Cheminformatics of Allosteric mGluR Modulation promotes Therapeutic Development

变构 mGluR 调节的化学信息学促进治疗发展

基本信息

批准号：
8055043
负责人：
Jens Meiler
金额：
$ 38.5万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-02 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8055043
关键词：
Algorithms Allosteric Site Benchmarking Biological Blood - brain barrier anatomy Brain Central Nervous System Diseases Chemical Structure Chemicals Chemistry Chemosensitization Cognitive Collaborations Complex Computer Simulation Computer software Computing Methodologies Consensus Databases Descriptor Development Disease Education Electronics Fragile X Syndrome G Protein-Coupled Receptor Genes Generations Hand Humulus Internet Lead Libraries Licensing Ligands Machine Learning Maps Membrane Proteins Mental disorders Metabotropic Glutamate Receptors Methods Modeling Molecular Molecular Bank Pharmaceutical Preparations Pharmacology Quantitative Structure-Activity Relationship Research Research Project Grants Scheme Schizophrenia Screening procedure Site Structure Symptoms Techniques Testing Therapeutic United States National Institutes of Health Universities Walking Work autism spectrum disorder base chemical synthesis cheminformatics cognitive function comparative design drug discovery experience high throughput screening nervous system disorder novel pharmacophore programs public health relevance research study scaffold therapeutic development therapeutic target tool treatment strategy virtual

项目摘要

DESCRIPTION (provided by applicant): Selective potentiators of the metabotropic glutamate receptor subtype mGluR5 have exciting potential for development of novel treatment strategies for schizophrenia and other disorders that disrupt cognitive func-tion. The latest generation of selective mGluR5 potentiators is based on the lead compound CDPPB and features systemically active compounds with long half-lives that cross the blood-brain barrier. A high-throughput screen (HTS) for mGluR5 potentiators at Vanderbilt's screening center revealed a large and diverse set of about 1400 substances (1% hit rate) whose activity was validated in independent experiments. A previous exploratory research grant "Novel Schizophrenia Therapeutics by Virtual High-Throughput Screening" (R21 MH082254) enabled testing of 813 compounds predicted through cheminformatics. 252 of these compounds were confirmed as active PAMs equaling an enrichment of >30 when compared with the original screen. The present proposal seeks to leverage these proof-of-principle results for the development of a tailored cheminformatics framework for drug discovery of allosteric modulators of brain GPCRs, apply these tools to inform an existing therapeutic discovery program of mGluR5 potentiators at Vanderbilt University, and disseminate the methods broadly through the NIH molecular libraries program. The central hypothesis of this proposal is that the complex relationship between chemical structure and biological activity of mGluR5 potentiators observed in this HTS can be used to generate a pharmacophore of the mGluR5 allosteric site. This map of steric and electronic features necessary for optimal interaction of modulators with mGluR5 will not only inform our understanding of the allosteric modulation of brain GPCRs. The methods proposed overcome limitations of present cheminformatics techniques by enabling identification of novel chemotypes through virtual screening (scaffold hoping), and allowing design of focused libraries in hit-to- lead optimization of novel schizophrenia therapeutics. The generalizbility of the approach will be tested through application on negative modulators of mGluR5, a potential novel treatment strategy of fragile X syndrome, a CNS disorder associated with autism spectrum disorders (ASD) among multiple other symptoms. The developed applications will be made freely and readily accessible for academic research. The employed QSAR models require no crystal structure of the target brain GPCR. Hence the method can be readily applied to membrane proteins-such as GPCRs-which are target of 40-50% of modern medicinal drugs. PUBLIC HEALTH RELEVANCE: Ligands for specific mGluR subtypes have potential for treatment of a wide variety of neurological and psychiatric disorders. We will use computational methods identify potentiators of mGluR5, compounds that have exciting potential as treatment strategy for schizophrenia. In silico hit compounds will be experimentally validated and enter hit-to-lead optimization.

描述（由申请人提供）：代谢性谷氨酸受体亚型MGLUR5的选择性增强剂具有令人兴奋的潜力，可以为精神分裂症和其他破坏认知功能的疾病的新型治疗策略发展。最新一代的选择性MGLUR5降低器基于铅化合物CDPPB，并具有横穿血脑屏障的长半衰期具有系统活跃的化合物。 Vanderbilt筛查中心的MGLUR5电位器的高通量屏幕（HTS）显示，在独立实验中验证了一组大约1400种物质（1％的命中率）。先前的探索性研究授予“通过虚拟高通量筛查的新型精神分裂症治疗”（R21 MH082254）实现了通过化学形式预测的813种化合物的测试。与原始屏幕相比，这些化合物中的252种被证实为活性PAM，相当于富集> 30。本提案旨在利用这些原则证明结果来开发用于发现脑GPCR的变构型调制器的量身定制的化学形式框架，应用这些工具来告知范德比尔特大学的MGLUR5增强剂的现有治疗性发现计划，并通过NIH IH Irecular Ibleraliral Ibleriles Programs将方法传播出来。该提议的中心假设是，在本HTS中观察到的MGLUR5增强剂的化学结构与生物学活性之间的复杂关系可用于生成MGLUR5变构位点的药理。这张用于调制器与MGLUR5最佳相互作用所必需的空间和电子特征图不仅可以告知我们对脑GPCR的变构调节的理解。这些方法提出的方法通过通过虚拟筛选（脚手架希望）鉴定新的化学型来克服当前化学信息学技术的局限性，并允许设计集中的库以对新型精神分裂症治疗剂的命中率优化。该方法的普遍性将通过对MGLUR5的负调节剂的应用进行测试，MGLUR5是一种潜在的脆弱X综合征的新型治疗策略，这是一种与自闭症谱系障碍（ASD）相关的中枢神经系统疾病。开发的应用程序将自由且容易访问以进行学术研究。使用的QSAR模型不需要目标脑GPCR的晶体结构。因此，该方法可以很容易地应用于膜蛋白（例如GPCR），而GPCR是40-50％的现代药用药物的靶标。公共卫生相关性：特定MGLUR亚型的配体具有治疗多种神经和精神疾病的潜力。我们将使用计算方法识别MGLUR5的增强剂，这些化合物具有令人兴奋的精神分裂症治疗策略。在计算机上，命中化合物将经过实验验证，并输入命中至铅优化。