ADFR: A Modular Software Framework for Docking into Flexible Receptors

ADFR：用于对接灵活受体的模块化软件框架

• 批准号: 9239951
• 负责人: MICHEL F. SANNER
• 金额: $ 39.66万
• 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 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9239951
• 关键词: Accounting; Area; Automated Abstracting; Award; Benchmarking; Binding; Binding Sites; Biochemical Pathway; Biological; Biological Process; Biomedical Research; Cells; Chemicals; Clinical Research; Communities; Computer software; Computers; Data Set; Descriptor; Development; Disease; Docking; Documentation; Drug Design; Environment; Funding; Infection; Lead; Life; Ligand Binding; Ligands; Maintenance; Malignant Neoplasms; Metabolic Diseases; Methods; Modeling; Molecular; Molecular Conformation; Motion; Neighborhoods; Pathway interactions; Peptides; Performance; Pharmaceutical Preparations; Proteins; Research; Research Support; Resolution; Scheme; Scientist; Side; Software Engineering; Software Framework; Speed; Staging; Techniques; Testing; Torsion; Training; Translational Research; Trees; Vertebral column; Weight; Writing; base; computerized tools; design; flexibility; graphical user interface; improved; insight; interest; macromolecule; method development; molecular assembly/self assembly; novel; novel therapeutic intervention; object motion; open source; programs; receptor; research study; response; screening; simulation; software development; success; therapeutic target; tool; virtual

Project Summary/Abstract Automated docking is an important tool for gaining a mechanistic understanding of the molecular interactions underpinning most biological processes. It supports biomedical applications ranging from drug and chemical probes design to investigating chemical pathways and identifying therapeutic targets for diseases such as cancer and metabolic disorders. Two major challenges for automated docking remain the conformational changes occurring in macromolecules upon ligand binding and the docking highly flexible ligands such as peptides, an area that has gained a lot of interest recently. Most docking programs use rigid models of macromolecules because of the exponential increase of computational complexity and the decreased docking accuracy associated receptor flexibility. Under the previous award, we made significant progress towards docking with flexible receptors. We developed and released a software program allowing the successful cross- docking of flexible ligands into apo conformations of receptors with up to 14 flexible side-chains, and demonstrated that down-weighting the contribution of the receptor internal energy to the scoring function increased docking success rates. For the next award, we propose to: 1) extend the set of motion objects for describing ligand conformational changes beyond rotatable bonds, and motion objects for representing local and global receptor backbone motions such as flexible loops and domain motions; 2) enhance our current search technique and develop a new representation and associate search technique for docking peptides; 3) calibrate and optimize the scoring function sused during docking specifically in the context of docking with receptor flexibility; and 4) make the software useful and usable through clearly written documentation and intuitive graphical user interfaces. Datasets compiled under this project will also be made freely 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 with pluggable search techniques and scoring functions, and an extensible set of molecular flexibility descriptors. This new docking engine will be part of the widely used and popular software suite AutoDock. It will be used on the World Community Grid for large virtual screens on therapeutically important targets. The ability to include receptor flexibility in docking simulations will extend the range of biological problems for which automated docking can be successfully applied. Hence, it will impact the research of many medicinal chemists and biologist, and extend the use of computational tools to a wider community of scientists thereby supporting the advancement of biomedical research.

项目摘要/摘要 自动对接是获得对分子机械理解的重要工具 支持大多数生物学过程的相互作用。它支持生物医学应用程序 从药物和化学探针设计到研究化学途径和识别 癌症和代谢疾病等疾病的治疗靶标。两个主要挑战 自动对接仍然是配体上大分子中发生的构象变化 绑定和对接高度柔韧的配体（例如肽），该区域已获得很多 最近的兴趣。大多数对接程序都使用僵化的大分子模型，因为 计算复杂性的指数增加和与扩展精度降低有关 受体灵活性。根据以前的奖项，我们取得了重大进展 柔性受体。我们制定并发布了一个软件程序，允许成功的交叉 将柔性配体对接成具有多达14个柔性侧链的受体的APO构象， 并证明了受体内部能量对 评分功能提高了对接成功率。对于下一个奖项，我们建议：1）扩展 一组运动对象，用于描述旋转键以外的配体构象变化， 表示局部和全球受体主链运动的运动对象，例如柔性循环 和域运动； 2）增强我们当前的搜索技术并开发新的表示 和用于对接肽的关联搜索技术； 3）校准和优化评分功能 在与受体灵活性对接的情况下，特别是在停靠期间感到震惊； 4） 该软件可通过清晰书面文档和直观的图形用户有用且可用 接口。该项目下编译的数据集也将免费提供给 社区并提供评估对接方法的基准。这个开源软件 开发项目将基于软件工程的最佳实践，并导致 具有可插入搜索技术和评分的基于模块化的，基于组件的软件环境 功能和一组可扩展的分子柔韧性描述符。这个新的对接引擎将 成为广泛使用和流行的软件套件自动售货机的一部分。它将在世界上使用 有关在治疗上重要目标的大型虚拟屏幕的社区网格。能力 在对接模拟中包括受体灵活性将扩大生物学问题的范围 可以成功应用哪个自动对接。因此，这将影响许多人的研究 药物化学家和生物学家，并将计算工具的使用扩展到更广泛的社区 科学家，从而支持生物医学研究的进步。