Research and deployment of binding-domain flexible MovableType (MTFlex) for free energy-based affinity prediction and crystallographic structure determination

研究和部署结合域柔性 MovableType (MTFlex),用于基于自由能的亲和力预测和晶体结构测定

基本信息

  • 批准号:
    10093097
  • 负责人:
  • 金额:
    $ 51.32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-01 至 2023-01-31
  • 项目状态:
    已结题

项目摘要

The study of protein/ligand binding is one of the central problems in computational biology because of its importance in understanding intermolecular interactions, and because of its practical payoff in drug discovery efforts. The transformative impact accurate target/ligand structure can have in the design of next generation medicines cannot be overstated. If we could routinely and accurately design molecules using these approaches it would revolutionize drug discovery by winnowing out compounds with no activity while focusing more effort and scrutiny on highly active compounds. Determining the structure of a small molecule (drug candidate or lead compound) bound to a biological receptor (protein implicated in disease) is a necessary step in this approach to drug discovery. In this proposal we describe a novel method we call MovableType (MT), which addresses the protein ligand binding and scoring problem using fundamental statistical mechanics combined with a novel way to generate the ensemble of a ligand in a protein binding pocket. Via a rapid assembly of the necessary partition functions we directly obtain binding free energies and the low free energy poses. Conceptually, the MT method is analogous to block and type set printing, which allows us to efficiently evaluate partition functions describing regions or systems of interest. In this approach we construct two databases that 1) describe the probability of certain pairwise interactions as a function of r obtained from a knowledge base (Protein Databank (PDB) or the Cambridge Structural Database (CSD)) and 2) the energetics of the pairwise interactions as a function of r obtained from empirical potentials, which can be either derived from the probabilities or can utilize extant pairwise potentials like AMBER. Overall, the MT method is a general one and can use a broad range of two-body potential functions and can be extended to higher-order interactions if so desired. Recent work with the MT method has led to the launch of three core product modules: MTScore (both endstate and ensemble binding affinity prediction), MTDock (ligand placement), and MTCS (ligand conformational search). In this project, we will extend our MT product line and deliver this methodology to X-ray crystallographers and computational chemists for use in automated sidechain rotamer and target loop sampling within and around the active site, accurate binding affinity prediction and minima selection, and crystallographic density matching and placement. This work will involve development of a new, integrated tool for automated structure/model preparation, rotamer/loop selection, rotamer/loop generation (“MTFlex proper”), loop/totamer minimization, and analysis. We will commercially deploy the technology, which we will call MTFlex, construct graphical user interfaces for use in MOE, Phenix, and our web-based cloud platform. Finally, this software will be used in real life structure-based drug discovery problems with our pharmaceutical collaborators (see Letters of Support).
蛋白质/配体结合的研究是计算生物学的核心问题之一

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)

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Lance M Westerhoff其他文献

Lance M Westerhoff的其他文献

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{{ truncateString('Lance M Westerhoff', 18)}}的其他基金

Research and cloud deployment of enhanced sampling methods in MovableType
MovableType中增强采样方法的研究和云部署
  • 批准号:
    10699159
  • 财政年份:
    2023
  • 资助金额:
    $ 51.32万
  • 项目类别:
Development of the Movable Type free energy method for ligand placement in X-ray crystallography
X 射线晶体学中配体放置的可移动式自由能方法的开发
  • 批准号:
    9347830
  • 财政年份:
    2017
  • 资助金额:
    $ 51.32万
  • 项目类别:
Development and Deployment of the Movable Type Method for Drug Discovery and Desi
用于药物发现和设计的可移动式方法的开发和部署
  • 批准号:
    8781973
  • 财政年份:
    2014
  • 资助金额:
    $ 51.32万
  • 项目类别:
A new approach to solvent determination in QM/MM-based X-ray crystallographic refinement
基于 QM/MM 的 X 射线晶体学精修中溶剂测定的新方法
  • 批准号:
    8834159
  • 财政年份:
    2014
  • 资助金额:
    $ 51.32万
  • 项目类别:
Development and Deployment of the Movable Type Method for Drug Discovery and Desi
用于药物发现和设计的可移动式方法的开发和部署
  • 批准号:
    9032505
  • 财政年份:
    2014
  • 资助金额:
    $ 51.32万
  • 项目类别:
Development and Deployment of the Movable Type Method for Drug Discovery and Desi
用于药物发现和设计的可移动式方法的开发和部署
  • 批准号:
    8931350
  • 财政年份:
    2014
  • 资助金额:
    $ 51.32万
  • 项目类别:
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:
    8721497
  • 财政年份:
    2013
  • 资助金额:
    $ 51.32万
  • 项目类别:
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:
    8201254
  • 财政年份:
    2011
  • 资助金额:
    $ 51.32万
  • 项目类别:
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
  • 财政年份:
    2011
  • 资助金额:
    $ 51.32万
  • 项目类别:
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:
    8475485
  • 财政年份:
    2011
  • 资助金额:
    $ 51.32万
  • 项目类别:

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合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
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