Several cholinesterase ( Acetylcholinesterase and Butyrylcholinesterase) inhibitors are either being utilized for symptomatic treatment of Alzheimer’s disease or are in advanced clinical trials. A series of 12 known pyrazinamide derivatives that display inhibitory activity toward both acetylcholinesterase and butyrylcholinesteras e (ChEs) was considered for theoretical studies. These theoretic al approaches employed quantum mechanics and molecu lar docking data from both ChEs that were previously su bmitted to molecular dynamics (MD) simulations. Doc king studies revealed that the complex formed between Ch Es and the best pyrazinamide derivatives compounds reproduced the binding mode for theoretical calcula tion reported, where the ligand was coupled into th e choline-binding site and stabilized through the hyd rogen bonds interactions with Tyr121 or Tyr332 for AChE and BuChE, respectively, suggesting that these compound s could be an efficients inhibitors. The careful ana lysis of the investigation gave the compounds L 3 and L 4 as the most promising compounds based on the docki ng score energies and hydrogen bonds distances. The best possible int eractions of the lead compounds are simulated for s tability using molecular dynamics. The results of this inves tigation provide valuable information on the design of highly selective pyrazinamide derivatives.
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