Enhancement and Deployment of the Quantum Mechanical X-ray Refinement Model

描述(由申请人提供)：通过更快、更便宜地开发药物来改善人类健康是NIH使命的重要组成部分。这部分是通过引入和不断改进使能技术来实现的。其中一项技术是基于结构的药物设计。在这种方法学中，确定生物受体(与疾病有关的蛋白质)的小分子(候选药物或先导化合物)的结构是必要的步骤。实现这一目标的主要实验方法是X射线结晶学，而核磁共振(核磁共振)的作用较小。X射线技术为蛋白质-配体复合体的结构提供了惊人的洞察力，但由于缺乏新的小分子化合物的良好潜力，晶体衍射率的分辨率和精化过程可能会受到阻碍。这项研究的目的是推广和进一步验证我们的线性尺度半经验量子力学分子力学X射线精化方法(QM/MMXray)。总的来说，将研究适用范围，特别是在第一阶段项目中将提出以下问题：QM/MMX-射线能为蛋白质-配体复合体提供更好的结构质量吗？通过各种结晶学度量(R、RFree、？A加权傅立叶差分图等)？在第一阶段项目成功完成后，我们将进一步增强和推广QM/MMXray方法，并产生商业质量代码。如果这种方法被证明足够强大，预计QM/MMXray在基于结构的设计工作中的使用将得到加强，Xray工具和服务的市场规模可以进一步扩大。值得注意的是，基于结构的药物设计工具箱将获得一种重要的新方法，它将使药物开发成为当今主流药物发现范式所无法企及的目标。因此，在不久的将来，可以更有效地针对服务不足的重要疾病。 与公共卫生的相关性：快速通道科学技术研究项目赠款的成功完成将对改善人类健康产生重大影响。它将提高蛋白质结构的质量，促进对生物分子动力学的理解，并将为蛋白质/配体(药物)相互作用提供更高质量的结构洞察，从而增强我们合理设计治疗人类疾病的新疗法的能力。

DESCRIPTION (provided by applicant): Combined Improving human health by enabling the development of drugs faster and cheaper is an important part of the NIH mission. This is partially achieved by introducing and constantly improving enabling technologies. One such technology is structure based drug design. Determining the structure of a small molecule (drug candidate or lead compound) to a biological receptor (protein implicated in disease) is a necessary step in this methodology. The dominant experimental approach used to achieve this goal is X-ray crystallography, while nuclear magnetic resonance (NMR) plays a lesser role. X-ray techniques provide astounding insights into the structure of protein-ligand complexes, but can be hampered by the resolution to which a crystal diffracts and the refinement process can be hampered by the lack of good potentials for novel small molecule compounds. The aim of the proposed research is to extend and further validate our linear-scaling semiempirical quantum mechanical molecular mechanical X-ray refinement approach (QM/MMXray). In general the limits of applicability will be researched and in particular the following question will be posed in the Phase I project: Can QM/MMX-ray provide better structure quality for a protein-ligand complex as measured by various crystallographic metrics (R, Rfree, ?A-weighted Fourier difference maps, etc.)? Upon successful completion of the Phase I project we will further enhance and extend the QM/MMXray method and produce commercial quality code. If this approach proves robust enough it is anticipated that the use of QM/MMXray in structure-based design efforts will be enhanced and the Xray tool and service market size can be further expanded. Significantly, the tool-box of structure based drug design will gain an important new method which will enable drug development for targets inaccessible to today's mainstream drug discovery paradigm. Thus, in the near future important underserved diseases can be targeted more efficiently. PUBLIC HEALTH RELEVANCE: The successful completion of the Fast-Track STTR grant will have a major impact on improving human health. It will improve the quality of protein structures, facilitate the understanding of biomolecular dynamics and will provide higher quality structural insights into protein/ligand (drug) interactions which will enhance our ability to rationally design novel therapeutics for human diseases.