Piechota, P (2015) Development of in silico models for the prediction of toxicity incorporating ADME information. Doctoral thesis, Liverpool John Moores University.

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Abstract

Drug discovery is a process that requires a significant investment in both time and resources. Although recent developments have reduced the number of drugs failing at the later stages of development due to poor pharmacokinetic and/or toxicokinetic profiles, late stage attrition of drug candidates remains a problem. Additionally, there is a need to reduce animal testing for toxicological risk assessment for ethical and financial reasons. In silico methods offer an alternative that can address these challenges.
A variety of computational approaches have been developed in the last two decades, these must be evaluated to ensure confidence in their use. The research presented in this thesis has assessed a range of existing tools for the prediction of toxicity and absorption, distribution, metabolism and elimination (ADME) parameters with an emphasis on absorption and xenobiotic metabolism. These two ADME properties largely determine bioavailability of a drug and, in turn, also influence toxicity. In vitro (Caco-2 cells and the parallel artificial membrane permeation assay) and in silico approaches, such as various druglikeness filters, can be used to estimate human intestinal absorption; a comparison between different methods was performed to identify relative strengths and weaknesses of the approaches. In terms of xenobiotic metabolism it is not only important to predict metabolites correctly, but it is also crucial to identify those compounds that can be biotransformed into species that can covalently bind to biomolecules. Structural alerts are routinely used to screen for such potential reactive metabolites. The balance between sensitivity and specificity of such reactive metabolite alerts has been discussed in the context of correctly predicting reactive metabolites of pharmaceuticals (using data available from DrugBank). Off-target toxicity, exemplified by human Ether-à-go-go-Related Gene (hERG) channel inhibition, was also explored. A number of novel structural alerts for hERG toxicity were developed based on groups of structurally similar compounds. Finally, the importance of predicting potential ecotoxicological effects of drugs was also considered. The utility of zebrafish embryos to distinguish between baseline and excess toxicity was investigated. In evaluating this selection of existing tools, improvements to the methods have been proposed where possible.

Item Type:	Thesis (Doctoral)
Subjects:	R Medicine > RA Public aspects of medicine > RA1190 Toxicology. Poisions R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica
Divisions:	Pharmacy & Biomolecular Sciences
Date Deposited:	18 Oct 2016 12:38
Last Modified:	03 Sep 2021 23:27
DOI or ID number:	10.24377/LJMU.t.00004554
Supervisors:	Madden, Judith and Cronin, Mark
URI:	https://researchonline.ljmu.ac.uk/id/eprint/4554

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