PMID- 28045255
OWN - NLM
STAT- MEDLINE
DCOM- 20170717
LR  - 20191210
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 30
IP  - 2
DP  - 2017 Feb 20
TI  - Validation of a Fragment-Based Profiler for Thiol Reactivity for the Prediction 
      of Toxicity: Skin Sensitization and Tetrahymena pyriformis.
PG  - 604-613
LID - 10.1021/acs.chemrestox.6b00361 [doi]
AB  - This study outlines the use of a recently developed fragment-based thiol 
      reactivity profiler for Michael acceptors to predict toxicity toward Tetrahymena 
      pyriformis and skin sensitization potency as determined in the Local Lymph Node 
      Assay (LLNA). The results showed that the calculated reactivity parameter from 
      the profiler, -log RC(50)(calc), was capable of predicting toxicity for both end 
      points with excellent statistics. However, the study highlighted the importance 
      of a well-defined applicability domain for each end point. In terms of 
      Tetrahymena pyriformis, this domain was defined in terms of how fast or slowly a 
      given Michael acceptor reacts with thiol leading to two separate quantitative 
      structure-activity models. The first, for fast reacting chemicals required only 
      -log RC(50)(calc) as a descriptor, while the second required the addition of a 
      descriptor for hydrophobicity. Modeling of the LLNA required only a single 
      descriptor, -log RC(50)(calc), enabling potency to be predicted. The 
      applicability domain excluded chemicals capable of undergoing polymerization and 
      those that were predicted to be volatile. The modeling results for both end 
      points, using the -log RC(50)(calc) value from the profiler, were in keeping with 
      previously published studies that have utilized experimentally determined 
      measurements of reactivity. These results demonstrate that the output from the 
      fragment-based thiol reactivity profiler can be used to develop quantitative 
      structure-activity relationship models where reactivity toward thiol is a driver 
      of toxicity.
FAU - Ebbrell, David J
AU  - Ebbrell DJ
AUID- ORCID: 0000-0001-5329-7539
AD  - School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University , 3 
      Byrom Street, Liverpool L3 3AF, England.
FAU - Madden, Judith C
AU  - Madden JC
AD  - School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University , 3 
      Byrom Street, Liverpool L3 3AF, England.
FAU - Cronin, Mark T D
AU  - Cronin MT
AD  - School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University , 3 
      Byrom Street, Liverpool L3 3AF, England.
FAU - Schultz, Terry W
AU  - Schultz TW
AD  - Department of Comparative Medicine, College of Veterinary Medicine, The 
      University of Tennessee , Knoxville, Tennessee 37996, United States.
FAU - Enoch, Steven J
AU  - Enoch SJ
AD  - School of Pharmacy and Bimolecular Sciences, Liverpool John Moores University , 3 
      Byrom Street, Liverpool L3 3AF, England.
LA  - eng
PT  - Journal Article
PT  - Validation Study
DEP - 20170119
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Sulfhydryl Compounds)
SB  - IM
MH  - Algorithms
MH  - Animals
MH  - Quantitative Structure-Activity Relationship
MH  - Skin/*drug effects
MH  - Sulfhydryl Compounds/chemistry/*toxicity
MH  - Tetrahymena pyriformis/*drug effects
EDAT- 2017/01/04 06:00
MHDA- 2017/07/18 06:00
CRDT- 2017/01/04 06:00
PHST- 2017/01/04 06:00 [pubmed]
PHST- 2017/07/18 06:00 [medline]
PHST- 2017/01/04 06:00 [entrez]
AID - 10.1021/acs.chemrestox.6b00361 [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2017 Feb 20;30(2):604-613. doi: 10.1021/acs.chemrestox.6b00361. 
      Epub 2017 Jan 19.