Muhammad Sibte Hasan Mahmood
The use of pesticides and insecticides has increased in agricultural field and household etc for pest control, pest management and to prevent diseases caused by insects respectively over a period. Insecticides are also a category of pesticides. Some of the most abundantly used pesticides contain organophosphate compounds as basic ingredient. Organophosphate compounds are ester, amide and thiol derivatives of phosphoric acid. Such compounds are highly toxic and their accumulation in the human body can cause neuro-poisoning. They deactivate the human acetylcholinesterase (AChE) and thus stop the acetylcholine neurotransmission. Although the process is not permanent, it depends upon how much time the interaction between organophosphate compound and AChE has taken before the aging and denaturation of the enzyme starts. Before aging of the enzyme, a group of compounds known as Oximes belonging to the family of amines can be used to reactivate the human acetylcholinesterase.
Oximes are divided into four sub-categories namely: aldoximes, ketoximes, oxime esters and steroid oximes depending upon their chemical orientation. The first oxime was developed by Czech Republic in 1956. Among them, obidoxime and pralidoxime are clinically used for years and are synthesised commercially. Oximes can reactivate the human AChE by removing the phosphate attached to its residues in the catalytic active sides, phosphorylated by organophosphate compounds. In this study, the structures of oximes were obtained from previously performed experiments. The structures were then converted to 2D structures (SDF) via PubChem. The SDF files were then converted to PDB (3D) format using PyRx tool which produced a tertiary structure of the oximes which was a requirement to perform docking. As for the human AChE, the structures of inhibited AChE were downloaded from Protein Data Bank in the PDB format and cleaned using Chimera tool. After preparing the 3D structures, oximes with highest chances of reactivating the inhibited AChE were selected by observing the AChE and oxime interactions. A total of 67 oximes from different categories were selected forming more than 600 conformations of enzyme-ligand complexes. To further improve the properties, characteristics if the toxicity and metabolism of these oximes were also checked using ligplot+ and Vega ZZ.