BUILDING COMPLEXITY INTO THE COMPUTER-AIDED DRUG DESIGN PIPELINE THROUGH

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 (A)目的 将核酸掺入药物发现方法中对于许多靶点是至关重要的，并且可以提供更不容易产生耐药性的更具选择性的治疗剂。 这将为蛋白质-核酸水平的分子识别和治疗设计的替代机制提供见解。 然而，缺乏有效和系统地将核酸包括在药物发现管道中的技术，并且由于其固有的不稳定性和灵活性，RNA的结晶可能具有挑战性。 这个合作项目的目标是开发计算方法，将核酸，特别是RNA系统地纳入宽松的复杂方案（RCS），并随后将这些新技术构建到我们的基于视觉的管道工具中，用于计算机辅助药物发现（CADD）。 开发一个系统的计算基础设施是我们的方法的核心。NBCR将开发的新CADD管道基础设施将：（i）通过Vision工作流程工具促进混合蛋白质-RNA生物分子系统的准确和逼真模拟，（ii）开发和提供这些模拟的分析工具，（iii）提供一个系统框架来分析并将所得核酸结构信息纳入RCS CADD管道。我们的实验合作者致力于测试我们的预测  无论是在生化分析方面还是在最佳粘合剂的晶体结构方面  这对验证我们的方法至关重要。最终，将开发一种能够处理RNA和基于杂交蛋白-核酸的药物靶标的RCS CADD工具，并将其作为更大科学界的工具分发。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. (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.