Deployment of Quantum Mechanical Pairwise Energy Decomposition for Drug Discovery

用于药物发现的量子机械成对能量分解的部署

• 批准号: 7929952
• 负责人: Lance M Westerhoff
• 金额: $ 9.99万
• 依托单位: QUANTUMBIO, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7929952
• 关键词: Active Sites; Address; Affect; Affinity; Algorithms; Amber; Arts; Automation; Binding; Biological; Characteristics; Client; Cognitive; Communication; Computer Simulation; Computer software; Consensus; Databases; Defect; Development; Drug Design; Drug Industry; Encapsulated; Entropy; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Florida; Genetic Recombination; Goals; Government; Hand; Head; Individual; Industry; Industry Collaboration; Laboratories; Letters; Ligands; Link; Marketing; Mechanics; Metalloproteases; Methodology; Methods; Modeling; Modernization; Molecular; Occupations; Pathway interactions; Pennsylvania; Performance; Pharmacopoeias; Phase; Phosphotransferases; Play; Population; Preparation; Process; Proteins; Publications; Quantum Mechanics; Research; Research Design; Research Infrastructure; Research Project Grants; Scientist; Secrecy; Secure; Serine Protease; Small Business Innovation Research Grant; Staging; Statistical Models; Structure; Support System; System; Technology; Technology Transfer; Testing; Time; Universities; Validation; Work; base; drug candidate; drug discovery; graphical user interface; improved; inhibitor/antagonist; insight; interest; molecular mechanics; novel; quantum; receptor; research and development; research study; software systems; technology development; theories; tool; usability; wasting

DESCRIPTION (provided by applicant): The current state of the art of in silico drug discovery relies almost exclusively on molecular mechanics force fields, such as AMBER, and empirical potentials. It is well known that while these approaches are excellent for certain applications, they have thus far proven less then satisfactory for thorough understanding the interactions of enzyme-inhibitor systems. To address these issues, our linear scaling, quantum mechanics (QM) algorithm will be applied in the Phase I effort to further research, transfer, and validate a QM-based tool to derive the pairwise energy decomposition (PWD) between a set of targets and a large population of inhibitors. Further, the multifaceted workflow of this process will be fully explored with the Discovery Machine (DM) platform in order to set the groundwork for continued development and to begin to address the ease of use concerns with this level of theory. In the Phase II effort, this PWD technology, along with our proprietary QMScore technology, will be developed as an InteractionProfiler tool and validated against a number of structures by leveraging new industry collaborations. We will also develop the client/server software and database backend necessary to properly exploit these powerful QM tools in an industrial or a government setting. DM will continue to play a significant roll in this process, and the ultimate goal of this fast track SBIR will be an intelligent and adaptive system for QM-based drug discovery with the capability of expanding the user's understanding of the types and strengths of enzyme-inhibitor interactions that play an important roll in the user's in silico drug discovery efforts.

描述（由申请人提供）：硅药物发现中艺术的当前状态几乎完全依赖于分子力学力场（例如琥珀色和经验潜力）。众所周知，尽管这些方法适用于某些应用，但迄今为止，这些方法对彻底理解酶抑制剂系统的相互作用的证明程度较低。为了解决这些问题，我们的线性缩放，量子力学（QM）算法将在第一阶段的工作中应用，以进一步研究，转移和验证基于QM的工具，以在一组目标和大量抑制剂群之间得出成对能量分解（PWD）。此外，该过程的多方面工作流将通过Discovery Machine（DM）平台充分探索，以为持续开发奠定基础，并开始解决与此理论水平的易用性问题。在第二阶段的工作中，这种PWD技术以及我们的专有QMScore技术将作为一种交互保护工具开发，并通过利用新的行业合作来对许多结构进行验证。我们还将开发必要的客户/服务器软件和数据库后端，以在工业或政府环境中正确利用这些强大的QM工具。 DM将继续在此过程中发挥重要作用，该快速轨道SBIR的最终目标将是一种智能和自适应系统，用于基于QM的药物发现，能够扩大用户对酶抑制剂相互作用的类型和优势的理解，从而在用户的硅胶药物发现工作中起着重要的作用。

项目成果

Quantum mechanical pairwise decomposition analysis of protein kinase B inhibitors: validating a new tool for guiding drug design.

蛋白激酶 B 抑制剂的量子机械成对分解分析：验证指导药物设计的新工具。

• DOI: 10.1021/ci9003333
• 发表时间: 2010
• 期刊: Journal of chemical information and modeling
• 影响因子: 5.6
• 作者: Zhang,Xiaohua;Gibbs,AlanC;Reynolds,CharlesH;Peters,MartinB;Westerhoff,LanceM
• 通讯作者: Westerhoff,LanceM

Computational alanine scanning with linear scaling semiempirical quantum mechanical methods.

• DOI: 10.1002/prot.22745
• 发表时间: 2010-08-01
• 期刊: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
• 影响因子: 2.9
• 作者: Diller, David J.;Humblet, Christine;Zhang, Xiaohua;Westerhoff, Lance M.
• 通讯作者: Westerhoff, Lance M.