The effects of fluorine substitution on the chemical properties and inhibitory capacity of Donepezil anti-Alzheimer drug; density functional theory and molecular docking calculations |
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| Affiliation: | 1. Department of New Materials, Institute of Science and High Technology and Environmental Science, Graduate University of Advanced Technology, Kerman, Iran;2. Department of Chemistry, Islamic Azad University, Sirjan Branch, Sirjan, Iran;3. Biophysical Chemistry Laboratory, Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran;1. Department of Chemistry, Stony Brook University–State University of New York, Stony Brook, NY, 11794-3400, USA;2. Institute of Chemical Biology & Drug Discovery, Stony Brook University–State University of New York, Stony Brook, NY, 11794-3400, USA;1. Department of Chemistry, Faculty of Chemistry, Islamic Azad University, Yazd, Iran;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran;3. Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medicinal Sciences, Kerman, Iran;4. Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medicinal Sciences, Tehran, Iran;5. Department of Medicinal Chemistry and Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran;6. Drug Design & Development Research Center, Tehran University of Medicinal Sciences, Tehran, Iran;1. Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, A. A. 25360, Cali, Colombia;2. Research Group in Development of Materials and Products, CDT ASTIN SENA, Calle 52 # 2Bis-15, Cali, Colombia;3. Organic Synthesis Laboratory and Biological Activity (LSO-Act-Bio), Institute of Chemistry of Natural Resources, Universidad de Talca, Casilla 747, Talca, Chile;4. Centro de Bioinformática y Simulación Molecular (CBSM), Faculty of Engineering, University of Talca, 1 Poniente 1141, Casilla 721, Talca, Chile;1. Department of Pharmacy Engineering, Tianjin University of Technology, Tianjin 300384, PR China;2. College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China |
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| 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 M06/6–31 g (d, p) and M062X/6–31 g (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. |
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| Keywords: | Alzheimer disease Donepezil Fluorination Molecular docking Density functional theory AIM NBO |
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