Cheminformatics of Allosteric mGluR Modulation promotes Therapeutic Development

描述（由申请人提供）：代谢型谷氨酸受体亚型mGluR 5的选择性增效剂具有开发精神分裂症和其他破坏认知功能的疾病的新治疗策略的令人兴奋的潜力。最新一代的选择性mGluR 5增效剂基于先导化合物CDPPB，其特点是具有穿过血脑屏障的长半衰期的全身活性化合物。在范德比尔特筛选中心进行的mGluR 5增效剂的高通量筛选（HTS）显示了一组大量且多样化的约1400种物质（命中率为1%），其活性在独立实验中得到验证。 先前的探索性研究资助“通过虚拟高通量筛选的新型精神分裂症治疗药物”（R21 MH 082254）能够测试通过化学信息学预测的813种化合物。这些化合物中的252种被确认为活性PAM，当与原始筛选相比时，相当于富集>30。本提案旨在利用这些原理验证结果来开发用于脑GPCR的变构调节剂的药物发现的定制化学信息学框架，应用这些工具来告知范德比尔特大学的mGluR 5增效剂的现有治疗发现计划，并通过NIH分子库计划广泛传播该方法。 该提议的中心假设是，在该HTS中观察到的mGluR 5增效剂的化学结构和生物活性之间的复杂关系可用于产生mGluR 5变构位点的药效团。这张图的空间和电子功能所需的最佳相互作用的调制器与mGluR 5不仅将告知我们的大脑GPCR的变构调制的理解。所提出的方法克服了目前化学信息学技术的局限性，通过虚拟筛选（支架希望），使新的化学型的鉴定，并允许设计集中的库中的命中到铅优化的新的精神分裂症治疗。 该方法的普遍性将通过应用于mGluR 5的负调节剂来测试，这是脆性X综合征的一种潜在的新治疗策略，脆性X综合征是一种与自闭症谱系障碍（ASD）相关的CNS疾病。开发的应用程序将免费提供给学术研究。所采用的QSAR模型不需要靶脑GPCR的晶体结构。因此，该方法可以很容易地应用于膜蛋白-如GPCR-这是40-50%的现代药物的目标。 公共卫生相关性：特定mGluR亚型的配体具有治疗各种神经和精神疾病的潜力。我们将使用计算方法确定mGluR 5的增效剂，这些化合物具有令人兴奋的潜力作为精神分裂症的治疗策略。将对计算机模拟命中化合物进行实验验证，并进入命中到铅的优化。

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.