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Molecular modeling of G protein-coupled receptors

G 蛋白偶联受体的分子建模

基本信息

批准号：
8553366
负责人：
Arthur Sherman
金额：
$ 6.21万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/8553366
关键词：
3-Dimensional Acetylcholine Adenosine A2A Receptor Adrenergic Receptor Agonist Arrhythmia Asthma Binding Bioinformatics Biological Cattle Cell membrane Chemicals Collaborations Complex Computer Assisted Computer Simulation Computing Methodologies Crystallization Databases Detection Development Discipline Docking Drug Design Evaluation Event Family Family Study Fibrinolytic Agents G-Protein-Coupled Receptors Heart Homology Modeling Laboratories Lead Left Ligands Literature Marketing Membrane Proteins Modeling Modification Molecular Molecular Evolution Molecular Models Molecular Structure Molecular Weight Muscarinic Acetylcholine Receptor Muscarinic Acetylcholine Receptor M3 Mutagenesis Names National Institute of Diabetes and Digestive and Kidney Diseases North Carolina Nucleotides Parkinson Disease Pharmaceutical Preparations Pharmacologic Substance Phylogenetic Analysis Physiology Play Positioning Attribute Publishing Quantitative Structure-Activity Relationship Research Resources Rhodopsin Role Screening procedure Smooth Muscle Stimulus Structure Structure-Activity Relationship System Techniques Testing Time Transmembrane Domain United States National Institutes of Health Universities Work X-Ray Crystallography beta-adrenergic receptor blind cheminformatics computer studies dimer drug discovery extracellular hypertension treatment improved interest molecular dynamics molecular modeling novel polypeptide purinoceptor P2Y1 receptor research study virtual

项目摘要

G protein-coupled receptors (GPCRs) are a large superfamily of membrane proteins, which act as cellular receivers for extracellular stimuli. GPCRs hold great pharmaceutical interest, given the fact than they are the target of a very large percentage of the drugs currently on the market. From the structural point of view, they consist of a single polypeptide chain that crosses seven times the cell membrane, hence the alternative name of seven transmembrane-spanning receptors. Since crystal structures are available only for bovine rhodopsin, the beta-adrenergic receptors, and the adenosine A2A receptor in the GPCR family, the study of the other receptors heavily relies on homology modeling and docking experiments conducted in an iterative manner with mutagenesis experiments and chemical modification of the ligands. A key focus of this project is GPCR modeling of ligand docking. My models of the adenosine A2A receptors with a bound antagonist were judged the most accurate in a blind assessment organized in coordination with the crystallization of this complex, definitely positioning us at the forefront of the field. My main activities at NIDDK, before leaving NIH on June 1st 2012, concerned the computational study of the structure-function relationships of GPCRs and the identification of low molecular weight compounds capable of modulating their activity through computer-assisted drug discovery (CADD). The latter embodies an ensemble of disciplines and techniques directed toward the rational identification of novel and diverse ligands for biological targets of pharmaceutical interest. Aiming at the structural characterization of the receptors and at lead identification and optimization, I utilized the most advanced techniques in 3-D molecular modeling, bioinformatics, and cheminformatics, some of which are: sequence and phylogenetic analyses, homology modeling, ligand docking, molecular dynamics, QSAR analyses, and virtual screenings. The latter allows a quick virtual evaluation of large databases of compounds in the quest for novel and diverse leads. Only a limited number of compounds are purchased and experimentally evaluated, with a conspicuous saving of time and economical and environmental resources. To achieve our drug discovery objectives and further the field of molecular modeling, I actively developed, improved, and tested novel computational methodologies and research strategies. I operated in strict collaboration with experimental medicinal chemists, molecular pharmacologists, and biologists. In the course of this year, before leaving NIH on June 1st 2012, I 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. Muscarinic receptors. The muscarinic receptors are a family of GPCRs stimulated by acetylcholine. Ligands of the muscarinic receptors are widely 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 year, I conducted the research and accomplished the results described in the following paragraphs. 1) Studied the Structural aspects of M3 muscarinic acetylcholine receptor dimer formation and activation. Experimental collaborator: Jrgen Wess (NIDDK). 2) Finalized and published a virtual screening for ligands of the P2Y1 receptor. Notably, we identified novel non-nucleotide receptor antagonists. Experimental collaborators: Kenneth A. Jacobson (NIDDK), T. Kendall Harden (University of North Carolina). 3) Finalized and published a review article on the homology modeling of G protein-coupled receptors. 4) Finalized and published an article on the implications of the use of inactive and activated structures of the beta2 adrenergic receptor on the in silico screening for agonists or blockers. 5) Studied and published an article on the molecular evolution of the transmembrane domains of G protein-coupled receptors. Experimental collaborator: Carson Chow (NIDDK). 6) Reviewed advances in X-ray crystallography of G protein-coupled receptors and their implication for drug design. 7) Within the field of drug discovery, beyond the field of G protein-coupled receptors, I also worked on a model for the detection of adverse drug events in pharmacovigilance databases using molecular structure similarity.

