國家衛生研究院 NHRI:Item 3990099045/14573

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Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/14573

Title:	In silico prediction of parkinsonian motor deficits-related neurotoxicants based on the adverse outcome pathway concept
Authors:	Kan, HL;Tung, CW;Chang, SE;Lin, YC
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	Exposure to neurotoxicants has been associated with Parkinson's disease (PD). Limited by the clinical variation in the signs and symptoms as well as the slow disease progression, the identification of parkinsonian neurotoxicants relies on animal models. Here, we propose an innovative in silico model for the prediction of parkinsonian neurotoxicants. The model was designed based on a validated adverse outcome pathway (AOP) for parkinsonian motor deficits initiated from the inhibition of mitochondrial complex I. The model consists of a molecular docking model for mitochondrial complex I protein to predict the molecular initiating event and a neuronal cytotoxicity Quantitative Structure-Activity Relationships (QSAR) model to predict the cellular outcome of the AOP. Four known PD-related complex I inhibitors and four non-neurotoxic chemicals were utilized to develop the threshold of the models and to validate the model, respectively. The integrated model showed 100% specificity in ruling out the non-neurotoxic chemicals. The screening of 41 neurotoxicants and complex I inhibitors with the model resulted in 16 chemicals predicted to induce parkinsonian disorder through the molecular initiating event of mitochondrial complex I inhibition. Five of them, namely cyhalothrin, deguelin, deltamethrin, diazepam, and permethrin, are cases with direct evidence linking them to parkinsonian motor deficit-related signs and symptoms. The neurotoxicant prediction model for parkinsonian motor deficits based on the AOP concept may be useful in prioritizing chemicals for further evaluations on PD potential.
Date:	2022-12
Relation:	Archives of Toxicology. 2022 Dec;96(12):3305-3314.
Link to:	http://dx.doi.org/10.1007/s00204-022-03376-1
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0340-5761&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000863221000003
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85139146354
Appears in Collections:	[Chun-Wei Tung] Periodical Articles

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