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Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking
Simeon S. - ไม่ระบุหน่วยงาน
ชื่อเรื่อง (EN): Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking
ผู้แต่ง / หัวหน้าโครงการ (EN): Simeon S.
บทคัดย่อ (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 for cognition and memory. A large non-redundant data set of 2,570 compounds with reported IC50 values against AChE was obtained from 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 models were constructed from 100 different data splits using random forest. Generated models afforded R2, QCV 2 and QExt 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 external set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it afforded R2, QCV 2 and QExt 2 values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-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, π-π stacking and hydrophobic interaction inside the binding pocket. These information may be used as guidelines for the design of novel and robust AChE inhibitors. © 2016 Simeon et al.
บทคัดย่อ: ไม่พบข้อมูลจากหน่วยงานต้นทาง
ภาษา (EN): en
เอกสารแนบ (EN): https://www.scopus.com/inward/record.uri?eid=2-s2.0-84992111809&doi=10.7717%2fPEERJ.2322&partnerID=40&md5=4b59a1ae5d04a0a5cf763e60538df361
เผยแพร่โดย (EN): มหาวิทยาลัยมหิดล
คำสำคัญ (EN): validation process
เจ้าของลิขสิทธิ์ (EN): มหาวิทยาลัยมหิดล
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Simeon S.. "Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking". ไม่ระบุหน่วยงาน. ม.ป.ป.

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Probing the origins of human acetylcholinesterase inhibition via QSAR modeling and molecular docking
Simeon S.
มหาวิทยาลัยมหิดล
ไม่ระบุวันที่เผยแพร่
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