligan G

Understanding Probe Dependency of an Allosteric Site at the Dopamine D2 Receptor

了解多巴胺 D2 受体变构位点的探针依赖性

• DOI: 10.22541/au.167766532.26342619/v1
• 发表时间: 2023
• 作者: Gill A