Kinetic and structural studies of novel isosorbide-based ligand binding to esterase enzymes

Abstract

The main goal of the project described herein was to examine and rationalise the binding of a novel class of compound based on isosorbide to cholinesterase enzymes. The compounds of interest had been prepared within the group and found to interact with both cholinesterase enzymes present in the human body, namely acetylcholinesterase (AChE) [E.C. 3.1.1.7] and butyrylcholinesterase (BChE) [E.C. 3.1.1.8]. They were structurally dissimilar to typical cholinesterase ligands and the basis of their affinity for the enzymes was not apparent at the outset. Kinetic studies and computational analyses were used to elucidate the binding modes of these ligands. The results reveal much regarding the recognition of ligands by cholinesterase enzymes and should prove useful in guiding the preparation of cholinesterase substrates and inhibitors going forward. Firstly, the isosorbide-based compounds were compared to conventional cholinesterase ligands, and such studies are described in Chapter 2. Flexible alignments of our compounds with physostigmine, rivastigmine and other related inhibitors were particularly useful, indicating that similar functional groups could be overlain well in three-dimensional space, and the compounds were not as different as initially suggested. As the complexes of such ligands with cholinesterase enzymes have been elucidated, these comparisons could guide further modelling work. For example, the 5-ester group of the isosorbide derivatives was important for activity and appeared to occupy similar space as the quaternary nitrogen of physostigmine-type ligands; both could interact with Trp82 of BChE via ion - R interactions.