Molecular Interactions between Acetylpolymine-aminohydrolases of Pseudomonas aeruginosa and small organic Ligands

铜绿假单胞菌乙酰多胺氨基水解酶与小有机配体之间的分子相互作用

• 批准号: 236178355
• 负责人: Professor Dr. Franz-Josef Meyer-Almes
• 金额: --
• 依托单位: Fachbereich Chemie- und Biotechnologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/236178355?language=en
• 关键词: Molecular; Interactions; between; Acetylpolymine; aminohydrolases

Our major aim is to dissect the driving forces behind the molecular interaction between small organic ligands and acetylpolyamine aminohydrolases (APAHs) from P. aeruginosa. We are particularly interested in increasing the selectivity of APAH inhibitors with respect to human histone deacetylases (HDACs). This knowledge will be important to develop drug candidates with only few side effects on humans.This general topic raises important scientific questions which will be addressed by the following major sub-objectives:1. Development of biochemical enzyme activity and binding assays for a quantitative and meaningful assessment of potential APAH inhibitors in terms of binding constants as well as thermodynamic parameters deltaH, TdeltaS and changes in heat capacity, deltaCp, upon binding.2. Design and Synthesis of novel fluorinated and unfluorinated selective APAH inhibitors 3. Study of antibacterial activity and cell permeability of APAH inhibitors4. Investigation of the thermodynamics and kinetics of the molecular interaction between newly synthesised ligands and P. aeuginosa APAHs or human HDACs.5. Structural analysis of APAH-ligand complexes.6. Supplement: Experimental and virtual screening of compound libraries to identify novel and selective lead structures which may interact with allosteric binding sites or lack the typical hydroxamate chelating group of most known HDAC inhibitors.

我们的主要目标是剖析小有机配体与铜绿假单胞菌乙酰多胺氨基水解酶 (APAH) 之间分子相互作用背后的驱动力。我们特别感兴趣的是提高 APAH 抑制剂对人组蛋白脱乙酰酶 (HDAC) 的选择性。这些知识对于开发对人类只有很少副作用的候选药物非常重要。这个一般主题提出了重要的科学问题，这些问题将通过以下主要子目标来解决：1。开发生化酶活性和结合测定，以对潜在的 APAH 抑制剂的结合常数以及热力学参数 deltaH、TdeltaS 和结合后热容量的变化 deltaCp 进行定量和有意义的评估。2．新型含氟和非含氟选择性APAH抑制剂的设计与合成3.APAH抑制剂的抗菌活性和细胞通透性研究4．研究新合成的配体与铜绿假单胞菌APAHs或人HDACs之间分子相互作用的热力学和动力学。 5． APAH-配体复合物的结构分析6．补充：对化合物库进行实验和虚拟筛选，以确定可能与变构结合位点相互作用或缺乏大多数已知 HDAC 抑制剂的典型异羟肟酸螯合基团的新型和选择性先导结构。

项目成果

The thermodynamic signature of ligand binding to histone deacetylase-like amidohydrolases is most sensitive to the flexibility in the L2-loop lining the active site pocket.

• DOI: 10.1016/j.bbagen.2017.04.001
• 发表时间: 2017-07
• 期刊: Biochimica et biophysica acta. General subjects
• 作者: C. Meyners;Andreas Krämer;Özkan Yildiz;F. Meyer‐Almes

Toward Photopharmacological Antimicrobial Chemotherapy Using Photoswitchable Amidohydrolase Inhibitors.

• DOI: 10.1021/acsinfecdis.6b00148
• 发表时间: 2017-02
• 期刊: ACS infectious diseases
• 影响因子: 5.3
• 作者: Claire E. Weston;Andreas Krämer;Félix Colin;Özkan Yildiz;M. Baud;F. Meyer‐Almes;M. Fuchter

A fluorescence lifetime-based binding assay for acetylpolyamine amidohydrolases from Pseudomonas aeruginosa using a [1,3]dioxolo[4,5-f][1,3]benzodioxole (DBD) ligand probe

使用 [1,3]dioxolo[4,5-f][1,3] 苯并间二氧杂环戊烯 (DBD) 配体探针对铜绿假单胞菌乙酰多胺酰胺水解酶进行基于荧光寿命的结合测定

• DOI: 10.1007/s00216-014-7886-5
• 发表时间: 2014
• 期刊: Analytical and Bioanalytical Chemistry
• 影响因子: 4.3
• 作者: Meyners C;Wawrzinek R;Krämer A;Hinz S;Wessig P;Meyer-Almes FJ
• 通讯作者: Meyer-Almes FJ

Kinetic binding assays for the analysis of protein-ligand interactions.

• DOI: 10.1016/j.ddtec.2015.08.004
• 发表时间: 2015-10-01
• 期刊: Drug discovery today. Technologies
• 作者: Meyer-Almes, Franz-Josef

Crystal Structure of a Histone Deacetylase Homologue from Pseudomonas aeruginosa.

铜绿假单胞菌组蛋白脱乙酰酶同源物的晶体结构

• DOI: 10.1021/acs.biochem.6b00613
• 发表时间: 2016
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Krämer A;Wagner T;Yildiz Ö;Meyer-Almes FJ
• 通讯作者: Meyer-Almes FJ