title: 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.
authors: Division of Computer Aided Drug Design, Green Research Centre, BICCB, 38 Green Road West, Dhaka, 1205 Bangladesh.
authors: Adhip
authors: A
authors: Rahman
authors: Division of Computer Aided Drug Design, Green Research Centre, BICCB, 38 Green Road West, Dhaka, 1205 Bangladesh ; Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000 Bangladesh.
authors: Mohammad Tuhin
authors: MT
authors: Ali
authors: Division of Computer Aided Drug Design, Green Research Centre, BICCB, 38 Green Road West, Dhaka, 1205 Bangladesh ; Department of Biochemistry and Molecular Biology, Jahangirnagar University, Dhaka, 1342 Bangladesh.
authors: Mohammad Mahfuz Ali Khan
authors: MM
authors: Shawan
authors: Fakultät für Chemie und Biochemie, Organische Chemie I, Ruhr-Universität Bochum, Universitätsstrasse 150, 44801 Bochum, Germany.
authors: Mohammed Golam
authors: MG
authors: Sarwar
authors: Department of General Studies, Jubail University College, Jubail Industrial City, 31961 The Kingdom of Saudi Arabia.
authors: Mohammad A K
authors: MA
authors: Khan
authors: Division of Computer Aided Drug Design, Green Research Centre, BICCB, 38 Green Road West, Dhaka, 1205 Bangladesh ; Institut Lumière Matière, Université Lyon 1 - CNRS, Université de Lyon, 69622 Villeurbanne Cedex, France.
authors: Mohammad A
authors: MA
authors: Halim
keywords: Alzheimer’s disease; Computer aided drug design; Density functional theory; Halogenation; Molecular docking; Nonbonding interactions