QSAR study of a series of acyl coenzyme A (CoA): cholesterol acyltransferase inhibitors using genetic function approximation

In cells, cholesterol esters are synthesized in an intracellular reaction catalyzed by acyl coenzyme A (CoA): cholesterol acyltransferase (ACAT) enzymes and, hence, inhibition of ACAT remains as a vital strategy for treatment of hyperlipidemia. Fobare et al. has reported potent ACAT inhibitory activity in a series of N,N',NaEuro(3)-trisubstituted-5-bisaminomethylene-1,3-dioxane-4,6-diones. QSAR models for these series were developed using genetic function approximation (GFA). Molecular solubility, Jurs, and Shadow descriptors were found to influence biological activity significantly. Lipophilicity of compounds was found to have a critical role in ACAT inhibition along with other structural, spatial, and electronic descriptors. Positive contribution of molecular shadow descriptors suggests that molecules with bulkier substituents are more likely to improve the potency. Developed models were found to be predictive as evidenced from their internal and external cross-validation statistics.