A Quantitative Structure-Activity Relationship (QSAR) for prediction of α 2μ-globulin nephropathy

Abstract

A number of chemicals induce a toxic syndrome in male rats—referred to as α 2μ-globulin nephropathy—that is characterized by an accumulation of the urinary protein α 2μ-globulin in renal lysosomes, subsequent cytotoxicity and cell death. Binding affinity to α 2μ-globulin has been identified as one of the determinants for α 2μ-globulin nephropathy. A quantitative structure-activity relationship (QSAR) has been derived by multiple regression analysis relating this binding to negative charge density of the binding molecule and its molecular volume. Previous data, 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.