BUILDING COMPLEXITY INTO THE COMPUTER-AIDED DRUG DESIGN PIPELINE THROUGH

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 (A)目的 将核酸并入药物发现方法对于药物发现是至关重要的。 并且可以提供更有选择性的治疗剂， 阻力 这将提供深入了解分子识别在蛋白质-核酸 酸水平和治疗设计的替代机制。 然而， 有效和系统地将核酸包括在药物发现管道中， RNA的缺乏和结晶由于其固有的不稳定性而具有挑战性， 灵活性. 这个合作项目的目标是发展计算方法 为了系统地将核酸，特别是RNA掺入松弛的复合物中， 方案（RCS），并随后将这些新技术构建到我们的基于视觉的 计算机辅助药物发现（CADD）的管道工具。 开发一个系统的计算基础设施是我们的方法的核心。的 NBCR将开发的新的CADD管道基础设施将：（i）促进 精确和现实的模拟混合蛋白质-RNA生物分子系统， Vision工作流程工具，（ii）为这些模拟开发和提供分析工具，（iii） 提供一个系统的框架来分析和整合所得到的核酸 将结构信息导入RCS CADD管道。我们的实验合作者是 致力于测试我们的预测  无论是在生化分析方面， 最佳粘合剂的结构  这些调查的结果，这将 对验证我们的方法至关重要最终，RCS CADD工具能够 将开发基于RNA和杂合蛋白-核酸的药物靶标， 作为一种工具分发给更大的科学界。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. (A) OBJECTIVE The incorporation of nucleic acids into the drug discovery methodology is critical for a host of targets and may provide more selective therapeutics that are less amenable to resistance. This will provide insights into molecular recognition at the protein-nucleic acid level and alternate mechanisms for therapeutic design. Yet, techniques that efficiently and systematically include nucleic acids in the drug discovery pipeline are lacking, and crystallization of RNA can be challenging due to its inherent instability and flexibility. The goal of this collaborative project is to develop computational methodology to systematically incorporate nucleic acids, particularly RNA into the relaxed complex scheme (RCS), and subsequently build these new technologies into our Vision-based pipeline tool for computer-aided drug discovery (CADD). Developing a systematic computational infrastructure is central to our approach. The new CADD pipeline infrastructure that will be developed by NBCR will: (i) facilitate accurate and realistic simulations of hybrid protein-RNA biomolecular systems through the Vision workflow tool, (ii) develop and provide analysis tools for these simulations, (iii) provide a systematic framework to analyze and incorporate the resulting nucleic acid structural information into the RCS CADD pipeline. Our experimental collaborators are committed to testing our predictions  both in terms of biochemical assays and crystal structures of the very best binders  that result from these investigations, and this will be critical for verifying our methodology. Ultimately, a RCS CADD tool that is capable of handling RNA and hybrid protein-nucleic acid based drug targets will be developed and distributed as a tool for the larger scientific community.