A Quantitative Structure‐ Activity Relationship (QSAR) for Prediction of α‐2μ‐Globulin Nephropathy

Abstract

AbstractA number of chemicals induce a toxic syndrome in male rats – referred to as α‐2‐μ‐globulin nephropathy – which is characterized by an accumulation of the urinary protein α‐2‐μ‐globulin in renal lysosomes, subsequent cytotoxicity and cell death. Borghoff et al. [1] measured the binding affinities to α‐2μ‐globulin for a number of molecules and metabolites recognised as causing α‐2μ‐nephropathy and suggested that binding is dependent on both hydrophobic interactions and hydrogen bonding. Binding affinity to α‐2μ‐globulin has been identified as one of the determinants for α‐2μ‐globulin nephropathy. A QSAR based on these data has been derived by multiple regression analysis relating the binding to negative charge density of the binding molecule and its molecular volume. Data of Bomhard et al. [2] correlating aliphatic and alicyclic hydrocarbon structures with ability to induce renal lysosome accumulation in male rats, were analysed by the technique of principal components analysis applied to the molecular volumes and principal inertial axes of alcohols predicted to be derived from the hydrocarbons. Mapping of the first and second principal components showed clustering of molecules relative to their biological activity. A combination of the two QSARs is useful in identifying molecules with a potential to cause α‐2μ‐globulin nephropathy.