Discovery of dual binding site acetylcholinesterase inhibitors identified by pharmacophore modeling and sequential virtual screening techniques |
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Authors: | Gupta Shikhar Fallarero Adyary Järvinen Päivi Karlsson Daniela Johnson Mark S Vuorela Pia M Mohan C Gopi |
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Institution: | a Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062 Punjab, India b Department of Biosciences, Åbo Akademi University, Artillerigatan 6A, FI-20520 Turku, Finland c Division of Pharmaceutical Biology, Faculty of Pharmacy, PO Box 56, FI-00014 University of Helsinki, Finland |
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Abstract: | Dual binding site acetylcholinesterase (AChE) inhibitors are promising for the treatment of Alzheimer’s disease (AD). They alleviate the cognitive deficits and AD-modifying agents, by inhibiting the β-amyloid (Aβ) peptide aggregation, through binding to both the catalytic and peripheral anionic sites, the so called dual binding site of the AChE enzyme. In this Letter, chemical features based 3D-pharmacophore models were developed based on the eight potent and structurally diverse AChE inhibitors (I-VIII) obtained from high-throughput in vitro screening technique. The best 3D-pharmacophore model, Hypo1, consists of two hydrogen-bond acceptor lipid, one hydrophobe, and two hydrophobic aliphatic features obtained by Catalyst/HIPHOP algorithm adopted in Discovery studio program. Hypo1 was used as a 3D query in sequential virtual screening study to filter three small compound databases. Further, a total of nine compounds were selected and followed on in vitro analysis. Finally, we identified two leads—Specs1 (IC50 = 3.279 μM) and Spec2 (IC50 = 5.986 μM) dual binding site compounds from Specs database, having good AChE enzyme inhibitory activity. |
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Keywords: | AD Alzheimer&rsquo s disease AChE acetylcholinesterase enzyme CS catalytic site PAS peripheral anionic site VS virtual screening DTNB 5 5&prime -dithiobis-2-nitrobenzoic acid ATCI acetylthiocholine iodide TcAChE Torpedo californica AChE PDB protein data bank GFS gold fitness score" target="_blank">gold fitness score BBB blood-brain barrier CNS central nervous system |
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