Search

Summary Traditional chemical weapon agents (CWAs) are known to bind acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Their lethality is known to be different for different mammalian species. We have modeled the binding affinity of CWAs to AChE and BuChE in human, rabbit, rat and mouse using molecular docking and free energy calculations. Through molecular docking we are able to correctly bind the CWAs at the active site. Using molecular mechanics generalized Born surface area (MMGBSA) calculations, we determined the binding free energy in the active site. Through these calculations, we observe that correct orientation at the active site is critical to binding.

Summary Acetylcholinesterase (AChE) reactivators (oximes) are generally used as antidotes in case of nerve agent poisoning. Because of their affinity to AChE, they may also act as weak inhibitors of AChE. Their inhibition potency against AChE was determined by an in vitro method based on the interaction between AChE and oxime reactivator in the concentration range 10 -1 to 10 -8 M. We used eel AChE for these assays. We found that AChE inhibition strongly depends on the oxime structure. The aim of the present study is to describe the structure-activity relationship (SAR) between oxime structure and inhibition of AChE. AChE reactivators tested include both monoquaternary and bisquaternary structures with the oxime group in different positions on the pyridine ring and with changes in the connecting linker in the case of the bisquaternary compounds. We found AChE inhibition to be highest in bisquaternary oximes that have a longer linker length and have the oxime group in the ortho position. Increased AChE inhibition in monoquaternary oximes was highest when the meta position was occupied by the oxime nucleophile. In addition, different substituents in the connecting chain (in case of bisquaternary oximes) modulated their inhibition potency.