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

描述（由申请人提供）：R21: ANCHOR：小分子量蛋白相互作用（蚂蚁）激动剂的PDB-Wide和基于web的发现资源。PI: Carlos J. Camacho匹兹堡大学计算生物系，宾夕法尼亚州匹兹堡15260摘要蛋白质-蛋白质相互作用（PPIs）是一类新兴的药物干预靶标，PDB提供了非常有价值的结构信息来源。然而，PPIs的多样性并不适合当前的药物发现模式，这种模式几乎完全集中于筛选（市售）小分子量化合物的大型历史集合。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，但硅筛选方法仍在继续发展和改进，作为高通量生化化合物筛选（HTS）的可靠和补充选择。该提案的最终目标是通过开发虚拟文库的虚拟筛选技术来克服这些限制，虚拟文库设计有一个内置的氨基酸热点或“锚点”，它深埋在受体蛋白中，并辅以真正的多组分反应（MCR）化学。具体目标是：(a)根据药物样敏感性对PDB进行分类，如单锚定或更高的基序，氨基酸的双核苷酸和三核苷酸；(b)为20种氨基酸开发一套独特的锚定类似物和一个包含100个小分子量支架的数据库，以创建一个新的虚拟的，但化学上可访问的文库，以靶向预先筛选的蛋白质-蛋白质相互作用；(c)基于锚定类似物与PPI复合物结构的预对接，对PPI进行系统的虚拟筛选；(d)为预测基于新化合物的（蚂蚁）激动剂提供公共资源，同时主动联系易于接近目标蛋白的结构基团，建立合作关系，其中化合物将以一锅方式快速合成（即使用MCR）进行验证。将药物样靶点的PDB广泛映射与专门设计用于模拟PPIs深埋锚定残基的化学和结构的新化合物相结合，是发现（蚂蚁）激动剂作为阐明生物途径的工具或作为药物化学计划起点的原始方法。

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.