TY - JOUR
T1 - Collaborative SAR Modeling and Prospective In Vitro Validation of Oxidative Stress Activation in Human HepG2 Cells
AU - Béquignon, Olivier J. M.
AU - Gómez-Tamayo, Jose C.
AU - Lenselink, Eelke B.
AU - Wink, Steven
AU - Hiemstra, Steven
AU - Lam, Chi Chung
AU - Gadaleta, Domenico
AU - Roncaglioni, Alessandra
AU - Norinder, Ulf
AU - Water, Bob van de
AU - Pastor, Manuel
AU - van Westen, Gerard J. P.
N1 - Funding Information: The authors thank Dr. Ian Copple (University of Liverpool) for kindly providing CDDO-Me; Marina Gorostiola González and Dr. Sohvi Luukkonen for their critical inputs about data management and during data analysis; Dr. Luukkonen for also helping with the formatting; Dr. Giulia Callegaro for her essential help on the characteristics of the cell line and assay; and Roelof van der Kleij for providing access and maintaining part of the IT infrastructure used for this work. 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. Funding Information: 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. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society
PY - 2023/9/11
Y1 - 2023/9/11
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85169891068&partnerID=8YFLogxK
U2 - https://doi.org/10.1021/acs.jcim.3c00220
DO - https://doi.org/10.1021/acs.jcim.3c00220
M3 - Article
C2 - 37616385
SN - 1549-9596
VL - 63
SP - 5433
EP - 5445
JO - Journal of chemical information and modeling
JF - Journal of chemical information and modeling
IS - 17
ER -