PMID- 18853302
OWN - NLM
STAT- MEDLINE
DCOM- 20081219
LR  - 20081014
IS  - 1029-046X (Electronic)
IS  - 1026-776X (Linking)
VI  - 19
IP  - 5-6
DP  - 2008
TI  - Identification of mechanisms of toxic action for skin sensitisation using a 
      SMARTS pattern based approach.
PG  - 555-78
LID - 10.1080/10629360802348985 [doi]
AB  - Skin sensitisation is a key endpoint under REACH as it is costly and its 
      assessment currently has a high dependency on animal testing. In order to reduce 
      both the cost and the numbers of animals tested, it is likely that (quantitative) 
      structure-activity relationships ((Q)SAR) and read-across methods will be 
      utilised as part of intelligent testing strategies. The majority of skin 
      sensitisers elicit their effect via covalent bond formation with skin proteins. 
      These reactions have been understood in terms of well defined 
      nucleophilic-electrophilic reaction chemistry. Thus, a first step in (Q)SAR 
      analysis is the assignment of a chemical's potential mechanism of action enabling 
      it to be placed in an appropriate reactivity domain. The aim of this study was to 
      design a series of SMARTS patterns capable of defining these reactivity domains. 
      This was carried out using a large database of local lymph node assay (LLNA) 
      results that had had potential mechanisms of action assigned to them using expert 
      knowledge. A simple algorithm was written enabling the SMARTS patterns to be used 
      to screen a database of SMILES strings. The SMARTS patterns were then evaluated 
      using a second, smaller, test set of LLNA results which had also had potential 
      mechanisms of action assigned by experts. The results showed that the SMARTS 
      patterns provided an excellent method of identifying potential electrophilic 
      mechanisms. The findings are supported, in part, by molecular orbital 
      calculations which confirm assignment of reactive mechanism of action. The 
      ability to define a chemical's potential reaction mechanism is likely to be of 
      significant benefit to regulators and risk assessors as it enables category 
      formation and subsequent read-across to be performed.
FAU - Enoch, S J
AU  - Enoch SJ
AD  - School of Pharmacy and Chemistry, Liverpool John Moores University, Liverpool, 
      UK.
FAU - Madden, J C
AU  - Madden JC
FAU - Cronin, M T D
AU  - Cronin MT
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - SAR QSAR Environ Res
JT  - SAR and QSAR in environmental research
JID - 9440156
RN  - 0 (Irritants)
SB  - IM
MH  - Algorithms
MH  - Animals
MH  - Databases, Factual
MH  - Dermatitis, Allergic Contact/*etiology
MH  - Irritants/chemistry/metabolism/*toxicity
MH  - Local Lymph Node Assay
MH  - *Quantitative Structure-Activity Relationship
MH  - Skin/*drug effects/immunology
MH  - Skin Irritancy Tests
MH  - Toxicity Tests
EDAT- 2008/10/15 09:00
MHDA- 2008/12/20 09:00
CRDT- 2008/10/15 09:00
PHST- 2008/10/15 09:00 [pubmed]
PHST- 2008/12/20 09:00 [medline]
PHST- 2008/10/15 09:00 [entrez]
AID - 904003758 [pii]
AID - 10.1080/10629360802348985 [doi]
PST - ppublish
SO  - SAR QSAR Environ Res. 2008;19(5-6):555-78. doi: 10.1080/10629360802348985.