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

锚点：小分子量 Pro 的 PDB 范围和基于网络的发现资源

基本信息

批准号：
7928195
负责人：
Carlos J. Camacho
金额：
$ 14.33万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-08 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7928195
关键词：
Agonist Amino Acids Ants Area Attributes of Chemicals Binding Binding Proteins Biochemical Biological Cellular biology Chemicals Chemistry Collaborations Collection Communities Complement Complex Computational Biology Computer Simulation Computer software Data Set Databases Disease Docking Generic Drugs Goals Hot Spot Internet Intervention Libraries Malignant Neoplasms Maps Medical Methods Minority Molecular Molecular Conformation Molecular Weight Nature Oncogenes Online Systems Organism Pathway interactions Pennsylvania Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacy facility Play Predisposition Property Protein Databases Protein p53 Proteins Reaction Research Resolution Resources Role Sampling Screening procedure Solvents Source Specific qualifier value Staging Structure Surface Techniques Technology Triplet Multiple Birth Universities Validation Virtual Library Weight abstracting analog base design drug discovery flexibility high throughput screening improved insight interest medical schools molecular recognition novel numb protein programs protein complex protein protein interaction protein structure scaffold small molecule small molecule libraries tool virtual

项目摘要

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.

描述（由申请人提供）： R21：锚点：小分子量蛋白质相互作用（蚂蚁）激动剂的 PDB 范围和基于网络的发现资源。 PI：Alexander Doemling，匹兹堡大学医学院药学和化学系，Pittsburgh，Pennsylvania 15260，USA PI：Carlos J. Camacho 匹兹堡大学计算生物学系，Pittsburgh，Pennsylvania 15260，USA 摘要蛋白质-蛋白质相互作用（PPI）构成了一类新兴的靶点 PDB 的药物干预为结构信息提供了非常有价值的来源。然而，质子泵抑制剂的多样性并不适合当前的药物发现范式，该范式几乎完全专注于筛选（市售的）小分子量化合物的大量历史集合。尽管化学空间采样和蛋白质-小分子对接构象评分存在计算限制，但计算机筛选方法仍在不断发展和改进，作为高通量生化化合物筛选 (HTS) 的可靠和补充替代方案。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，该技术在设计上具有内置的氨基酸热点或“锚点”，该热点深埋在受体蛋白中，并辅以真正的多组分反应（MCR）化学。具体目标是 (a) 根据 PDB 的药物敏感性（例如单锚或更高基序、氨基酸双联体和三联体）对 PDB 进行分类； (b) 开发一套独特的 20 种氨基酸锚定类似物和超过 100 个小分子量支架的数据库，以创建一个新颖的虚拟但化学可访问的库，以针对预先筛选的蛋白质-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，建立系统的 PPI 虚拟筛选； (d) 为基于新化合物的（蚂蚁）激动剂预测提供公共资源，同时主动联系易于获取目标蛋白的结构基团以建立合作，以一锅法（即使用 MCR）快速合成化合物进行验证。 PDB 广泛的类药物靶点图谱与专门设计用于模拟深埋的 PPI 锚残基的化学和结构的新型化合物相结合，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项目起点的原始方法。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

MCR synthesis of praziquantel derivatives.

DOI：
10.1111/j.1747-0285.2011.01288.x
发表时间：
2012-04
期刊：
Chemical biology & drug design
影响因子：
3
作者：
Liu H;William S;Herdtweck E;Botros S;Dömling A
通讯作者：
Dömling A

Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities.

DOI：
10.1021/cb400728e
发表时间：
2014-03-21
期刊：
ACS CHEMICAL BIOLOGY
影响因子：
4
作者：
Huang, Yijun;Wolf, Siglinde;Beck, Barbara;Koehler, Lisa-Maria;Khoury, Kareem;Popowicz, Grzegorz M.;Goda, Sayed K.;Subklewe, Marion;Twarda, Aleksandra;Holak, Tad A.;Domling, Alexander
通讯作者：
Domling, Alexander

Tricycles by a new Ugi variation and Pictet-Spengler reaction in one pot.

DOI：
10.1002/chem.201300962
发表时间：
2013-06-17
期刊：
CHEMISTRY-A EUROPEAN JOURNAL
影响因子：
4.3
作者：
Sinha, Mantosh K.;Khoury, Kareem;Herdtweck, Eberhardt;Doemling, Alexander
通讯作者：
Doemling, Alexander

Structure of the Complex of Human Programmed Death 1, PD-1, and Its Ligand PD-L1.

DOI：
10.1016/j.str.2015.09.010
发表时间：
2015-12-01
期刊：
Structure (London, England : 1993)
影响因子：
0
作者：
Zak KM;Kitel R;Przetocka S;Golik P;Guzik K;Musielak B;Dömling A;Dubin G;Holak TA
通讯作者：
Holak TA

Multicomponent synthesis of diverse 1,4-benzodiazepine scaffolds.

DOI：
10.1021/ol302837h
发表时间：
2012-12-07
期刊：
ORGANIC LETTERS
影响因子：
5.2
作者：
Huang, Yijun;Khoury, Kareem;Chanas, Tyler;Domling, Alexander
通讯作者：
Domling, Alexander

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Carlos J. Camacho其他文献

Predicting the Interactions between PDZ Adapter Domains and Disordered Peptides

DOI：
10.1016/j.bpj.2009.12.2324
发表时间：
2010-01-01
期刊：
Conference abstract
影响因子：
作者：
Weiyi Zhang;Carlos J. Camacho;Eran Eyal
通讯作者：
Eran Eyal

Oral 1812-2 - Structure guided chemical modifications of propylthiouracil reveal novel small molecule inhibitors of cytochrome B5 reductase 3

DOI：
10.1016/j.niox.2014.09.019
发表时间：
2014-11-15
期刊：
Conference abstract
影响因子：
作者：
Md. Mizanur Rahaman;David Koes;Courtney Sparacino-Watkins;Megan Miller;Carlos J. Camacho;Adam Straub
通讯作者：
Adam Straub