AutoDock-FR: A Modular Approach to Flexible Receptor Docking

AutoDock-FR：灵活受体对接的模块化方法

• 批准号: 8255452
• 负责人: MICHEL F. SANNER
• 金额: $ 37.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8255452
• 关键词: Address; Adoption; Algorithms; Amino Acids; Area; Benchmarking; Binding; Biochemical Pathway; Biological; Biological Process; Biomedical Research; Cells; Chemicals; Clinical Research; Communities; Complex; Computational Technique; Computer software; Computing Methodologies; DNA Sequence Rearrangement; Data Set; Development; Disease; Docking; Documentation; Drug Design; Environment; Infection; Lead; Life; Ligands; Macromolecular Complexes; Maintenance; Malignant Neoplasms; Metabolic Diseases; Methods; Modeling; Molecular; Molecular Conformation; Motion; Movement; Pathway interactions; Play; Procedures; Protein Analysis; Proteins; Research; Resolution; Role; Sampling; Scientist; Scoring Method; Screening procedure; Side; Software Engineering; Software Tools; Techniques; Testing; Therapeutic Intervention; Translational Research; Trees; base; combat; computerized tools; data structure; design; flexibility; graphical user interface; inhibitor/antagonist; interoperability; macromolecule; microbial; molecular assembly/self assembly; object motion; open source; operation; programs; protein protein interaction; public health relevance; receptor; research study; response; simulation; software development; success; therapeutic target; tool; user-friendly; virtual

DESCRIPTION (provided by applicant): Molecular interactions and the formation of molecular assemblies are underpinning most biological processes. Automated docking is an important tool for gaining a mechanistic understanding of these interactions and supporting biomedical applications ranging from drug design to the design of chemical probes used to investigate chemical pathways and identify therapeutic targets for diseases such as cancer and metabolic disorders. It is known that a variety of conformational changes ranging from amino side chain rearrangement to flexible loops and domain motions in macromolecules are often an essential and integral part of the interaction mechanism with a ligand. The representation of macromolecules as rigid molecules during the docking simulation is one of the most severe limitations of these techniques. We have developed a hierarchical data structure called the "Flexibility Tree" (FT) allowing the efficient representation and encoding of conformational subspaces of macromolecules and we have demonstrated using FTs for docking flexible ligand molecules into flexible receptors. We propose to incorporate the FT in the widely used docking program AutoDock in order to support docking flexible ligands against flexible receptors. Specifically, we will: 1) extend the AutoDock docking software suite with a new FT-based docking engine: AutoDock-FR that will support multi-resolution receptor flexibility, and pluggable search engines and scoring functions. We will also extend the Graphical User Interface AutoDockTools to support this new docking backend; 2) extend the FT with the ability to better represent flexible loops and rotatmeric side chains, and interface protein flexibility prediction methods to support users in building FTs; and 3) create a dataset of molecular complexes in which macromolecular flexibility is known to be required for the success of automated docking procedures. This dataset will be used to test and validate the proposed software and will be made available to the community and provide a benchmark for evaluating docking methods. This Open-Source software development project will be based on best practices in software engineering and result in a modular, component-based software environment in which search techniques and scoring functions can be substituted and combined. The modular design we propose also defines a clear and clean mechanism for the addition of new algorithms as they become available, making AutoDock-FR evolvable and maintainable. This effort will greatly leverage methods developed by the community and provide unprecedented inter- operability. The fully fledged, user friendly, highly customizable, fully documented software we propose will be made available within an already widely used a popular docking program which will help its dissemination and adoption. AutoDock-FR will greatly extend the range of biological problems for which automated docking will be used successfully. It will impact the research of many chemists and biologist, extend the use of computational tools to a wider community of scientists, and greatly impact biomedical research. PUBLIC HEALTH RELEVANCE: Automated docking has proven to be a useful tool for a variety of applications including: rational drug design, lead optimization and the design of chemical probes, however, the rigid models of macromolecules used by most docking programs severely limits the success rate of automated docking. We propose to extend the widely used and well established docking program AutoDock with a new docking engine AutoDock-FR that will allow for the representation of flexible receptor and the optimization of the receptor's conformation in the presence of the ligand during the docking simulation. This new capability in AutoDock will impact the research of many computational and medicinal chemists and biologist and contribute to our understanding of biological processes and thus significantly impact research in biomedicine.

描述(申请人提供)：分子相互作用和分子组装的形成是大多数生物过程的基础。自动对接是从机制上了解这些相互作用并支持从药物设计到化学探针设计的生物医学应用的重要工具，这些探针用于研究化学途径并确定癌症和代谢疾病等疾病的治疗靶点。众所周知，大分子中从氨基侧链重排到柔性环和结构域运动的各种构象变化往往是与配体相互作用机制中必不可少的组成部分。在对接模拟中，将大分子表示为刚性分子是这些技术最严重的限制之一。我们已经开发了一种称为“柔性树”(FT)的分层数据结构，允许高效地表示和编码大分子的构象子空间，并且我们已经展示了使用FT将柔性配体分子对接到柔性受体中。我们建议将FT结合到广泛使用的对接程序AutoDock中，以支持柔性配体与柔性受体的对接。具体地说，我们将：1)用一个新的基于FT的对接引擎AutoDock-FR扩展AutoDock对接软件套件，该引擎将支持多分辨率接收器灵活性，以及可插拔的搜索引擎和评分功能。我们还将扩展图形用户界面AutoDockTools，以支持这一新的对接后端；2)扩展FT，使其能够更好地表示柔性环和旋转单体侧链，并提供界面蛋白质灵活性预测方法，以支持用户构建FT；以及3)创建分子复合体数据集，其中已知成功的自动对接过程需要大分子灵活性。该数据集将用于测试和验证拟议的软件，并将向社区提供，并为评估对接方法提供基准。这个开放源码软件开发项目将以软件工程的最佳做法为基础，产生一个模块化的、基于组件的软件环境，在这种环境中，搜索技术和评分功能可以被替代和组合。我们提出的模块化设计还定义了一种清晰、干净的机制，用于在新算法可用时添加它们，使AutoDock-FR具有可演进性和可维护性。这项工作将极大地利用社区开发的方法，并提供前所未有的互操作性。我们建议的成熟、用户友好、高度可定制、文档齐全的软件将在已经广泛使用的流行对接程序中提供，这将有助于其传播和采用。AutoDock-FR将极大地扩展自动对接将成功用于解决的生物问题的范围。它将影响许多化学家和生物学家的研究，将计算工具的使用扩展到更广泛的科学家社区，并极大地影响生物医学研究。 与公共健康相关：自动对接已被证明是一种有用的工具，可用于各种应用，包括：合理的药物设计、铅优化和化学探针设计，然而，大多数对接项目使用的刚性大分子模型严重限制了自动对接的成功率。我们建议用一个新的对接引擎AutoDock-FR来扩展广泛使用和成熟的对接程序AutoDock-FR，它将允许在对接模拟过程中在配体存在的情况下表示灵活的受体和优化受体的构象。AutoDock的这一新功能将影响许多计算和药物化学家以及生物学家的研究，并有助于我们理解生物过程，从而对生物医学研究产生重大影响。