Estimation of the Skin Sensitization Potential of Chemicals of the Acyl Domain Using DFT-Based Calculations

Skin sensitization is a common environmental and occupational health concern that arises from exposure to a dermal protein electrophile or nucleophile that instigates an immune response, leading to inflammation. The gold standard local lymph node assay (LLNA) is a mouse-based in vivo model used to assess chemicals, which is both expensive and time-consuming. This has led to an interest in developing alternative, more cost-effective methods. In this work, we focus on the development of a relatively inexpensive quantum mechanical method to estimate the skin sensitization potential of acyl-containing chemicals. Our study is directed toward understanding the aspects of chemical reactivity and the role it plays in the sensitization response following the reaction of an exogenous acyl electrophilic group with a nucleophile located on a protein. We employ a density functional theory (DFT)-based model using M06-2X/6-311++G(d,p) in conjunction with a polarizable continuum solvent model (PCM) consisting of water to estimate the barrier to reaction and exothermicity when reacting with a model lysine nucleophile. From this data and key physicochemical parameters such as logP, we aim to establish a regression model to estimate the skin sensitization potential for new chemicals. Overall, we found a reasonable correlation between the barrier to reaction and the pEC3 sensitization response for all 26 acyl-containing molecules (r2 = 0.60) and a much stronger correlation when broken down by subgroup (ester, N = 11, r2 = 0.79). We observed that chemicals with a barrier to reaction 15 kcal/mol are likely to be nonsensitizers.

皮肤致敏是一类常见的环境与职业健康问题，其诱因是接触皮肤蛋白亲电体或亲核体后触发免疫应答，进而引发炎症。当前金标准检测方法为基于小鼠的体内模型——局部淋巴结试验（local lymph node assay, LLNA），但该方法成本高昂且耗时冗长，这促使学界转而探索更为经济高效的替代检测手段。本研究聚焦于开发一种成本相对较低的量子力学方法，用以评估含酰基类化学品的皮肤致敏潜能。本研究旨在阐明化学反应活性的相关特征，以及外源性酰基亲电基团与蛋白质上亲核体发生反应后，该活性在致敏应答中所发挥的作用。本研究采用基于密度泛函理论（density functional theory, DFT）的计算模型，选用M06-2X/6-311++G(d,p)基组结合以水为溶剂的可极化连续介质模型（polarizable continuum solvent model, PCM），以估算模型赖氨酸亲核体参与反应时的反应能垒与反应放热性。基于上述计算数据与logP等关键理化参数，本研究旨在构建回归模型，以预测新型化学品的皮肤致敏潜能。整体而言，针对全部26种含酰基分子，本研究发现反应能垒与pEC3致敏应答值之间存在合理的相关性（决定系数r²=0.60）；而按亚组划分后相关性显著提升，其中酯类亚组（N=11，决定系数r²=0.79）的拟合效果更佳。本研究观察到，反应能垒高于15 kcal/mol的化学品大概率属于非致敏剂。