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。这部分是通过引入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）的作用较小，尽管学术界和工业界都投入了大量资金。核磁共振受到可以研究的蛋白质的大小和需要经历漫长的结构确定过程的阻碍。然而，随着基于片段的药物设计的出现，核磁共振正在发挥更大的作用，如果有可能减少解决蛋白质-配体复合物结构所需的时间和精力，它将发挥更大的作用。此外，在不可能获得晶体的情况下，核磁共振可以发挥重要作用。通过使用固态核磁共振研究可以研究膜蛋白或具有溶解度问题的蛋白质，或者在只有蛋白质的同源模型可用的情况下，核磁共振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）扩展和商业化到化学位移微扰（CSP）分析。在本建议的第一阶段，将探讨适用性的限制。在第二阶段的建议中，将通过1H， 13c17o和15N核磁共振的重新参数化来扩展方法，并将开发一个新的经典核磁共振预测器。此外，还将研究和实现工作流程的简化。最后，本提案旨在使这一突破性技术充分产品化和商业化。预计通过使这一应用商业化，核磁共振在基于结构的设计工作中的应用将得到加强，核磁共振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，这将使药物开发能够针对当今主流药物发现范式无法达到的靶点。因此，在不久的将来，可以更有效地针对重要的服务不足的疾病。

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.