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）：基于碎片的药物设计（FBDD）是一种组合方法，其中单个碎片与目标位点区域结合的单个碎片是从碎片库中选择的，然后组合成形成潜在的铅化合物。在过去的几年中，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目标以及增加成功概率的片段来潜在地降低FBDD的价格，但所有探索碎片大小配体与蛋白质结合的方法至少至少15岁，因此并未考虑到最近的进度。波士顿大学的VAJDA实验室一直在开发蛋白质映射的方法，最近发布了高效且高度准确的映射程序FTMAP。该方法移动分子探针 - 包含各种官能基团的小有机分子 - 围绕蛋白质，以找到偏爱特定官能团的结合热点。该提案的目标是（1）将FTMAP开发为一个称为Atlas的有效且可移植的FBDD软件产品，（2）在开发的第二阶段，将计算步骤添加到Atlas，以设计靶向蛋白质蛋白质相互作用的抑制剂。 VAJDA组的程序包含在Atlas中的是FTMAP映射程序，该程序是一种用于生成替代侧链构象异构体的程序，该程序是一种迭代映射的程序，用于识别优先绑定到目标位点的功能组，以及蛋白质prote protein protein docking docking docking programiper。 Acpharis将开发五个其他程序，（1）根据映射结果，使用通用药体进行虚拟筛查； （2）有效地将结果传达给药物学家，以设计较大化合物的碎片命中； （4）实施基于创新的片段算法来对同源化合物进行排名，以优化给定脚手架的R组； （4）制备用于映射的蛋白质结构，（5）构造扩展和目标特异性探针文库，包括分子的参数化。所有元素都将合并为一个称为ATLA的功能强大的FBDD软件包，该软件包将在多核处理器上和作为基于云计算的虚拟机上实现，该虚拟机构建了亚马逊的弹性计算云。地图集的使用将减少FBDD所需的X射线晶体学或基于NMR的筛查实验的数量，因此将大大降低与这种方法相关的成本，这是小型公司和学术实验室的重要考虑因素。 公共卫生相关性：基于碎片的药物设计（FBDD）是一种组合方法，其中单个碎片与目标位点区域结合的单个碎片是从碎片文库中选择的，然后合并以形成潜在的铅化合物。该提案的一般目标是开发可移植的FBDD软件产品，称为Atlas，至少在设计的早期阶段，可以为核磁共振或X射线晶体学的昂贵片段筛选提供可行的替代方法。