Anchor: A PDB-Wide And Web-Based Discovery Resource Of Small Molecular Weight Pro

描述(由申请人提供)：R21：锚：小分子量蛋白质相互作用(Ant)激动剂的PDB范围和基于网络的发现资源。PI：美国宾夕法尼亚州匹兹堡大学医学院药剂学和化学系亚历山大·杜姆林15260，美国PI：卡洛斯·J·卡马乔，匹兹堡大学计算生物学系，匹兹堡，匹兹堡，宾夕法尼亚州15260，美国抽象蛋白质相互作用(PPI)构成了一类新兴的药物干预靶点，蛋白质相互作用委员会为结构信息提供了一个非常有价值的来源。然而，PPI的多样性并不适合目前的药物发现范式，目前的药物发现范式几乎完全专注于筛选(商业上可获得的)小分子化合物的大量历史集合。尽管在化学空间采样和蛋白质-小分子对接构象评分方面存在计算限制，但在电子筛选中，作为高通量生物化学化合物筛选(HTS)的可靠和补充替代方法，仍在继续开发和改进。这一提议的最终目标是通过开发一种虚拟文库的虚拟筛选技术来克服这些限制，该虚拟文库的设计具有内置的氨基酸热点或“锚”，它深入到受体蛋白中，并辅之以真实的多组分反应(MCR)化学。具体目标是(A)根据PDB的类药物敏感性，如单个锚基或更高的氨基酸基序、二联体和三联体，对PDB进行分类；(B)开发一套独特的20种氨基酸的锚定类似物和一个数据库&gt；100小分子支架，以创建一个新的虚拟的、但可化学访问的、针对预先筛选的蛋白质-蛋白质相互作用的库；(C)基于锚定类似物与PPI复杂结构的预先对接，建立PPI的系统虚拟筛选；和(D)，为基于新化合物的(ANT)激动剂的预测提供公共资源，同时主动联系容易获得目标蛋白质的结构基团，以建立合作，其中化合物将以一锅方式快速合成(即使用MCR)进行验证。PDB广泛的类药物靶标图谱与专门设计用于模拟深埋在PPI锚定残基的化学和结构的新化合物相结合，是发现(ANT)激动剂作为阐明生物途径的工具或药物化学计划的起点的一种原创性方法。

DESCRIPTION (provided by applicant): R21: ANCHOR: A PDB-Wide And Web-based Discovery Resource of Small Molecular Weight Protein Interaction (Ant)agonists. PI: Alexander Doemling Departments of Pharmacy and Chemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA PI: Carlos J. Camacho Department of Computational Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA Abstract Protein-protein interactions (PPIs) constitute an emerging class of targets for pharmaceutical intervention with the PDB providing a highly valuable source for structural information. However, the diversity of PPIs does not fit well in the current drug discovery paradigm that focus almost exclusively on screening large historical collections of (commercially available) small molecular weight compounds. Despite computational limitations on the sampling of chemical space and scoring of protein-small molecule docked conformations, in silico screening methods continue to be developed and improved as credible and complementary alternatives to high-throughput biochemical compound screening (HTS). The ultimate goal of this proposal is to overcome these limitations by developing a virtual screening technology of virtual libraries that by design have a built-in amino acid hot spot, or "anchor," that is burying deep into acceptor proteins complemented with real multi-component reaction (MCR) chemistry. Specific aims are to (a) classify the PDB based on their drug-like susceptibility such as single anchors or higher motifs, doublets and triplets of amino-acids; (b) develop a unique set of anchor- analogs for the 20 amino acids and a database of >100 small molecular weight scaffolds to create a novel virtual, but chemically accessible, library to target pre-screened protein-protein interactions; (c) set up a systematic virtual screening of the PPIs based on the pre-docking of anchor-analogs to the PPI complex structure; and (d), provide a public resource for the prediction of (ant)agonists based on novel compounds, while proactively contact structural groups with easy access to the target protein to establish collaborations where compounds will be rapidly synthesized in a one-pot manner (i.e., using MCR) for validation. A PDB wide mapping of drug-like targets combined with novel compounds specifically designed to mimic the chemistry and structure of deeply buried anchor residues of PPIs is an original approach to discover (ant)agonists as tools to elucidate biological pathways or as starting points for medicinal chemistry programs.