Halogen-directed drug design for Alzheimer's disease: a combined density functional and molecular docking study

Abstract : A series of halogen-directed donepezil drugs has been designed to inhibit acetyl cholinesterase (AChE). Density Functional theory (DFT) has been employed to optimize the chair as well as boat conformers of the parent drug and modified ligands at B3LYP/MidiX and B3LYP/6-311G + (d,p) level of theories. Charge distribution, dipole moment, enthalpy, free energy and molecular orbitals of these ligands are also investigated to understand how the halogen-directed modifications impact the ligand structure and govern the non-bonding interactions with the receptors. Molecular docking calculation has been performed to understand the similarities and differences between the binding modes of unmodified and halogenated chair-formed ligands. Molecular docking indicated donepezil and modified ligands had non-covalent interactions with hydrophobic gorges and anionic subsites of AChE. The –CF₃-directed ligand possessed the most negative binding affinity. Non-covalent interactions within the ligand–receptor systems were found to be mostly hydrophobic and π- stacking type. F, Cl and –CF₃ containing ligands emerge as effective and selective AChE inhibitors, which can strongly interact with the two active sites of AChE. In addition, we have also investigated selected pharmacokinetic parameters of the parent and modified ligands.