Exploring the potential for allergic contact dermatitis via computed heats of reaction of haptens with protein end-groups -: Heats of reaction of haptens with protein end-groups by computation

Unlike human sensitization in allergic contact dermatitis, the primary event in the guinea pig maximization test (GPMT) is not penetration to the viable epidermis as the skin is compromised in both the sensitization and elicitation steps. The primary event is the chemical reaction of a hapten with simple protein end-groups at the recognition site of the major histocompatibility complex, class 2 (MHC II) on the cell surface of the Langerhans cells (LC). This reaction converts a benign LC into an allergen presenting cell that a T(CD4) lymphocyte recognizes as non-self and initiates the sensitizing sequence in the local draining lymph node. The widely used GPMT was selected for the purpose of modelling the sensitizing reaction without the complications of penetration to the viable epidermis. The compounds selected for study represent the class of electrophilic haptens that, along with their metabolic precursors (prohaptens) comprise the majority of known contact allergens. As the whole MHC II structure has no involvement with the sensitizing reaction beyond the first few atoms of the end group, methoxide ion and thiomethoxide ion were used to model activated serine and cysteine. In addition, the GPMT has a relatively broad range of error which allows the use of AM1 as an adequate method for modelling the relative heats of reaction in the rate determining step. The relative reactivity of most of the known electrophilic haptens in the simplest aliphatic and aromatic form are modelled in this study. For many of those that are sensitive to substituent effects, sets of 7-10 substituted analogs were modelled to provide excellent Hammett relations with the heats of reaction. These linear free energy relations allow prediction of ACD potential in new related haptens. As a final validation of the procedure, a set of compounds scoring non (1), weak (2), moderate (3) and strong (4) as measured in the GPMT are computed for comparison with the test results and found to be in good concordance.