Novel pyridinium oximes: synthesis, molecular docking and in vitro reactivation studies

Abstract

A computational approach has been attempted for the screening of 4-pyridoxinium (4P) ring based reactivators for paraoxon inhibited AChE. The oxime molecules were designed with the common 4P skeleton and varying the carbon linkers. Initially, the AChE binding capability was assessed by molecular docking with PDB:2WHP and 3ZLV, which showed important interactions with Ser298, Try124 and Trp286. These computational results were validated by an in vitro AChE binding assay, which showed binding affinities in the range of 10–90%. Finally, reactivation potency was calculated as % reactivation on paraoxon inhibited eelAChE in the concentration range of 10⁻⁵ to 10⁻⁷ M. It was observed that introduction of an aliphatic linker attached to 4-pyridoxime has a high binding affinity and hence, may act as a good reactivator as compared to the aromatic pyridoximes.