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

用于基于片段的药物的量子力学核磁共振工具的研究和部署

• 批准号: 8449871
• 负责人: Lance M Westerhoff
• 金额: $ 53.86万
• 依托单位: QUANTUMBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8449871
• 关键词: Academia; Active Sites; Address; Algorithms; Amides; Area; Binding; Biological; Boxing; Chemicals; Complex; Computer software; Data; Databases; Development; Disease; Docking; Drug Design; Drug Interactions; Future; Goals; Grant; Growth; Health; Homology Modeling; Human; Industry; Investments; Lead; Letters; Ligand Binding; Ligands; Mainstreaming; Marketing; Measures; Mechanics; Membrane Proteins; Methodology; Methods; Mission; Molecular; Nuclear Magnetic Resonance; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Population; Positioning Attribute; Preparation; Price; Process; Proteins; Relative (related person); Research; Research Personnel; Role; Scoring Method; Services; Small Business Innovation Research Grant; Solubility; Structure; Technology; Time; Training; United States National Institutes of Health; Ursidae Family; Validation; Work; X-Ray Crystallography; base; density; design; drug candidate; drug development; drug discovery; graphical user interface; human disease; improved; insight; interest; next generation; novel therapeutics; phase 1 study; phase 2 study; product development; protein structure; quantum; receptor; research study; small molecule; solid state nuclear magnetic resonance; success; theories; tool; validation studies

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.

描述（由申请人提供）：通过更快，更便宜的毒品开发来改善人类健康是NIH任务的重要组成部分。这是通过引入和不断改进启用技术来部分实现的。这样的技术是基于结构的药物设计。在这种方法中，确定针对生物受体的小分子（候选药物或铅化合物）的结构（与疾病有关的蛋白质）是必要的一步。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）在学术界和工业中都有大量投资，扮演的角色较小。 NMR受到可以研究的蛋白质的大小的阻碍，并且需要经过冗长的结构测定过程。但是，随着基于碎片的药物设计的出现，NMR起着更大的作用，如果可以减少解决蛋白质配体复合物的结构所需的时间努力，它将发挥更大的作用。此外，如果无法获得晶体NMR，则可以发挥重要作用。通过使用固态NMR研究，可以研究膜蛋白或具有溶解性问题的蛋白质，或者在只有可用的蛋白质同源模型的情况下，NMR可以通过验证在同源性建模研究中产生的主动位点结构来发挥作用。拟议的研究的目的是通过添加目标观察到的CSP和AbriO obio nmr NMR方法，将Quantumbio成功的线性线性尺度半经验量子量子NMR方法（NMRSCORE）扩展到化学位移扰动（CSP）分析。在该提案的第一阶段，将探讨适用性的限制。在II期提案扩展中，将通过1H，13C 17O和15N NMR进行重新聚集，并将开发新的经典NMR预测指标。此外，将研究和实施工作流的简化。最后，该建议旨在使这项突破性技术充分生产和商业化。可以预计，通过使该应用程序在市售中使用，NMR在基于结构的设计工作中的使用将得到增强，并且可以进一步扩大NMR工具和服务市场规模。值得注意的是，基于结构的药物设计工具盒将获得一种重要的新方法，这将使当今主流药物发现范式无法接近的靶标的药物开发。因此，在不久的将来，可以更有效地将重要的不足疾病靶向。