GBR DOPAMINE TRANSPORTER BINDING:PHARMACOPHORE MODELING

GBR 多巴胺转运蛋白结合：药效团建模

• 批准号: 6748849
• 负责人: KATHLEEN M GILBERT
• 金额: $ 0.1万
• 依托单位: NEW JERSEY INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-24 至 2005-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6748849
• 关键词: binding sites; chemical models; chemical structure function; dopamine transporter; drug vehicle; model design /development; molecular dynamics; piperazines; predoctoral investigator

DESCRIPTION (provided by applicant): Cocaine addiction is a problem in the U.S. and around the world. Initial research into the abuse of cocaine revealed its addictive effects on the human body. Cocaine's addictive effects are thought to be related to its binding to several neurotransrnitter transporters, especially the dopamine transporter (DAT) Cocaine is a doparnine reuptake inhibitor which causes less dopamine to be taken up by the DAT. The GBR series of dialkyl piperazines have been identified as selective dopamine uptake inhibitors that could be used to treat cocaine addiction. These compounds have been explored in the laboratory using traditional structure-activity relationship techniques, but pharmacophore development using molecular modeling methods have not been performed on them.The proposed research is a comprehensive molecular modeling study of 300 GBR analogs. The purpose of the study is to identify two pharmacophores: one for the DAT binding site and one for dopamine uptake at the DAT. The pharmacophores will be developed using a Comparative Molecular Field Analysis (CoMFA) study performed in vacuum, and the results refined by repeating the study in solvent. The Partial Least Squares method will be used to model the CoMFA results versus the binding and reuptake data. A bioactive conformer will be selected based on the most predictive model, then used as the basis for the pharmacophores

描述（申请人提供）：可卡因成瘾是美国和世界各地的一个问题。对滥用可卡因的最初研究揭示了其对人体的上瘾作用。可卡因的成瘾作用被认为与其与多种神经释放蛋白转运蛋白的结合有关，尤其是多巴胺转运蛋白（DAT） 可卡因是一种多丙宁再摄取抑制剂，导致DAT吸收的多巴胺较少。 GBR系列的二烷基哌嗪已被确定为可用于治疗可卡因成瘾的选择性多巴胺摄取抑制剂。这些化合物已经在实验室中使用了传统的结构 - 活性关系技术进行了探索，但是使用分子建模方法进行了药效团的开发。拟议的研究是对300种GBR类似物的全面分子建模研究。 该研究的目的是识别两个药物归因：一个用于DAT结合位点，一个用于DAT的多巴胺摄取。将使用在真空中进行的比较分子场分析（COMFA）研究来开发药效团，并通过在溶剂中重复研究来完善结果。部分最小二乘方法将用于对COMFA结果进行建模与结合和再摄取数据。将基于最预测的模型选择生物活性构象体，然后用作药算术的基础