A QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIP (QSAR) FOR PREDICTION OF ALPHA-2-MU-GLOBULIN NEPHROPATHY

A number of chemicals induce a toxic syndrome in male rats - referred to as alpha-2-mu-globulin nephropathy - which is characterized by an a ccumulation of the urinary protein alpha-2-mu-globulin in renal lysoso mes, subsequent cytotoxicity and cell death. Borghoff et al. [1] measu red the binding affinities to alpha-2 mu-globulin for a number of mole cules and metabolites recognised as causing alpha-2 mu-nephropathy and suggested that binding is dependent on both hydrophobic interactions and hydrogen bonding. Binding affinity to alpha-2 mu-globulin has been identified as one of the determinants for alpha-2 mu-globulin nephrop athy. A QSAR based on these data has been derived by multiple regressi on analysis relating the binding to negative charge density of the bin ding molecule and its molecular volume. Data of Bomhard et al. [2] cor relating aliphatic and alicyclic hydrocarbon structures with ability t o induce renal lysosome accumulation in male rats, were analysed by th e technique of principal components analysis applied to the molecular volumes and principal inertial axes of alcohols predicted to be derive d from the hydrocarbons. Mapping of the first and second principal com ponents showed clustering of molecules relative to their biological ac tivity. A combination of the two QSARs is useful in identifying molecu les with a potential to cause alpha-2 mu-globulin nephropathy.