Synthetic Chemistry

CTT的药物发现和合成化学核心将利用MUSC药物发现中心（DDC）的资源来支持CTT COBRE中的所有四个项目。DDC的目的是促进学术药物发现工作，为提交新药研究申请准备新的化学实体，并将基础研究成果转化为临床。DDC表征了学院研究人员发现的生物靶点；识别，合成和优化先导化合物，并进行体外和体内研究，以支持IND应用。DDC与学院研究人员密切合作，开发高通量分析方法，并保持5万种化合物的商业收集，用于这些分析中进行测试。该中心进行实际的筛选过程，并使用内部计算方法分析数据。通过这一过程鉴定的新化合物可以被合成，并且由此产生的合成途径用于生产具有最佳功效和药代动力学特征的类似物。然后，DDC可以扩大优化化合物的规模，用于高级临床前研究。DDC与整个MUSC和附属大学的相关核心设施合作，并最终利用MUSC校园内可用的临床试验网络。该中心还在整个区域推广，期望制药公司和小型生物技术公司将利用DDC药物开发设施进行筛选，药物化学或药代动力学分析。DDSC核心将追求以下具体目标：1)通过设计潜在目标分子的从头合成，为本COBRE申请中描述的项目提供合成化学支持，并利用这些合成路线引入化学多样性，以实现先导物优化（项目1-4）；2)为活性化合物的新发现和系列衍生物的筛选提供快速、自动化的筛选服务。将提供大型商业库的一般筛选和化学相关同系物的重点筛选（项目1-3）；3)为本提案中描述的所有药物发现工作提供计算机支持。这将包括通过对可公开获得的小分子、可药物分子数据库的虚拟筛选来产生先导物，并分析药物/生物分子相互作用，以建议合理的结构变化，从而增强活性。项目2和项目3将立即利用这些服务。

The Drug Discovery and Synthetic Chemistry Core of the CTT will take advantage of the resources of the MUSC Drug Discovery Center (DDC) to support all four projects in the CTT COBRE. The purpose of the DDC is to facilitate academic drug discovery efforts, to prepare new chemical entities for submission of an Investigational New Drug application, and to translate basic research results into the clinic. The DDC characterizes biological targets discovered by faculty researchers; identifies, synthesizes and optimizes lead compounds, and performs in vitro and in vivo studies that will support an IND application. The DDC closely collaborates with faculty researchers to develop high-throughput assays, and maintains a commercial collection of 50,000 compounds to be tested in these assays. The center conducts the actual screening process and analyzes data using in-house computational methods. Novel compounds identified through this process can be synthesized, and the resulting synthetic pathway used to produce analogues that have optimal efficacy and pharmacokinetic profiles. The DDC can then scale up optimized compounds for advanced pre-clinical studies. The DDC works with associated core facilities throughout MUSC and affiliated universities, and ultimately makes use of the clinical trial network available on the MUSC campus. The Center is also promoted throughout the region, with the expectation that pharmaceutical companies and small biotech companies will make use of the DDC drug development facility for screening, medicinal chemistry or pharmacokinetic analysis. The DDSC Core will pursue the following Specific Aims: 1) to provide synthetic chemistry support to the projects described in this COBRE application by designing de novo syntheses for potential target molecules, and to use these synthetic routes to introduce chemical diversity with the goal of lead optimization (Projects 1-4); 2) to provide rapid, automated screening services for de novo discovery of active compounds and screening of serial derivatives. Both general screens of a large commercial library and focused screens of chemically related congeners will be available (Projects 1-3); 3) to provide in silico support for all drug discovery efforts described in this proposal. This will include lead generation through virtual screening of publicly available databases of small, druggable molecules, and analysis of drug/biomolecular interactions to suggest rational structural changes that will enhance activity. Projects 2 and 3 will take immediate advantage of these services.