Bao, Wei2018-08-272018-08-272018http://udspace.udel.edu/handle/19716/23704In chapter one, a new concept of catalytic acetyl transfer enzyme inhibitor design was explored. Thiolsalicylamide analogues were recently used to transfer acetyl group in vitro and in vivo to lysine/serine of target proteins. The ability of thiolsalicylamide compounds to re-acetylate make them ideal to catalytically transfer acetyl groups. Here this approach is used to make a catalytic cyclooxygenase (COX) inhibitor. A catalytic COX inhibitor would have unique inhibition kinetics. ☐ Based on known inhibitors and the crystal structure of COX-1/2, we initially synthesized several compounds and tested their catalytic inhibition. The IC50 and kinetics of pre-acetylated thiolsalicylamide compounds were tested. ☐ Using molecular dynamics simulation, the binding affinity of several proposed inhibitors were assessed. The potential mean force (PMF) from bound acetylated compounds to access COX’s Ser530 were evaluated. The combined results of these two properties were used to select several candidates to be synthesized. Candidates were then tested in vitro and in vivo for their COX inhibition efficiency and kinetics. The top hit, WB3/AcWB3 proved to be an efficient catalytic inhibitor that had a sustained effect in COX inhibition in cells. ☐ In chapter two, a new approach was explored to modify positively charged pyridinium oxime (PAM) reactivator drugs in a manner that would facilitate their ability to cross the blood brain barrier (BBB). ☐ PAM is currently used to reactivate organophosphorus inhibited acetylcholinesterase. However, PAM has very low CNS activity due to its low BBB permeability. The high abundance of glucose transporter 1 (GLUT1) in human BBB could potentially be exploited to facilitate transportation of PAM to across the BBB. Glucose conjugated sugar-oximes (SOx) were synthesized and tested in vitro. The reactivity of SOx was characterized using an in vitro enzyme kinetics assay. To assess the permeability of BBB, a cell model was used combing with LC-MS quantification. ☐ A complete molecular dynamics model of SOxs’ GLUT1 transportation was constructed. Three stages of GLUT1 (outward facing state, ligand binding state, inward facing state) were built from crystal structures in an explicit membrane system. Adaptive steered MD was used to evaluate the SOx’s transportation through GLUT1.Pure sciencesCOXSer530WB3Thesis1049937859https://doi.org/10.58088/nvva-f6582018-07-23en