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和乙酰多胺氨基水解酶（APAH）从铜绿假单胞菌的分子之间的相互作用背后的驱动力。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将是重要的。这个一般性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：1.开发生化酶活性和结合测定法，用于定量和有意义地评估潜在的APAH抑制剂的结合常数以及热力学参数Δ H、TdeltaS和结合后热容的变化Δ Cp。新型氟代和非氟代选择性APAH抑制剂的设计和合成3. APAH拮抗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APAH或人HDAC之间分子相互作用的热力学和动力学。APAH-配体复合物的结构分析。补充：化合物库的实验和虚拟筛选，以鉴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。

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.