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A robust, mechanistically-based in silico structural profiler for hepatic cholestasis

Firman, JW, Pestana, CB, Rathman, JF, Vinken, M, Yang, C and Cronin, MTD (2020) A robust, mechanistically-based in silico structural profiler for hepatic cholestasis. Chemical Research in Toxicology, 34 (2). pp. 641-655. ISSN 0893-228X

A robust, mechanistically-based in silico structural profiler for hepatic cholestasis.pdf - Accepted Version

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Owing to the primary role which it holds within metabolism of xenobiotics, the liver stands at heightened risk of exposure to, and injury from, potentially hazardous substances. A principal manifestation of liver dysfunction is cholestasis – the impairment of physiological bile circulation from its point of origin within the organ to site of action at the small intestine. The capacity for early identification of compounds liable to exert cholestatic effect is of particular utility within the field of pharmaceutical development, where contribution towards candidate attrition is great. Shortcomings associated with present in vitro methodologies forecasting cholestasis render their predictivity questionable, permitting scope for adoption of computational toxicology techniques. As such, the intention of this study has been to construct an in silico profiler, founded upon clinical data, highlighting structural motifs most reliably associated with the endpoint. Drawing upon a list of greater than 1500 small molecular drugs, compiled and annotated by Kotsampasakou and Ecker, we have formulated a series of fifteen structural alerts. These describe fragments intrinsic within distinct pharmaceutical classes including psychoactive tricyclics, beta-lactam antimicrobials and oestrogenic/androgenic steroids. Description of the coverage and selectivity of each is provided, alongside consideration of underlying reactive mechanisms and relevant structure-activity concerns. Provision of mechanistic anchoring ensures that potential exists for framing within the adverse outcome pathway (AOP) paradigm – the chemistry conveyed through the alert in particular enabling rationalisation at the level of the molecular initiating event (MIE).

Item Type: Article
Uncontrolled Keywords: 0302 Inorganic Chemistry, 0304 Medicinal and Biomolecular Chemistry, 0305 Organic Chemistry
Subjects: Q Science > QP Physiology
R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
R Medicine > RA Public aspects of medicine > RA1190 Toxicology. Poisions
R Medicine > RS Pharmacy and materia medica
Divisions: Pharmacy & Biomolecular Sciences
Publisher: American Chemical Society
Date Deposited: 03 Dec 2020 11:01
Last Modified: 06 Jan 2022 13:45
URI: https://researchonline.ljmu.ac.uk/id/eprint/14116
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