PMID- 37616385
OWN - NLM
STAT- MEDLINE
DCOM- 20230912
LR  - 20230915
IS  - 1549-960X (Electronic)
IS  - 1549-9596 (Print)
IS  - 1549-9596 (Linking)
VI  - 63
IP  - 17
DP  - 2023 Sep 11
TI  - Collaborative SAR Modeling and Prospective In Vitro Validation of Oxidative 
      Stress Activation in Human HepG2 Cells.
PG  - 5433-5445
LID - 10.1021/acs.jcim.3c00220 [doi]
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.
FAU - Bequignon, Olivier J M
AU  - Bequignon OJM
AUID- ORCID: 0000-0002-7554-9220
AD  - Leiden Academic Centre for Drug Research, Leiden University, Wassenaarseweg 76, 
      2333 AL Leiden, The Netherlands.
FAU - Gomez-Tamayo, Jose C
AU  - Gomez-Tamayo JC
AD  - Research Programme on Biomedical Informatics (GRIB), Department of Medicine and 
      Life Sciences, Hospital del Mar Medical Research Institute, Universitat Pompeu 
      Fabra, Carrer del Dr. Aiguader 88, 08002 Barcelona, Spain.
FAU - Lenselink, Eelke B
AU  - Lenselink EB
AUID- ORCID: 0000-0001-5459-2978
AD  - Leiden Academic Centre for Drug Research, Leiden University, Wassenaarseweg 76, 
      2333 AL Leiden, The Netherlands.
FAU - Wink, Steven
AU  - Wink S
AD  - Leiden Academic Centre for Drug Research, Leiden University, Wassenaarseweg 76, 
      2333 AL Leiden, The Netherlands.
FAU - Hiemstra, Steven
AU  - Hiemstra S
AD  - Leiden Academic Centre for Drug Research, Leiden University, Wassenaarseweg 76, 
      2333 AL Leiden, The Netherlands.
FAU - Lam, Chi Chung
AU  - Lam CC
AD  - Leiden Academic Centre for Drug Research, Leiden University, Wassenaarseweg 76, 
      2333 AL Leiden, The Netherlands.
FAU - Gadaleta, Domenico
AU  - Gadaleta D
AUID- ORCID: 0000-0002-3154-5930
AD  - Laboratory of Environmental Chemistry and Toxicology, Department of Environmental 
      Health Sciences, IRCCS horizontal line Istituto di Ricerche Farmacologiche Mario Negri, Via la 
      Masa 19, 20156 Milano, Italy.
FAU - Roncaglioni, Alessandra
AU  - Roncaglioni A
AD  - Laboratory of Environmental Chemistry and Toxicology, Department of Environmental 
      Health Sciences, IRCCS horizontal line Istituto di Ricerche Farmacologiche Mario Negri, Via la 
      Masa 19, 20156 Milano, Italy.
FAU - Norinder, Ulf
AU  - Norinder U
AD  - MTM Research Centre, School of Science and Technology, Orebro University, 
      SE-70182 Orebro, Sweden.
FAU - Water, Bob van de
AU  - Water BV
AUID- ORCID: 0000-0002-5839-2380
AD  - Leiden Academic Centre for Drug Research, Leiden University, Wassenaarseweg 76, 
      2333 AL Leiden, The Netherlands.
FAU - Pastor, Manuel
AU  - Pastor M
AUID- ORCID: 0000-0001-8850-1341
AD  - Research Programme on Biomedical Informatics (GRIB), Department of Medicine and 
      Life Sciences, Hospital del Mar Medical Research Institute, Universitat Pompeu 
      Fabra, Carrer del Dr. Aiguader 88, 08002 Barcelona, Spain.
FAU - van Westen, Gerard J P
AU  - van Westen GJP
AUID- ORCID: 0000-0003-0717-1817
AD  - Leiden Academic Centre for Drug Research, Leiden University, Wassenaarseweg 76, 
      2333 AL Leiden, The Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230824
PL  - United States
TA  - J Chem Inf Model
JT  - Journal of chemical information and modeling
JID - 101230060
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Xenobiotics)
SB  - IM
MH  - Humans
MH  - Reactive Oxygen Species
MH  - Hep G2 Cells
MH  - Prospective Studies
MH  - *Xenobiotics
MH  - *Oxidative Stress
MH  - Structure-Activity Relationship
PMC - PMC10498489
COIS- The authors declare no competing financial interest.
EDAT- 2023/08/24 18:41
MHDA- 2023/09/12 06:41
PMCR- 2023/09/13
CRDT- 2023/08/24 14:12
PHST- 2023/09/12 06:41 [medline]
PHST- 2023/08/24 18:41 [pubmed]
PHST- 2023/08/24 14:12 [entrez]
PHST- 2023/09/13 00:00 [pmc-release]
AID - 10.1021/acs.jcim.3c00220 [doi]
PST - ppublish
SO  - J Chem Inf Model. 2023 Sep 11;63(17):5433-5445. doi: 10.1021/acs.jcim.3c00220. 
      Epub 2023 Aug 24.