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

我们的主要目的是剖析来自铜绿假单胞菌的小有机配体和乙酰多胺氨基水解酶（APAHs）分子相互作用背后的驱动力。我们对提高APAH抑制剂对人组蛋白去乙酰化酶（hdac）的选择性特别感兴趣。这些知识对于开发对人体副作用很小的候选药物非常重要。这个一般的主题提出了重要的科学问题，这些问题将通过以下主要的子目标来解决：开发生化酶活性和结合试验，从结合常数、热力学参数δ tah、tdelta和结合时热容量δ tacp的变化等方面对潜在的APAH抑制剂进行定量和有意义的评估。新型氟化和非氟化选择性APAH抑制剂的设计与合成APAH抑制剂抑菌活性及细胞通透性的研究[j]。新合成配体与绿藻假单胞菌APAHs或人hdac分子相互作用的热力学和动力学研究。apah配体的结构分析。补充：化合物文库的实验和虚拟筛选，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抑制剂的典型羟酸盐螯合基团的新型和选择性先导结构。

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.