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（GPCR）是膜蛋白的大型超家族，它是细胞外刺激的细胞接收器。鉴于事实，GPCR具有极大的药品兴趣，而不是目前市场上很大一部分药物的目标。从结构的角度来看，它们由一个单个多肽链组成，该链穿过细胞膜的七倍，因此是七个跨膜跨膜受体的替代名称。由于晶体结构仅适用于GPCR家族中的牛杜波蛋白，β-肾上腺素能受体和腺苷A2A受体，因此对其他受体的研究很大程度上依赖于同源性建模和对接实验，并以迭代方式进行了杂物化实验和化学修饰的效率。该项目的重点是配体对接的GPCR建模。我对具有结合拮抗剂的腺苷A2A受体的模型被认为是与这种复合物结晶组织的盲目评估中最准确的，这肯定会使我们处于该领域的最前沿。我在NIDDK的主要活动是在2012年6月1日离开NIH之前，涉及GPCR的结构功能关系的计算研究以及能够通过计算机辅助的药物发现（CADD）调节其活性的低分子量化合物的鉴定。后者体现了针对新型和多种配体的制药生物学靶标的合理鉴定的学科和技术的合奏。针对受体的结构表征以及铅识别和优化，我利用了3-D分子建模，生物信息信息和化学形式的最先进的技术，其中一些是：序列和系统发育分析，同源性模型，配体模型，分子动力学，QSAR分析和优质筛选。后者可以快速对化合物的大型数据库进行快速的虚拟评估，以追求新颖和多样化的铅。仅购买和实验评估的化合物数量有限，并节省了时间，经济和环境资源。为了实现我们的药物发现目标并进一步发展了分子建模的领域，我积极开发，改进和测试了新型的计算方法和研究策略。我严格与实验药物学家，分子药物学家和生物学家进行了严格合作。在今年的过程中，在2012年6月1日离开NIH之前，我研究了以下段落中描述的GPCR系统。其中一些系统在文献中非常有特征，其中可以找到大量信息，包括实验性衍生的结构。因此，它们构成了随后适用于整个超家族的计算方法的理想平台。相反，其他系统的特征较低，但构成了制定药物开发的有吸引力的目标。 β-肾上腺素受体。 β-肾上腺素能受体（Beta-ars）主要存在于平滑肌肉中，并在心脏和气道生理学中起着至关重要的作用。 Beta-AR的拮抗剂广泛用于各种适应症，尤其是高血压和心律不齐的治疗。 beta2-ar的激动剂在临床上用于治疗哮喘。毒蕈碱受体。毒蕈碱受体是乙酰胆碱刺激的GPCR家族。毒蕈碱受体的配体被广泛用于治疗包括帕金森氏病在内的各种疾病。 P2Y受体。 P2Y受体是由细胞外核苷酸激活的GPCR。值得注意的是，P2Y12受体的拮抗剂被充分用作抗血栓形成剂。特别是，在今年，我进行了研究，并完成了以下段落中描述的结果。 1）研究了M3毒蕈碱乙酰胆碱受体二聚体的形成和激活的结构方面。实验合作者：Jrgen Wess（NIDDK）。 2）最终确定并发布了P2Y1受体配体的虚拟筛选。值得注意的是，我们确定了新型的非核苷酸受体拮抗剂。实验合作者：Kenneth A. Jacobson（Niddk），T。KendallHarden（北卡罗来纳大学）。 3）完成并发表了有关G蛋白偶联受体的同源性建模的评论文章。 4）最终确定并发表了一篇文章，介绍了使用beta2肾上腺素能受体对激动剂或阻滞剂的硅酸盐筛选的使用的含义。 5）研究并发表了一篇有关G蛋白偶联受体跨膜结构域的分子进化的文章。实验合作者：Carson Chow（NIDDK）。 6）回顾了G蛋白偶联受体的X射线晶体学及其对药物设计的影响。 7）在药物发现领域，除了G蛋白偶联受体领域，我还使用分子结构相似性来检测药物守护数据库中不良药物事件的模型。