Cheminformatics of Allosteric mGluR Modulation promotes Therapeutic Development

描述（由申请人提供）：代谢性谷氨酸受体亚型mGluR5的选择性增强剂在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方面具有令人兴奋的潜力。最新一代的选择性mGluR5增强剂是基于先导化合物CDPPB，具有半衰期长的系统活性化合物，可以穿过血脑屏障。Vanderbilt筛选中心对mGluR5增强剂进行了高通量筛选（HTS），发现了大约1400种物质（1%的命中率），其活性在独立实验中得到了验证。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方法”（R21 MH082254）使通过化学信息学预测的813种化合物得以测试。其中252个化合物被证实为活性PAMs，与原始筛选相比，富集了bbb30。目前的提案旨在利用这些原理证明结果来开发一个量身定制的化学信息学框架，用于脑gpcr变构调节剂的药物发现，将这些工具应用于范德比尔特大学现有的mGluR5增强剂的治疗发现项目，并通过NIH分子文库项目广泛传播这些方法。本研究的中心假设是，在HTS中观察到的mGluR5增强剂的化学结构和生物活性之间的复杂关系可以用来产生mGluR5变构位点的药效团。这张空间和电子特征图是调制剂与mGluR5最佳相互作用所必需的，它不仅将告诉我们对脑gpcr的变构调节的理解。提出的方法克服了现有化学信息学技术的局限性，通过虚拟筛选（scaffold希望）能够识别新的化学型，并允许在新型精神分裂症治疗方法的hit- lead优化中设计重点文库。该方法的普遍性将通过应用于mGluR5的负调节剂来测试，mGluR5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）相关的中枢神经系统疾病，以及多种其他症状。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，如gpcr，这是40-50%的现代药物的目标。

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.