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The development of structure-activity relationships for mitochondrial dysfunction: uncoupling of oxidative
Russell T Naven1, Rachel Swiss, Jacquelyn Klug-McLeod
1Compound Safety Prediction, Pfizer Inc, Groton, CT 06340, USA. russell.naven@pfizer.com
Toxicological Sciences : an Official Journal of the Society of Toxicology
|September 15, 2012
Summary
Structural alerts can predict mitochondrial dysfunction, a key factor in drug toxicity. This method identifies toxicophores, improving early drug candidate selection and focusing resources on safer compounds.
Area of Science:
- Drug Discovery
- Toxicology
- Mitochondrial Biology
Background:
- Mitochondrial dysfunction is linked to idiosyncratic organ toxicity.
- Early prediction of mitochondrial dysfunction aids drug development by identifying safety liabilities.
Purpose of the Study:
- To identify structural and physicochemical features associated with mitochondrial uncoupling of oxidative phosphorylation.
- To develop a predictive model for mitochondrial dysfunction in drug candidates.
Main Methods:
- Analysis of a database of over 2000 compounds.
- Identification of toxicophores causing protonophore and redox cycler mechanisms.
- Development of a structural-alert model with confidence levels.
Main Results:
- Identified toxicophores categorized as protonophores (influenced by lipophilicity) and redox cyclers.
- Developed a model with 11 toxicophores, achieving >68% identification of uncouplers with >99% specificity.
- Model alerts categorized by confidence levels (high, medium, low).
Conclusions:
- Structural alert methodology effectively identifies toxicophores linked to mitochondrial dysfunction.
- This approach aids in early screening but does not replace in vitro mitochondrial assays.
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