Prediction of skin irritation from organic chemicals using membrane-interaction QSAR analysis.
Membrane-interaction (MI) quantitative structure activity relationship (QSAR) analysis was carried out for a training set of 22 hydroxy organic compounds for which the Draize skin irritation scores, PII, had been determined. Significant MI-QSAR models were constructed in which skin irritation potency is predicted to increase with (1) increasing effective concentration of the compound available for uptake into phospholipid-rich regions of a cellular membrane, (2) increasing binding of the compound to the phospholipid-rich regions of a cellular membrane, and (3) the chemical reactivity of the compound as reflected by the highest occupied molecular orbital (HOMO) and/or lowest unoccupied molecular orbital (LUMO) of the molecule. Overall, the MI-QSAR models constructed for skin irritation are very similar, with respect to the types of descriptors, to those found for eye irritation. In turn, the skin irritation MI-QSAR models suggest a similar molecular mechanism of action to that postulated for eye irritation from MI-QSAR analysis. Significant and predictive QSAR models cannot be constructed unless test compound-membrane interaction descriptors are computed and used to build the QSAR models.
Kodithala
Kiran
K
Laboratory of Molecular Modeling and Design, M/C-781, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.
Hopfinger
A J
AJ
Thompson
Edward D
ED
Robinson
Michael K
MK
D000826:Animal Testing Alternatives; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects; D007509:Irritants / Q000737:chemistry / Q000633:toxicity*; D008954:Models, Biological; D009930:Organic Chemicals / Q000737:chemistry / Q000633:toxicity*; D021281:Quantitative Structure-Activity Relationship; D011817:Rabbits; D012867:Skin / Q000187:drug effects* / Q000648:ultrastructure
D007509:Irritants; D009930:Organic Chemicals