High-throughput portable software for fragment-based drug design

用于基于片段的药物设计的高通量便携式软件

• 批准号: 8124328
• 负责人: SANDOR VAJDA
• 金额: $ 9.81万
• 依托单位: ACPHARIS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-20 至 2013-05-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8124328
• 关键词: 15 year old; 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Accounting; Affinity; Algorithms; Atlases; Binding; Boston; Chemicals; Collection; Computer Simulation; Computer software; Computers; Computing Methodologies; Crystallography; Development; Docking; Drug Design; Elements; Goals; Hot Spot; Individual; Lead; Libraries; Ligands; Maps; Methods; Molecular; Molecular Conformation; Molecular Probes; Motion; Motivation; Nuclear Magnetic Resonance; Pharmaceutical Preparations; Preparation; Price; Probability; Protein Fragment; Proteins; Research; Screening procedure; Side; Site; Software Design; Staging; Structure; Therapeutic; Universities; Vertebral column; X-Ray Crystallography; base; combinatorial; conformer; cost; design; flexibility; functional group; inhibitor/antagonist; innovation; interest; pharmacophore; preference; programs; protein protein interaction; protein structure; research study; scaffold; small molecule; software development; success; tool; user-friendly; virtual

DESCRIPTION (provided by applicant): Fragment-based drug design (FBDD) is a combinatorial approach in which individual fragments binding to regions of the target site are selected from a fragment library, and then combined to form potential lead compounds. Interest in this approach has significantly increased during the last few years, with many companies using FBDD methods based on X-ray crystallography or NMR. Although computational methods can potentially reduce the price of FBDD by selecting appropriate targets as well as fragments with increased probability of success, all methods that that explore the binding of fragment-sized ligands to proteins are at least 15 years old, and hence do not account for the recent progress. The Vajda lab at Boston University has been developing methods for the mapping of proteins and has recently released the efficient and highly accurate mapping program FTMAP. The method moves molecular probes - small organic molecules containing various functional groups - around the protein to find binding hot spots with preference for specific functional groups. The goals of this proposal are (1) developing FTMAP into an effective and portable FBDD software product called Atlas, and (2) in a second stage of development, adding computational steps to Atlas for the design of inhibitors that target protein-protein interactions. The programs from the Vajda group to be included in Atlas are the FTMAP mapping program, a program developed for generating alternative side chain conformers, a program for iterative mapping to identify functional groups that preferentially bind to a target site, and the protein-protein docking program PIPER. Acpharis will develop five additional programs that (1) perform virtual screening using generalized pharmacophores based on the mapping results; (2) effectively communicate the results to medicinal chemists for the design of larger compounds from the fragment hits identified; (4) implement an innovative fragment based algorithm for ranking homologous compounds in order to optimize R-groups for a given scaffold; (4) prepare protein structures for mapping, and (5) construct extended and target-specific probe libraries, including the parameterization of the molecules. All elements will be combined into a powerful FBDD software package called Atlas which will be implemented both on multi- core processors and as a cloud-computing based virtual machine built on Amazon's Elastic Compute Cloud. The use of Atlas will reduce the number of X-ray crystallography or NMR based screening experiments required for FBDD, and hence will substantially reduce the costs associated with this approach, an important consideration for small companies and academic labs. PUBLIC HEALTH RELEVANCE: Fragment-based drug design (FBDD) is a combinatorial approach in which individual fragments binding to regions of a target site are selected from a fragment library, and then combined to form potential lead compounds. The general goal of this proposal is to develop portable FBDD software product called ATLAS that, at least in the early stages of the design, can provide a viable alternative to the expensive fragment screening by Nuclear Magnetic Resonance or X-ray crystallography.

描述（由申请人提供）：基于片段的药物设计（FBDD）是一种组合方法，其中从片段库中选择与靶位点区域结合的单个片段，然后组合以形成潜在的先导化合物。在过去几年中，人们对这种方法的兴趣显着增加，许多公司使用基于 X 射线晶体学或 NMR 的 FBDD 方法。尽管计算方法可以通过选择适当的靶标以及增加成功概率的片段来潜在地降低 FBDD 的价格，但所有探索片段大小的配体与蛋白质结合的方法都至少有 15 年历史，因此并不能说明最近的进展。波士顿大学 Vajda 实验室一直在开发蛋白质图谱方法，最近发布了高效、高精度的图谱程序 FTMAP。该方法将分子探针（含有各种官能团的有机小分子）移动到蛋白质周围，以寻找特定官能团的结合热点。该提案的目标是 (1) 将 FTMAP 开发为名为 Atlas 的有效且可移植的 FBDD 软件产品，以及 (2) 在开发的第二阶段，向 Atlas 添加计算步骤，以设计针对蛋白质-蛋白质相互作用的抑制剂。 Atlas 中包含的 Vajda 小组的程序包括 FTMAP 作图程序（一个为生成替代侧链构象异构体而开发的程序）、一个用于迭代作图以识别优先与目标位点结合的功能基团的程序，以及蛋白质-蛋白质对接程序 PIPER。 Acpharis 将开发五个额外的程序，(1) 根据绘图结果使用广义药效团进行虚拟筛选； (2) 有效地将结果传达给药物化学家，以便从识别的片段命中中设计更大的化合物； (4) 实施基于片段的创新算法对同源化合物进行排序，以优化给定支架的 R 基团； (4) 准备用于作图的蛋白质结构，以及 (5) 构建扩展的目标特异性探针库，包括分子的参数化。所有元素将被组合成一个名为 Atlas 的强大 FBDD 软件包，该软件包将在多核处理器上实施，并作为构建在 Amazon 弹性计算云上的基于云计算的虚拟机。 Atlas 的使用将减少 FBDD 所需的 X 射线晶体学或基于 NMR 的筛选实验的数量，因此将大大降低与此方法相关的成本，这是小公司和学术实验室的重要考虑因素。 公共卫生相关性：基于片段的药物设计 (FBDD) 是一种组合方法，其中从片段库中选择与靶位点区域结合的单个片段，然后组合以形成潜在的先导化合物。该提案的总体目标是开发名为 ATLAS 的便携式 FBDD 软件产品，至少在设计的早期阶段，该产品可以为通过核磁共振或 X 射线晶体学进行昂贵的片段筛选提供可行的替代方案。