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。这部分是通过引进和不断改进使能技术来实现的。其中一种技术是基于结构的药物设计。确定小分子（候选药物或先导化合物）与生物受体（与疾病有关的蛋白质）的结构是该方法的必要步骤。用于实现这一目标的主要实验方法是X射线晶体学，而核磁共振（NMR）起着较小的作用。X射线技术为蛋白质-配体复合物的结构提供了令人震惊的见解，但可能受到晶体衍射分辨率的阻碍，并且由于缺乏新的小分子化合物的良好潜力，可能会阻碍精制过程。该研究的目的是扩展和进一步验证我们的线性标度半经验量子力学分子力学X射线精化方法（QM/MMXray）。一般来说，将研究适用性的限制，特别是以下问题将在第一阶段项目中提出：QM/MMX射线可以提供更好的结构质量的蛋白质-配体复合物测量的各种晶体学指标（R，Rfree，？A加权傅立叶差分映射等）？在第一阶段项目成功完成后，我们将进一步增强和扩展QM/MMX射线方法，并产生商业质量代码。如果这种方法被证明足够稳健，预计QM/MMX射线在基于结构的设计工作中的使用将得到加强，X射线工具和服务市场规模将进一步扩大。值得注意的是，基于结构的药物设计工具箱将获得一个重要的新方法，这将使药物开发的目标无法达到今天的主流药物发现范式。因此，在不久的将来，可以更有效地针对得不到充分治疗的重要疾病。 公共卫生相关性：快速通道STTR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见解，这将提高我们合理设计人类疾病新疗法的能力。

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.