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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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2996-5) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects 5.4 million people and is the 6th leading cause of death in the United States alone
It is a form of dementia that worsens over time until a person can no longer have a conversation or respond to environmental stimuli
Binding affinity of Donepezil (D) and modified drugs (D1–D5) in chair form against acetyl cholinesterase (AChE) Halogen-directed modifications on donepezil significantly influence the structural properties of the ligands in terms of energy, partial charge distribution and dipole moment
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that affects 5.4 million people and is the 6th leading cause of death in the United States alone. The major constituents of this disease are senile plaques and tangles that result in the death and damage of nerve cells through oxidative stress (Association 2012). Understanding the interaction between acetyl cholinesterase (AChE) and small molecules such as drugs which can inhibit this protein are important to develop the therapeutic strategies against AD (McGleenon et al 1999; Rees and Brimijoin 2003). Small drug molecules were successful to inhibit the acetyl cholinesterase (AChE) due to the presence of catalytic triad and aromatic gorge. These two most important binding sites are frequently targeted by AChE inhibitor
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