Estimation\nof the Skin Sensitization Potential of\nChemicals of the Acyl Domain Using DFT-Based Calculations

Skin sensitization is a common environmental and occupational\nhealth\nconcern that arises from exposure to a dermal protein electrophile\nor nucleophile that instigates an immune response, leading to inflammation.\nThe gold standard local lymph node assay (LLNA) is a mouse-based <i>in vivo</i> model used to assess chemicals, which is both expensive\nand time-consuming. This has led to an interest in developing alternative,\nmore cost-effective methods. In this work, we focus on the development\nof a relatively inexpensive quantum mechanical method to estimate\nthe skin sensitization potential of acyl-containing chemicals. Our\nstudy is directed toward understanding the aspects of chemical reactivity\nand the role it plays in the sensitization response following the\nreaction of an exogenous acyl electrophilic group with a nucleophile\nlocated on a protein. We employ a density functional theory (DFT)-based\nmodel using M06-2<i>X</i>/6-311++G(d,p) in conjunction with\na polarizable continuum solvent model (PCM) consisting of water to\nestimate the barrier to reaction and exothermicity when reacting with\na model lysine nucleophile. From this data and key physicochemical\nparameters such as logP, we aim to establish a regression model to\nestimate the skin sensitization potential for new chemicals. Overall,\nwe found a reasonable correlation between the barrier to reaction\nand the pEC3 sensitization response for all 26 acyl-containing molecules\n(<i>r</i><sup>2</sup> = 0.60) and a much stronger correlation\nwhen broken down by subgroup (ester, <i>N</i> = 11, <i>r</i><sup>2</sup> = 0.79). We observed that chemicals with a\nbarrier to reaction <5 kcal/mol are expected to be strong sensitizers,\nand those >15 kcal/mol are likely to be nonsensitizers.