QSAR FOR ALLERGIC CONTACT-DERMATITIS

Allergic contact dermatitis (ACD) is a widespread concern in which sen sitization occurs to low molecular weight chemicals. Currently, animal and human assays are used to identify chemicals with potential to cau se ACD. MultiCASE, a computer based structure-activity relational syst em was employed to evaluate a data base of contact sensitizers and ide ntify structural determinants (biophores) associated with sensitizatio n. The data base was derived from reports of animal and human studies and consisted of 1034 chemicals of which 317 were classified as sensit izers (extreme, strong, moderate, or weak), 22 chemicals had marginal (questionable) activity, and 695 were inactive. MultiCASE identified 4 9 biophores with related expanded fragments which accounted for the ac tivity of all active chemicals. The major biophores consisted of: 1) a nitrogen double-bonded to a carbon or a nitrogen; 2) substituted arom atic structures; 3) thiol and disulfide containing fragments; and 4) e lectrophilic moieties. Modulators of each biophore, which either augme nted or decreased potency, included additional structural fragments, t wo dimensional distance descriptors, as well as physico-chemical chara cteristics. Internal evaluation of the data base indicated the sensiti vity was 99.6%, and the specificity of the data set was 99.4%. Predict ion of the activity of chemicals not in the learning set gave a concor dance of 90.2% with experimental results. These findings demonstrate t he ability of MultiCASE to identify contact sensitizers and sus est it s ability to screen chemicals for their potential to produce ACD.