Molecular modeling of G protein-coupled receptors

G 蛋白偶联受体的分子建模

• 批准号: 8349643
• 负责人: Stefano Costanzi
• 金额: $ 16.04万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8349643
• 关键词: 3-Dimensional; Acetylcholine; Adenosine A2A Receptor; Adrenergic Receptor; Agonist; Arrhythmia; Asthma; Binding; Bioinformatics; Biological; Blood Platelets; Blood Vessels; Cattle; Cell membrane; Chemicals; Collaborations; Complex; Computer Assisted; Computer Simulation; Computing Methodologies; Crystallization; Databases; Development; Discipline; Docking; Evaluation; Evolution; Family; Family Study; Fibrinolytic Agents; G-Protein-Coupled Receptors; Heart; Homology Modeling; Human body; Laboratories; Lead; Ligands; Light; Literature; Lung; Malignant neoplasm of prostate; Marketing; Mediating; Membrane Proteins; Modeling; Modification; Molecular; Molecular Models; Molecular Weight; Muscarinic Acetylcholine Receptor; Muscarinic M3 Receptor; Mutagenesis; Names; National Institute of Diabetes and Digestive and Kidney Diseases; Nucleotides; Organ; Parkinson Disease; Pharmaceutical Preparations; Pharmacologic Substance; Phylogenetic Analysis; Physiological; Physiology; Platelet aggregation; Play; Positioning Attribute; Publishing; Purinergic P1 Receptors; Purinoceptor; Quantitative Structure-Activity Relationship; Research; Resources; Rhodopsin; Role; Screening procedure; Smooth Muscle; Stimulus; Structure; Structure-Activity Relationship; System; Techniques; Testing; Time; Validation; Work; base; beta-adrenergic receptor; blind; cancer cell; cheminformatics; computer studies; dimer; drug discovery; extracellular; hypertension treatment; improved; interest; molecular dynamics; molecular modeling; novel; polypeptide; purinoceptor P2Y1; purinoceptor P2Y4; receptor; research study; virtual

In the course of this fiscal year, we have worked on the GPCR systems described in the following paragraphs. Some of these systems are very well characterized in the literature, where a wealth of information, including experimentally derived structures, can be found. Thus, they constitute an ideal platform for the development of computational methodologies subsequently applicable to the whole superfamily. Conversely, other systems are less well characterized, but constitute attractive targets for the development of pharmaceutical agents. Beta-adrenergic receptors. The beta-adrenergic receptors (beta-ARs) reside predominantly in smooth muscles and play crucial roles in the physiology of heart and airways. Antagonists of the beta-ARs are widely used for various indications, particularly the treatment of hypertension and cardiac arrhythmias. Agonists of the beta2-AR are clinically used in the treatment of asthma. Adenosine receptors. The adenosine receptors are widely expressed in several organs of the human body, and mediate important physiological functions in the heart, lungs, blood vessels, and platelets. Muscarinic receptors. The muscarinic receptors are a family of GPCRs stimulated by acetylcholine. Ligands of the muscarinic receptors are amply used for the treatment of a variety of conditions, including Parkinsons disease. P2Y receptors. P2Y receptors are GPCRs activated by extracellular nucleotides. Of note, antagonists of the P2Y12 receptor are amply used as antithrombotic agents. In particular, during this fiscal year, we have conducted the research and accomplished the results described in the following paragraphs. 1) Finalized and published a controlled a posteriori virtual screening for beta2-adrenergic receptors ligands. Notably, we devised a way of steering the screening towards the identification of agonists or blockers. 2) Finalized and published a strategy intended to computationally classify ligands of the adrenergic receptors into agonists and blockers. Notably, the study furnished also an insightful view into the mechanism of agonist binding. 3) Studied the implications of the use of inactive and activated structures of the beta2 adrenergic receptor on the in silico screening for agonists or blockers. 4) Identified the inhibitory effect of the activation of the P2Y1 receptor on the proliferation of prostate cancer cells. Experimental collaborator: Kenneth A. Jacobson (NIDDK). 5) Identified novel ligands of the P2Y4 receptor. Experimental collaborator: Kenneth A. Jacobson (NIDDK). 6) Reviewed the involvement of purinergic receptors on platelet aggregation. Collaborator: Kenneth A. Jacobson (NIDDK). 7) Studied the structural bases underlying the formation of dimers and/or oligomers of the muscarinic M3 receptor. Experimental collaborator: Jrgen Wess (NIDDK). 8) Worked on a review of the most effective techniques for the construction and validation of homology models of G protein-coupled receptors. 9) Worked on a review on the combined use of ligand-based and docking-based techniques for the prediction of biological activities. 10) Continued a bioinformatics study, in collaboration with Carson C. Chow (NIDDK), intended to shed light onto the evolution of the GPCR superfamily.

在本财政年度，我们致力于以下段落所述的气相化学还原系统。这些系统中的一些在文献中有很好的特征，在文献中可以找到丰富的信息，包括实验衍生的结构，因此，它们构成了一个理想的平台，用于发展随后适用于整个超家族的计算方法。相反，其他系统的特点不太好，但构成了有吸引力的目标，用于开发药物。 β-肾上腺素受体。β-肾上腺素能受体（β-AR）主要存在于平滑肌中，在心脏和气道的生理学中起着至关重要的作用。β-AR的拮抗剂广泛用于各种适应症，特别是治疗高血压和心律失常。β 2-AR激动剂在临床上用于治疗哮喘。 腺苷受体。腺苷受体在人体的几个器官中广泛表达，并介导心脏、肺、血管和血小板中的重要生理功能。 毒蕈碱受体。毒蕈碱受体是由乙酰胆碱刺激的GPCR家族。毒蕈碱受体的配体被广泛用于治疗各种病症，包括帕金森病。 P2 Y受体。P2 Y受体是由细胞外核苷酸激活的GPCR。值得注意的是，P2 Y12受体的拮抗剂广泛用作抗血栓形成剂。 特别是在本财政年度，我们进行了研究，并取得了以下段落所述的成果。 1)完成并发表了β 2-肾上腺素能受体配体的受控后验虚拟筛选。值得注意的是，我们设计了一种方法，引导筛选对激动剂或阻滞剂的识别。 2)最终确定并发表了一项旨在通过计算将肾上腺素能受体配体分为激动剂和阻滞剂的策略。值得注意的是，该研究还提供了激动剂结合机制的深刻见解。 3)研究了使用β 2肾上腺素能受体的非活性和活化结构对激动剂或阻滞剂计算机筛选的影响。 4)鉴定P2 Y1受体活化对前列腺癌细胞增殖的抑制作用。实验合作者：Kenneth A. Jacobson（NIDDK）. 5)鉴定了P2 Y 4受体的新型配体。实验合作者：Kenneth A. Jacobson（NIDDK）. 6)综述了嘌呤受体对血小板聚集的影响。合作者：Kenneth A. Jacobson（NIDDK）. 7)研究了毒蕈碱M3受体二聚体和/或寡聚体形成的结构基础。实验合作者：Jrgen Wess（NIDDK）。 8)致力于审查用于构建和验证G蛋白偶联受体同源模型的最有效技术。 9)对结合使用基于配体和基于对接的技术预测生物活性进行了审查。 10)继续与卡森C. Chow（NIDDK），旨在揭示GPCR超家族的进化。