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

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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.