Designing Second Generation Anti-Alzheimer Compounds as Inhibitors of Human Acetylcholinesterase: Computational Screening of Synthetic Molecules and Dietary Phytochemicals.
Alzheimer's disease (AD), a big cause of memory loss, is a progressive neurodegenerative disorder. The disease leads to irreversible loss of neurons that result in reduced level of acetylcholine neurotransmitter (ACh). The reduction of ACh level impairs brain functioning. One aspect of AD therapy is to maintain ACh level up to a safe limit, by blocking acetylcholinesterase (AChE), an enzyme that is naturally responsible for its degradation. This research presents an in-silico screening and designing of hAChE inhibitors as potential anti-Alzheimer drugs. Molecular docking results of the database retrieved (synthetic chemicals and dietary phytochemicals) and self-drawn ligands were compared with Food and Drug Administration (FDA) approved drugs against AD as controls. Furthermore, computational ADME studies were performed on the hits to assess their safety. Human AChE was found to be most approptiate target site as compared to commonly used Torpedo AChE. Among the tested dietry phytochemicals, berberastine, berberine, yohimbine, sanguinarine, elemol and naringenin are the worth mentioning phytochemicals as potential anti-Alzheimer drugs The synthetic leads were mostly dual binding site inhibitors with two binding subunits linked by a carbon chain i.e. second generation AD drugs. Fifteen new heterodimers were designed that were computationally more efficient inhibitors than previously reported compounds. Using computational methods, compounds present in online chemical databases can be screened to design more efficient and safer drugs against cognitive symptoms of AD.
Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan; National Center of Excellence in Molecular Biology, University of the Punjab, Lahore, Pakistan.
Hafsa
H
Amat-Ur-Rasool
Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan.
Mehboob
M
Ahmed
D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D062105:Molecular Docking Simulation; D018697:Nootropic Agents / Q000737:chemistry* / Q000494:pharmacology; D064209:Phytochemicals / Q000737:chemistry* / Q000494:pharmacology; D017385:Sequence Homology
D002800:Cholinesterase Inhibitors; D018697:Nootropic Agents; D064209:Phytochemicals; D000110:Acetylcholinesterase