Neuroleptic Spacer Length Governs Molecular Recognition

描述(由申请人提供)：这项提案的广泛目标是识别和表征具有抗精神病活性或潜在的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的分子位点。我们的目标是了解激动剂选择性激活和反向激动剂失活的分子机制，以及中性拮抗剂选择性结合D2和D4受体的鉴别结构特征，这些拮抗剂是用于治疗神经精神疾病的药物的靶标。为了实现这些目标，分子建模技术被用来预测可能与选择性和非选择性激动剂和拮抗剂相互作用的受体微域，这些激动剂和拮抗剂对接到基于视紫红质的多巴胺D2和D4受体模型中。这些模型的推论将通过受体微域的点突变进行探索，这些微域似乎负责功能相互作用。在迭代研究中，配体的结合和功能性质将通过计算和实验相结合的方案来确定，以测试突变型和野生型受体结构中基于特定结构的假设，并将它们与功能结果联系起来。这些结果将被解释为设计新的假定治疗药物的有用指南。拟议的研究将按照以下四个相互关联的具体目标系列所述进行：在基于视紫红质的多巴胺D2和D4 GPCRs模型的结构背景下，利用高亲和力配体的结构信息，以区分受体微域和配体结合方式与激动剂和配体的拮抗剂活性之间的关系，2.表征配体的结构与其激活或失活多巴胺D2和D4受体的能力相关的方式，基于所识别的受体微域内的不同结合和相互作用模式，3)为了确定某些芳香的1，4-二取代哌嗪配体是否与一组共同的受体微域相互作用，这些配体对D4亚型的多巴胺受体具有非常高的选择性。将多巴胺受体微区中配体相互作用的分子模型和受体激活模式与实验测试相结合，以探索预测对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.