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Novel Druggable Exosites in Protein Kinases

蛋白激酶中新型可药物外泌体

基本信息

批准号：
7961365
负责人：
RUBEN ABAGYAN
金额：
$ 19.61万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7961365
关键词：
Address Affect Binding Binding Sites Biological Assay Biological Factors Catalytic Domain Chemicals Complex Computer Analysis Computing Methodologies Cyclic AMP-Dependent Protein Kinases Data Set Databases Detection Diabetes Mellitus Disease Docking Drug Delivery Systems Enzymes Event Family Goals Heart Diseases Homology Modeling Human Inflammation Label Libraries Ligand Binding Ligands Location Malignant Neoplasms Mediator of activation protein Membrane Proteins Methodology Molecular Molecular Conformation Names Nature Online Systems Pharmaceutical Preparations Phosphorylated Peptide Phosphotransferases Property Protein Kinase Proteins Proto-Oncogene Proteins c-akt Research Research Design Research Personnel Resolution Resources Roentgen Rays Ruthenium Ben Screening procedure Series Signal Transduction Site Structure Structure-Activity Relationship Surface Techniques Testing Therapeutic analog aurora-A kinase base design drug discovery flexibility gel electrophoresis human STK6 protein improved in vivo inhibitor/antagonist member mutant novel novel therapeutic intervention protein function receptor small molecule structural biology success virtual working group

项目摘要

DESCRIPTION (provided by applicant): Protein Kinases are critical constituents of signal transduction networks and their malfunction is associated with disease including cancer, inflammation, diabetes, and heart disease. Traditional drug discovery efforts have pursued inhibitors that target the ATP binding site with little consideration for other sites on protein kinase surfaces. Our hypothesis is that we can use structure-based design techniques to identify novel small molecule binding sites (exosites) on the surface of protein kinases. We know that other exosites must exist because screens of natural products and synthetic libraries have identified ATP-noncompetitive inhibitors for many members of the kinase family. The first goal of this research is to provide a new therapeutic approach to target three protein kinases, Protein Kinase A, Protein Kinase B and Aurora A Kinase. This will be achieved by the successful completion of three aims (I) To identify, through computational analysis, novel druggable sites ('exosites') on PKA, PKB and Aurora A; (II) To identify, by virtual ligand screening, small drug-like molecules that bind to exosites on these kinases and inhibit function; (III) To develop these inhibitors into drug-leads through chemical optimization, structural characterization and iteration. In our final aim: (IV) We will apply our computational analysis to the whole kinase family and identify druggable exosites for other members. We will make available our findings through the Protein Kinase Resource (a public web-based kinase resource), so that these novel exosites can be targeted by academic groups working on specific protein kinases. The nature of the project is multi-disciplinary and we believe that the goals are within reach due to our combined expertise in computational, molecular and structural biology.

描述（由申请人提供）：蛋白激酶是信号转导网络的关键组成部分，其功能障碍与包括癌症、炎症、糖尿病和心脏病在内的疾病相关。传统的药物发现努力追求靶向ATP结合位点的抑制剂，而很少考虑蛋白激酶表面上的其他位点。我们的假设是，我们可以使用基于结构的设计技术，以确定新的小分子结合位点（exosites）的蛋白激酶的表面。我们知道，其他exosite必须存在，因为屏幕的天然产物和合成库已确定ATP-非竞争性抑制剂的激酶家族的许多成员。本研究的第一个目标是提供一种新的治疗方法，靶向三种蛋白激酶，蛋白激酶A，蛋白激酶B和极光A激酶。这将通过三个目标的成功完成来实现：（I）通过计算分析来识别新的可药物化位点（II）通过虚拟配体筛选，鉴定与这些激酶上的外切位点结合并抑制功能的小药物样分子;（III）通过化学优化、结构表征和迭代将这些抑制剂开发成药物先导物。在我们的最终目标：（IV）我们将我们的计算分析应用于整个激酶家族，并确定其他成员的可药用外位点。我们将通过蛋白激酶资源（一个公共的基于网络的激酶资源）提供我们的研究结果，以便这些新的外部位点可以被研究特定蛋白激酶的学术团体所瞄准。该项目的性质是多学科的，我们相信，由于我们在计算，分子和结构生物学方面的综合专业知识，这些目标是可以实现的。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Druggable exosites of the human kino-pocketome.

人类动袋组的可药物外位点。

DOI：
10.1007/s10822-019-00276-y
发表时间：
2020
期刊：
Journal of computer-aided molecular design
影响因子：
3.5
作者：
Nicola,George;Kufareva,Irina;Ilatovskiy,AndreyV;Abagyan,Ruben
通讯作者：
Abagyan,Ruben

2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action.

DOI：
10.1021/acs.jmedchem.8b01765
发表时间：
2019-02-28
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Bestgen B;Kufareva I;Seetoh W;Abell C;Hartmann RW;Abagyan R;Le Borgne M;Filhol O;Cochet C;Lomberget T;Engel M
通讯作者：
Engel M

Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states.