Docking-based comparative intermolecular contacts analysis and in silico screening reveal new potent acetylcholinesterase inhibitors
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The positive impact of acetylcholinesterase enzyme inhibitors on neurodegenerative diseases impelled continuous attempts to discover and optimize new acetylcholinesterase enzyme inhibitors. The combined recent interest inacetylcholinesterase enzyme inhibitors, together with known shortages of docking and docking validation methods prompted us to use our new 3D-QSAR method, namely, docking-based comparative intermolecular contacts analysis, to identify optimal docking conditions required to dock certain group of inhibitors into acetylcholinesterase enzyme binding site. Additionally, optimal docking-based comparative intermolecular contacts analysis models were converted into pharmacophore models, which were validated by receiver operating characteristic curve analysis. The pharmacophores were subsequently used as search queries to mine the national cancer institute list of compounds for new acetylcholinesterase enzyme inhibitors. Five low micromolar acetylcholinesterase enzyme inhibitors were identified. The most potent gave IC50 value of 2.55 μM.
KeywordsAcetylcholinesterase Docking-based Comparative Intermolecular Contacts Analysis Libdock virtual screening
This project was sponsored by the Deanship of Scientific Research at the University of Jordan. The authors wish to thank the National Cancer Institute for freely providing hit compounds for experimental validation.
Compliance with ethical standards
Conflict of Interest
The authors declare that they have no competing interests.
- Boyd S (2007) FlexX suite. Chem World 4:72Google Scholar
- Decker M, Kraus B, Heilmann J (2008) Design, synthesis and pharmacological evaluation of hybrid molecules out of quinazolinimines and lipoic acid lead to highly potent and selective butyrylcholinesterase inhibitors with antioxidant properties. Bioorg Med Chem 16:4252–4261CrossRefPubMedGoogle Scholar
- Kryger G, Silman I, Sussman JL (1998) Three-dimensional structure of a complex of E2020 with acetylcholinesterase from Torpedo californica. J Physiol 92:191–194Google Scholar
- Morris GM, Olson AJ, Goodsell DS (2000) Protein-ligand docking. Methods Princ Med Chem 8:31–48Google Scholar
- Rajamani R, Good AC (2007) Ranking poses in structure-based lead discovery and optimization: current trends in scoring function development. Curr Opin Drug Disc 10:308–315Google Scholar
- Taha MO, Dahbiyeh LA, Bustanji Y, Zalloum H, Saleh S (2008) Combining ligand-based pharmacophore modeling, quantitative structure−activity relationship analysis and in silico screening for the discovery of new potent hormone sensitive lipase inhibitors. J Med Chem 51:6478–6494CrossRefPubMedGoogle Scholar
- Taha MO, Habash M, Al-Hadidi Z, Al-Bakri A, Younis K, Sisan S (2011) Docking-based comparative intermolecular contacts analysis as new 3-D QSAR concept for validating docking studies and in silico screening: NMT and GP inhibitors as case studies. J Chem Inf Model 51:647–669CrossRefPubMedGoogle Scholar