Expansion of the scaffold diversity for the development of highly selective butyrylcholinesterase (BChE) inhibitors: Discovery of new hits through the pharmacophore model generation,virtual screening and molecular dynamics simulation |
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Institution: | 1. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran;2. Cellular and Molecular Research Center, Gerash University of Medical Sciences, Gerash, Iran;3. Behbahan Faculty of Medical Sciences, Behbahan, Iran;4. Salman-e Fars Hospital, Bushehr, Iran;5. Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;1. Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche (STEBICEF), Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy;2. Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale Annunziata, 98168 Messina, Italy |
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Abstract: | Butyrylcholinesterase (BChE) is recently considered as a new target for the treatment of Alzheimer’s disease (AD). There is an increasing interest in the development of BChE inhibitors. In the present study, a set of pharmacophore models for BChE was developed and validated. Based on the models, virtual screening was performed on five compound collections, from which seventeen potential hits were retained for biological investigation. In total, eight of these seventeen potential hits showed selective BChE inhibitory activity. Moreover, four compounds displayed IC50 values in sub-micromolar range on eqBChE and three displayed IC50 values < 2 μM on huBChE. The diverse scaffolds of the active compounds provided good starting point further development of selective BChE inhibitors. As far as we concerned, here we disclose the first selective pharmacophore model targeting BChE. The high rate of the model in the identification of active hits indicates it is a valuable tool for the development of selective BChE inhibitors, which may benefit the treatment of AD. |
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Keywords: | Selective butyrylcholinesterase Pharmacophore modeling Virtual screening Molecular dynamics Alzheimer’s disease |
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