A series of halogen-directed donepezil drugs has been designed to inhibit acetyl\ncholinesterase (AChE). Density Functional theory (DFT) has been employed to optimize\nthe chair as well as boat conformers of the parent drug and modified ligands at B3LYP/\nMidiX and B3LYP/6-311G + (d,p) level of theories. Charge distribution, dipole moment,\nenthalpy, free energy and molecular orbitals of these ligands are also investigated to\nunderstand how the halogen-directed modifications impact the ligand structure and\ngovern the non-bonding interactions with the receptors. Molecular docking calculation\nhas been performed to understand the similarities and differences between\nthe binding modes of unmodified and halogenated chair-formed ligands. Molecular\ndocking indicated donepezil and modified ligands had non-covalent interactions with\nhydrophobic gorges and anionic subsites of AChE. The ââ?¬â??CF3-directed ligand possessed\nthe most negative binding affinity. Non-covalent interactions within the ligandââ?¬â??receptor\nsystems were found to be mostly hydrophobic and Ãâ?¬- stacking type. F, Cl and ââ?¬â??CF3\ncontaining ligands emerge as effective and selective AChE inhibitors, which can\nstrongly interact with the two active sites of AChE. In addition, we have also investigated\nselected pharmacokinetic parameters of the parent and modified ligands.
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