Collaborative SAR modeling and prospective in vitro validation of oxidative stress activation in human HepG2 cells

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• dc.contributor.author Béquignon, Olivier J. M.
• dc.contributor.author Gómez-Tamayo, José C.
• dc.contributor.author Lenselink, Eelke B.
• dc.contributor.author Wink, Steven
• dc.contributor.author Hiemstra, Steven
• dc.contributor.author Lam, Chi Chung
• dc.contributor.author Gadaleta, Domenico
• dc.contributor.author Roncaglioni, Alessandra
• dc.contributor.author Norinder, Ulf
• dc.contributor.author van de Water, Bob
• dc.contributor.author Pastor Maeso, Manuel
• dc.contributor.author van Westen, Gerard J. P.
• dc.date.accessioned 2023-10-16T06:59:41Z
• dc.date.available 2023-10-16T06:59:41Z
• dc.date.issued 2023
• dc.description.abstract Oxidative stress is the consequence of an abnormal increase of reactive oxygen species (ROS). ROS are generated mainly during the metabolism in both normal and pathological conditions as well as from exposure to xenobiotics. Xenobiotics can, on the one hand, disrupt molecular machinery involved in redox processes and, on the other hand, reduce the effectiveness of the antioxidant activity. Such dysregulation may lead to oxidative damage when combined with oxidative stress overpassing the cell capacity to detoxify ROS. In this work, a green fluorescent protein (GFP)-tagged nuclear factor erythroid 2-related factor 2 (NRF2)-regulated sulfiredoxin reporter (Srxn1-GFP) was used to measure the antioxidant response of HepG2 cells to a large series of drug and drug-like compounds (2230 compounds). These compounds were then classified as positive or negative depending on cellular response and distributed among different modeling groups to establish structure-activity relationship (SAR) models. A selection of models was used to prospectively predict oxidative stress induced by a new set of compounds subsequently experimentally tested to validate the model predictions. Altogether, this exercise exemplifies the different challenges of developing SAR models of a phenotypic cellular readout, model combination, chemical space selection, and results interpretation.
• dc.description.sponsorship This project received funding from the EU-ToxRisk and RISK-HUNT3R projects, which received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement Nos. 681002 and 964537, respectively, and was part of the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 777365 (eTRANSAFE) receiving support from the European Union’s Horizon 2020 research and innovation program and EFPIA. Additional funding was received from the VHP4Safety project, a research project funded by the Netherlands Research Council (NWO) “Netherlands Research Agenda: Research on Routes by Consortia” (NWA-ORC 1292.19.272). The authors declare that this work reflects only the author’s view and that the Innovative Medicines Initiative 2 Joint Undertaking and NWO are not responsible for any use that may be made of the information it contains.
• dc.format.mimetype application/pdf
• dc.identifier.citation Béquignon OJM, Gómez-Tamayo JC, Lenselink EB, Wink S, Hiemstra S, Lam CC, Gadaleta D, Roncaglioni A, Norinder U, Water BV, Pastor M, van Westen GJP. Collaborative SAR modeling and prospective in vitro validation of oxidative stress activation in human HepG2 cells. J Chem Inf Model. 2023 Sep 11;63(17):5433-45. DOI: 10.1021/acs.jcim.3c00220
• dc.identifier.doi http://dx.doi.org/10.1021/acs.jcim.3c00220
• dc.identifier.issn 1549-9596
• dc.identifier.uri http://hdl.handle.net/10230/58071
• dc.language.iso eng
• dc.publisher American Chemical Society (ACS)
• dc.relation.ispartof J Chem Inf Model. 2023 Sep 11;63(17):5433-45
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681002
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/964537
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/777365
• dc.rights © 2022 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cluster chemistry
• dc.subject.keyword Free radicals
• dc.subject.keyword Molecular modeling
• dc.subject.keyword Oxidative stress
• dc.subject.keyword Transition metals
• dc.title Collaborative SAR modeling and prospective in vitro validation of oxidative stress activation in human HepG2 cells
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion