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（由申请人提供）：分子相互作用和分子组件的形成是大多数生物过程的基础。自动对接是获得对这些相互作用的机械理解并支持从药物设计到用于研究化学途径并确定诸如癌症和代谢性疾病等疾病的治疗靶标的生物医学应用的重要工具。众所周知，从氨基侧链重排到大分子中的柔性环和域运动，通常是与配体相互作用机制的重要组成部分。在模拟中，大分子作为刚性分子的表示是这些技术最严重的局限性之一。我们已经开发了一种层次数据结构，称为“灵活性树”（FT），允许有效表示和编码大分子的构象子空间，我们已经使用FTS证明，将柔性配体分子对接为柔性受体。我们建议将FT纳入广泛使用的对接程序Autodock中，以支持对抗柔性受体的柔性配体。具体来说，我们将：1）使用新的基于FT的底座引擎：AutoDock-FR扩展Autodock对接软件套件，该套件将支持多分辨率受体灵活性以及可插入的搜索引擎和评分功能。我们还将扩展图形用户界面AutoDockTools，以支持此新的对接后端； 2）扩展FT，能够更好地表示灵活的环和旋转侧链，以及接口蛋白灵活性预测方法，以支持用户在构建FT中； 3）创建一个分子络合物数据集，其中已知大分子柔韧性才能成功进行自动对接程序。该数据集将用于测试和验证所提出的软件，并将提供给社区，并为评估对接方法提供基准。这个开源软件开发项目将基于软件工程中的最佳实践，并导致基于模块化的，基于组件的软件环境，在该环境中，搜索技术和评分功能可以被替换和组合。我们建议的模块化设计还定义了一种清晰清洁的机制，用于在可用时添加新算法，从而使AutoDock-FR可发展且可维护。这项工作将极大地利用社区开发的方法，并提供前所未有的可操作性。我们建议的完全刚起步的，用户友好，可自定义的，可自定义的完整软件将提供在已经广泛使用的一个流行的码头程序中，这将有助于其传播和采用。 AutoDock-FR将大大扩展成功使用自动对接的生物学问题范围。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。 公共卫生相关性：自动对接已被证明是用于各种应用的有用工具，包括：理性的药物设计，铅优化和化学探针的设计，但是，大多数停靠计划使用的大分子的刚性模型严重限制了自动扩建的成功率。我们建议使用新的对接引擎自动售货机延长广泛使用且建立的对接程序自动货车，该机构将允许在对接模拟过程中的配体存在下的情况下表示柔性受体的代表以及受体构型的优化。这种新的自动货物能力将影响许多计算化学家和生物学家的研究，并有助于我们对生物学过程的理解，从而显着影响生物医学的研究。