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Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking
Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
Mahidol Univ, Fac Med Technol, Ctr Data Min & Biomed Informat, Bangkok, Thailand..
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2016 (English)In: PeerJ, ISSN 2167-8359, E-ISSN 2167-8359, Vol. 4, e2322Article in journal (Refereed) Published
Abstract [en]

Alzheimer's disease (AD) is a chronic neurodegenerative disease which leads to the gradual loss of neuronal cells. Several hypotheses for AD exists (e.g., cholinergic, amyloid, tau hypotheses, etc.). As per the cholinergic hypothesis, the deficiency of choline is responsible for AD; therefore, the inhibition of AChE is a lucrative therapeutic strategy for the treatment of AD. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine that is essential Ifor cognition arid memory. A large non-redundant data set of 2,570 compounds with reported IC50 values against AChE was obtained frorn ChEMBL and employed in quantitative structure-activity relationship (QSAR) study so as to gain insights on their origin of bioactivity. AChE inhibitors were described by a set of 12 fingerprint descriptors and predictive rnodels were constructed from 100 different data splits using random forest. Generated models afforded R-2, Q(cv)(2) and Q(Ext)(2) values in ranges of 0.66-0.93, 0.55-0.79 and 0.56-0.81 for the training set, 10-fold cross-validated set and lexternal set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it afforded R-2, Q(CV)(2) and Q(Ext)(2) values of 0.92 +/- 0.01, 0.78 +/- 0.06 and 018 +/- 0.05, respectively. Furthermore, IT-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover Kennard Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals interaction. Molecular docking revealed that compounds 13, 5 and 28 exhibited the lowest binding energies of -12.2, -12.0 and -12.0 kcal/mol, respectively, against human AChE, which is modulated by, hydrogen bonding, pi-pi stacking and hydrophobic interaction inside the binding pocket. These information may be used as guidelines for the design of novel and robust AChE inhibitors.

Place, publisher, year, edition, pages
2016. Vol. 4, e2322
Keyword [en]
Acetylcholinesterase, Acetylcholinesterase inhibitor, Alzheimer's disease, Dementia, Neurodegenerative disease, Quantitative structure-activity relationship, QSAR, Data mining
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-303741DOI: 10.7717/peerj.2322ISI: 000381255900007PubMedID: 27602288OAI: diva2:973888
Swedish Research Council, C0610701
Available from: 2016-09-23 Created: 2016-09-23 Last updated: 2016-09-23Bibliographically approved

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Wikberg, Jarl E. S.
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