Molecular modeling of G protein-coupled receptors

在本财政年度期间，我们致力于以下各段所述的GPCR制。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。 腺苷受体。腺苷受体广泛表达于人体的几个器官，在心脏、肺、血管和血小板中发挥重要的生理功能。 毒鼠碱受体。M受体是一个受乙酰胆碱刺激的GPCRs家族。M受体的配体被大量用于治疗各种疾病，包括帕金森氏病。 P2Y受体。P2Y受体是由胞外核苷酸激活的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，在本财政年度，我们进行了研究，并取得了以下各段所述的成果。 1)完成并发表了一项关于β2-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来指导筛选以识别激动剂或阻滞剂。 2)最终确定并发布了一项旨在通过计算将肾上腺素能受体的配体分类为激动剂和阻滞剂的策略。值得注意的是，这项研究还为激动剂结合的机制提供了一个有洞察力的观点。 3)研究了使用β2肾上腺素能受体的非活性结构和激活结构在电子筛选激动剂或阻滞剂中的意义。 4)明确了P2Y1受体的激活对前列腺癌细胞增殖的抑制作用。实验合作者：Kenneth A.Jacobson(NIDDK)。 5)发现了新的P2Y4受体配体。实验合作者：Kenneth A.Jacobson(NIDDK)。 6)综述了嘌呤能受体参与血小板聚集的研究进展。合作者：Kenneth A.Jacobson(NIDDK)。 7)研究了M_3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)对构建和验证G蛋白偶联受体同源模型的最有效技术进行了综述。 9)对结合使用基于配体和基于对接的技术预测生物活动进行了审查。 10)继续与Carson C.Chow(NIDDK)合作进行生物信息学研究，旨在揭示GPCR超家族的进化。

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.