High-throughput portable software for fragment-based drug design

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点区域结合的单个片段，然后组合形成潜在的先导化合物。在过去的几年里，人们对这种方法的兴趣显著增加，许多公司使用基于x射线晶体学或核磁共振的FBDD方法。尽管计算方法可以通过选择合适的靶标和片段来潜在地降低FBDD的价格，并增加成功的可能性，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年的历史，因此不能解释最近的进展。波士顿大学的Vajda实验室一直在开发蛋白质图谱的方法，最近发布了高效、高精度的图谱程序FTMAP。该方法移动分子探针——含有各种官能团的小有机分子——在蛋白质周围寻找具有特定官能团偏好的结合热点。该提案的目标是(1)将FTMAP开发成一种有效且可移植的FBDD软件产品，称为Atlas；(2)在开发的第二阶段，为Atlas增加计算步骤，以设计靶向蛋白质-蛋白质相互作用的抑制剂。来自Vajda组的程序将被包括在Atlas中，包括FTMAP映射程序，一个用于生成替代侧链构象的程序，一个用于识别优先结合靶点的功能基团的迭代映射程序，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)基于映射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，以便从鉴定的片段命中设计更大的化合物；(4)实现一种创新的基于片段的同源化合物排序算法，以优化给定支架的r基团；(4)制备用于定位的蛋白质结构；(5)构建扩展的和靶向的探针文库，包括分子的参数化。所有元素将被整合到一个强大的FBDD软件包Atlas中，该软件包将在多核处理器上实现，并作为基于云计算的虚拟机构建在亚马逊的弹性计算云上。Atlas的使用将减少FBDD所需的x射线晶体学或核磁共振筛选实验的数量，因此将大大降低与该方法相关的成本，这是小公司和学术实验室的一个重要考虑因素。

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.