title: The effects of fluorine substitution on the chemical properties and inhibitory capacity of Donepezil anti-Alzheimer drug; density functional theory and molecular docking calculations.
abstract: Drug fluorination has the potential to reproduce useful drugs with decreasing the side effect of them. Identifying the effect of this improvement on the chemical properties and biological interactions of drug symbolizes a meaningful progress in drug design. Here the fluorination of Donepezil as an anti-Alzheimer drug, including 7 fluorinated derivatives of it, was investigated computationally. In the first part of our calculations, the most important chemical properties of drug that affects the drug efficiency were investigated by applying the M06/6-31g (d, p) and M062X/6-31g (d, p) levels of theories. Findings showed that the fluorine substitution changed the drug stability as altered the solubility and molecular polarity. Furthermore, the intramolecular hydrogen bonding, charge distribution and electron delocalization of the drug were affected by this replacement. In the second section, the effect of fluorination on the drug⋯enzyme interactions was evaluated by using two effective methods Based on the molecular docking and density functional theory (DFT) calculations fluorine substitution influenced the Donepezil⋯Acetylcholinesterase interactions. Calculated binding energies by two computational methods displayed that the fluorine replacement changed the binding affinity of drug. Finally, the most significant non-bonded interactions between drugs and involved residues were investigated by bond length data analysis.
authors.affiliation: Department of New Materials, Institute of Science and High Technology and Environmental Science, Graduate University of Advanced Technology, Kerman, Iran. Electronic address: a.khosravan@kgut.ac.ir.
authors.forename: Azita
authors.initials: A
authors.lastname: Khosravan
authors.affiliation: Department of Chemistry, Islamic Azad University, Sirjan Branch, Sirjan, Iran.
authors.forename: Safora
authors.initials: S
authors.lastname: Marani
authors.affiliation: Department of Chemistry, Islamic Azad University, Sirjan Branch, Sirjan, Iran; Biophysical Chemistry Laboratory, Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran. Electronic address: sadeghi.mohammadsadegh@gmail.com.
authors.forename: Mohammad Sadegh
authors.initials: MS
authors.lastname: Sadeghi Googheri
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000077265:Donepezil; D004583:Electrons; D005461:Fluorine / Q000737:chemistry* / Q000627:therapeutic use; D006801:Humans; D006860:Hydrogen Bonding; D007189:Indans / Q000737:chemistry* / Q000627:therapeutic use; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000737:chemistry* / Q000627:therapeutic use; D011789:Quantum Theory; D017550:Spectroscopy, Fourier Transform Infrared; D013059:Spectrum Analysis, Raman; D055672:Static Electricity
chemical_list: D007189:Indans; D010880:Piperidines; D005461:Fluorine; D000077265:Donepezil
keywords: AIM; Alzheimer disease; Density functional theory; Donepezil; Fluorination; Molecular docking; NBO