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Gadaleta, D, Spinu, N, Roncaglioni, A, Cronin, MTD and Benfenati, E (2022) Prediction Of The Neurotoxic Potential Of Chemicals Based On Modelling Of Molecular Initiating Events Upstream Of The Adverse Outcome Pathways Of (Developmental) Neurotoxicity. International Journal of Molecular Sciences, 23. ISSN 1422-0067
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Abstract
Developmental and adult/ageing neurotoxicity are an area needing alternative methods for chemical risk assessment. The formulation of a strategy to screen large numbers of chemicals is highly relevant due to potential exposure to compounds that may have long-term adverse health consequences on the nervous system, leading to neurodegeneration. Adverse Outcome Pathways (AOPs) provide information on relevant molecular initiating events (MIEs) and key events (KEs) that could inform the development of computational alternatives for these complex effects. We propose a screening method integrating multiple Quantitative Structure–Activity Relationship (QSAR) models. The MIEs of existing AOP networks of developmental and adult/ageing neurotoxicity were modelled to predict neurotoxicity. Random Forests were used to model each MIE. Predictions re-turned by single models were integrated and evaluated for their capability to predict neurotoxicity. Specifically, MIE predictions were used within various types of classifiers and compared with other reference standards (chemical descriptors and structural fingerprints) to benchmark their predictive capability. Overall, classifiers based on MIE predictions returned predictive performances compa-rable to those based on chemical descriptors and structural fingerprints. The integrated computa-tional approach described here will be beneficial for large-scale screening and prioritisation of chem-icals as a function of their potential to cause long-term neurotoxic effects.
| Item Type: | Article |
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| Uncontrolled Keywords: | 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Divisions: | Pharmacy & Biomolecular Sciences |
| Publisher: | MDPI AG |
| Date Deposited: | 08 Mar 2022 15:27 |
| Last Modified: | 28 Mar 2022 14:30 |
| DOI or ID number: | 10.3390/ijms23063053 |
| URI: | https://researchonline.ljmu.ac.uk/id/eprint/16469 |
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