Neuroleptic Spacer Length Governs Molecular Recognition

描述（由申请方提供）：本提案的主要目的是鉴定和表征具有抗精神病活性或潜在抗注意缺陷多动障碍（ADHD）活性的药物与其G蛋白偶联受体（GPCR）靶标之间相互作用的最关键分子位点。我们的目标是实现的分子机制的激动剂的选择性激活，和反向激动剂的失活，以及中性拮抗剂，选择性地结合到D2和D4受体的判别结构特征的理解，这是用于治疗神经精神疾病的药物的目标。为了实现这些目标，分子建模技术已被用来预测受体微区，可能是相互作用的选择性和非选择性激动剂和拮抗剂，对接到视紫红质为基础的模型多巴胺D2和D4受体。从这些模型的推论将与受体微区的点突变，似乎是负责的功能相互作用进行探测。在迭代研究中，配体的结合和功能特性将在计算和实验方案的组合中确定，以测试突变体和野生型受体构建体中基于特定结构的假设，并将其与功能结果联系起来。结果将被解释为新的推定的治疗药物的设计有用的指南。拟议的研究将按照以下四个相互关联的具体目标进行：1）在多巴胺D2和D4 GPCR的基于视紫红质的模型的结构背景下利用关于高亲和力配体的结构信息，以便区分受体微结构域和与配体的激动剂活性相对于拮抗剂活性相关的配体结合模式，2.）基于在鉴定的受体微结构域内的不同结合和相互作用模式，表征配体的结构与它们激活或抑制多巴胺D2和D4受体的能力相关的方式，3.）以确定某些对多巴胺受体的D4亚型具有非常高的选择性的芳香族1，4-二取代哌嗪配体是否与一组共同的受体微结构域相互作用，以及4.）应用多巴胺受体微区中配体相互作用的分子模型和受体活化模式的组合，通过实验测试来探测预测对D2和D4受体具有特定作用的新配体。

DESCRIPTION (provided by applicant): The broad objective of this proposal is to identify and characterize the most critical molecular sites of interaction between drugs with antipsychotic activity, or potential anti-attention deficit hyperactivity disorder (ADHD) activity, and their G protein-coupled receptor (GPCR) targets. We aim to achieve an understanding of the molecular mechanisms of selective activation by agonists, and inactivation by inverse agonists, as well as the discriminant structural features of neutral antagonists that selectively bind to the D2 and D4 receptors and that are the targets for the drugs used to treat neuropsychiatric disorders. To achieve these objectives, molecular modeling techniques have been employed to predict receptor microdomains that might be interacting with selective and nonselective agonists and antagonists that were docked into rhodopsin-based models of dopamine D2 and D4 receptors. The inferences from these models will be probed with point mutations of the receptor microdomains that appear to be responsible for the functional interactions. In iterative studies, the binding and functional properties of the ligands will be determined in combinedcomputational and experimental protocols to test specific structure-based hypotheses in the mutant and wild type receptor constructs and to relate them to functional outcomes. The results will be interpreted as useful guides for the design of new putative therapeutic agents. The proposed studies will proceed as described in the following series of four interrelated specific aims: 1.) to utilize structural information about high affinity ligands in the structural context ofrhodopsin-based models for dopamine D2 and D4 GPCRs, in order to discriminate receptor microdomains and modes of ligand binding in relation to the agonist versus the antagonist activity of the ligands, 2.) to characterize the manner in which the structures of the ligands relate totheir ability to activate or inactivate dopamine D2 and D4 receptors based on different modes of binding and interaction within identified receptor microdomains, 3.) to determine if certain aromatic 1,4-disubstitutedpiperizine ligands that share an extraordinarily high selectivity for the D4 subtype of dopamine receptor are interacting with a common set of receptor microdomains, and 4.) to apply the combination of molecular models of ligand interaction in dopaminc receptor microdomains and modes of receptor activation, with experimental testing to probe new ligands predicted to have specified effects on D2 and D4 receptors.