G蛋白偶联受体(GPCRs)是一个膜蛋白超家族，是细胞内对细胞外刺激的受体。GPCRs拥有巨大的医药利益，因为它们是目前市场上非常大比例药物的靶标。从结构上看，它们由一个跨越细胞膜七倍的多肽链组成，因此又被称为七个跨膜受体。由于晶体结构只适用于牛视紫红质、β-肾上腺素能受体和腺苷A2a受体，因此对其他受体的研究在很大程度上依赖于同源建模和对接实验，并以迭代的方式进行诱变实验和配体的化学修饰。该项目的一个关键焦点是配体对接的GPCR建模。在与这种复合体的结晶相协调的盲目评估中，我的腺苷A2A受体与结合拮抗剂的模型被认为是最准确的，这无疑将我们定位在该领域的前沿。在2012年6月1日离开NIH之前，我在NIDDK的主要活动涉及对GPCRs结构-功能关系的计算研究，以及识别能够通过计算机辅助药物发现(CADD)调节其活性的低分子化合物。后者体现了一系列的学科和技术，旨在合理地识别具有药用价值的生物靶标的新的和多样化的配体。针对受体的结构特征和先导识别和优化，我利用了三维分子建模、生物信息学和化学信息学中最先进的技术，其中包括：序列和系统发育分析、同源建模、配体对接、分子动力学、QSAR分析和虚拟筛选。后者允许对化合物的大型数据库进行快速虚拟评估，以寻找新的和多样化的线索。只购买了有限数量的化合物并进行了实验评估，显著节省了时间和经济和环境资源。为了实现我们的药物发现目标和进一步的分子建模领域，我积极开发、改进和测试新的计算方法和研究策略。我与实验药物化学家、分子药理学家和生物学家密切合作。今年，在2012年6月1日离开美国国立卫生研究院之前，我研究了下面几段所述的GPCR系统。其中一些系统在文献中有很好的特征，其中可以找到丰富的信息，包括实验得出的结构。因此，它们构成了开发随后适用于整个超级家族的计算方法的理想平台。相反，其他系统的特性不那么好，但构成了药物制剂发展的有吸引力的目标。 β肾上腺素能受体。β-肾上腺素能受体(β-AR)主要存在于平滑的肌肉中，在心脏和呼吸道的生理中起着至关重要的作用。β-受体拮抗剂被广泛用于各种适应症，特别是治疗高血压和心律失常。β2-AR激动剂在临床上用于哮喘的治疗。毒鼠碱受体。M受体是一个受乙酰胆碱刺激的GPCRs家族。M受体的配体被广泛用于治疗各种疾病，包括帕金森氏病。 P2Y受体。P2Y受体是被细胞外核苷酸激活的GPCRs。值得注意的是，P2Y12受体的拮抗剂被广泛用作抗血栓药。特别是，在这一年里，我进行了研究，并取得了以下几段所述的成果。 1)研究了M3乙酰胆碱受体二聚体的形成和激活的结构。实验合作者：Jrgen Wess(NIDDK)。 2)最终确定并发布了一份关于P2Y1受体配体的虚拟筛选。值得注意的是，我们发现了新的非核苷酸受体拮抗剂。实验合作者：Kenneth A.Jacobson(NIDDK)、T.Kendall Harden(北卡罗来纳大学)。 3)完成并发表了一篇关于G蛋白偶联受体同源模型的综述文章。 4)完成并发表了一篇关于使用β2肾上腺素能受体的非活性和激活结构对电子筛查激动剂或阻滞剂的影响的文章。 5)研究并发表了一篇关于G蛋白偶联受体跨膜区的分子进化的文章。实验合作者：Carson Chow(NIDDK)。 6)综述了G蛋白偶联受体的X射线结晶学研究进展及其对药物设计的意义。 7)在药物发现领域，除了G蛋白偶联受体领域，我还研究了一个利用分子结构相似性在药物警戒数据库中检测不良药物事件的模型。