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REPUBLIC OF SERBIA MINISTRY OF DEFENCE
MINISTRY OF DEFENCE Material Resources Sector Defensive Technologies Department
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Exploring AN INTERACTIONS between 4-aryl-4-oxo-2-(N-aryl)butanamides and acetylcholinesterase by docking calculations and molecular dynamics simulation
maja vitorović-todorović Military Technical Institute, Belgrade, mvitod@chem.bg.ac.rs sonja bauk Military Technical Institute, Belgrade, sbauk@gmail.com
Abstract: Recently, we synthesized congeneric set of thirty-eight 4-aryl-4-oxo-2-(N-aryl/cycloalkyl)butanamides and evaluated their acetyl- and butyrylcholinesterase inhibitory activity. To explore possible ligand-AChE interactions, both enantiomers of the seven most active compounds were docked into the AChE active site. Docking studies provided valuable insight into possible interactions between the examined derivatives and AChE active site residues. Exhaustive analysis of the docking poses revealed that R and S enantiomers of 2,4-diisopropylsubstituted compounds 4 and 5, were docked very similarly inside AChE active site. There are two possible orientations of the ligands within the AChE active site gorge. In the best ranked poses, the aroyl moiety is directed toward the bottom of the gorge, while in the most populated poses is directed toward the entrance of the gorge. Enatiomers of tetralinyl-substituted compounds 6 and 7, were docked with opposite orientations inside AChE active site, but best ranked and the most populated pose were very similar. However, majority of the derivatives, in both orientations showed hydrogen bonding with Tyr 124 residue. According to the 5 ns MD simulation, for compound 5, the most persistent, and therefore probably the most important interaction between the most active compound and AChE active site residues involve hydrogen bond between Tyr 124 -OH group and the amido -NH- moiety of the ligand. Keywords: 4-Aryl-4-oxo-2-aminylbutyramides; Anticholinesterase activity; Docking study; Molecular dynamics.
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