Research and Deployment of a quantum mechanical NMR tool for fragment based drug

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）尽管在学术界和工业界都有大量投资，但作用较小。核磁共振是阻碍了蛋白质的大小，可以研究和需要通过一个漫长的结构确定过程。然而，随着基于片段的药物设计的出现，NMR正在发挥更大的作用，如果可以减少解决蛋白质-配体复合物结构所需的时间，它可以发挥更大的作用。此外，在不可能获得晶体的情况下，NMR可以发挥重要作用。通过使用固态NMR研究，可以研究膜蛋白或具有溶解度问题的蛋白，或者在只有蛋白质的同源模型可用的情况下，NMR可以通过验证同源建模研究中产生的活性位点结构假设来发挥作用。拟议研究的目的是通过添加目标观察的化学位移微扰（CSP）和从头算核磁共振方法，将QuantumBio成功的线性标度半经验量子力学核磁共振方法（NMRScore）扩展到化学位移微扰（CSP）分析并商业化。在本提案的第一阶段，将探讨适用范围。在第二阶段的建议扩展的方法，通过重新参数化的1H，13 C 17 O和15 N NMR将进行和一个新的经典NMR预测器将开发。此外，还将研究和实施精简工作流程的办法。最后，该提案旨在将这项突破性技术完全产品化和商业化。预计通过使这种应用商业化，NMR在基于结构的设计工作中的使用将得到加强，NMR工具和服务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SBIR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): 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 in spite of large investments both in academia and industry. NMR is hampered by the size of protein that can be studied and the need to go through a lengthy structure determination process. However, with the advent of fragment based drug design, NMR is playing a much larger role and it could play an even greater role if it was possible to reduce the time effort necessary to solve the structure of a protein-ligand complex. Moreover, in cases where it is not possible to obtain a crystal NMR can play a significant role. Through the use of solid-state NMR studies membrane proteins or proteins with solubility problems can be studied or in cases where only homology models of a protein are available NMR could play a role through the validation of active site structure hypotheses generated in homology modeling studies. The aim of the proposed research is to extend and commercialize QuantumBio's successful linear-scaling semiempirical quantum mechanical NMR approach (NMRScore) to chemical shift perturbation (CSP) analysis through the addition of target-observed CSP and ab initio NMR methods. In Phase I of this proposal the limits of applicability will be explored. In the Phase II proposal extension of the methodology via reparameterization of 1H, 13C 17O and 15N NMR will be carried out and a new classical NMR predictor will be developed. Furthermore, the streamlining of the workflow will be researched and implemented. Finally, this proposal is aiming to fully productize and commercialize this breakthrough technology. It is anticipated that by making this application commercially available the use of NMR in structure-based design efforts will be enhanced and the NMR 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 SBIR 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.