Cheminformatics of Allosteric mGluR Modulation promotes Therapeutic Development

描述(申请人提供)：代谢型谷氨酸受体亚型mGluR5的选择性增强剂具有开发精神分裂症和其他扰乱认知功能的障碍的新治疗策略的令人兴奋的潜力。最新一代的选择性mGluR5增强剂是以先导化合物CDPPB为基础的，具有系统活性的化合物具有较长的半衰期，可以穿越血脑屏障。Vanderbilt筛选中心的mGluR5增强剂高通量筛选(HTS)显示了一组约1400种物质(命中率为1%)的大而多样的集合，其活性在独立实验中得到了验证。先前的一项探索性研究拨款“通过虚拟高通量筛选的新型精神分裂症治疗药物”(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个化合物被确认为活性PAM，与原始筛选相比相当于&gt；30的浓缩。本提案旨在利用这些原则验证结果来开发用于脑GPCRs变构调节剂药物发现的定制化学信息学框架，将这些工具应用于为范德比尔特大学现有的mGluR5增强剂的治疗发现计划提供信息，并通过NIH分子图书馆计划广泛传播这些方法。这一建议的中心假设是，在该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。这张调节剂与mGluR5最佳相互作用所需的空间和电子特征图不仅将使我们了解大脑GPCRs的变构调制。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)识别新的化学类型，并允许在新的精神分裂症治疗药物的点击到领先的优化中设计集中的文库。该方法的普适性将通过应用mGluR5的负调制子来测试，mGluR5是一种潜在的治疗脆性X综合征的新策略，脆性X综合征是一种与自闭症谱系障碍(ASD)等多种症状相关的中枢神经系统障碍。开发的应用程序将免费提供给学术研究人员使用。所采用的定量构效关系模型不需要目标脑GPCR的晶体结构。因此，该方法可以很容易地应用于膜蛋白--如GPCRs--现代药物中40%-50%的靶标。

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.