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

我们的主要目的是剖析小分子有机配体与来自铜绿假单胞菌的乙酰多胺氨基水解酶(APAHs)之间的分子相互作用的驱动力。我们特别感兴趣的是增加APAH抑制剂对人组蛋白脱乙酰基酶(HDAC)的选择性。这一一般性主题提出了重要的科学问题，将通过以下主要的子目标来解决：1.生化酶活性的发展和结合分析，根据结合常数以及热力学参数DeltaH，TdeltaS和结合时热容的变化，对潜在的APAH抑制剂进行定量和有意义的评估。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新合成的配体与白对虾APAHs或人HDACs分子相互作用的热力学和动力学研究。APAH-配体络合物的结构分析。补充：对化合物文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少最已知的HDAC抑制剂的典型羟甲酸络合基的新的和选择性的先导结构。

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.