Exploring QSAR of thiazole and thiadiazole derivatives as potent and selective human adenosine A3 receptor antagonists using FA and GFA techniques

Binding affinity data of thiazole and thiadiazole derivatives (n=30) for human adenosine A3 receptor subtype have been subjected to Quantitative Structure-Activity Relationship (QSAR) analysis using quantum chemical and hydrophobicity parameters. Wang-Ford charges of the common atoms of the compounds [calculated from molecular electrostatic potential surface of energy minimized geometry using Austin Model 1 (AM1) technique] were used as independent variables apart from partition coefficient (logP) and suitable dummy parameters. The variables for the multiple regression analyses were selected based on principal component factor analysis (FA), and generated equations were statistically validated using leave-one-out technique. The best equation thus obtained explained and predicted 74.4% and 68.9% respectively of the variance of the binding affinity. The results suggested importance of Wang-Ford charges of atoms C2, C5 and C7. Furthermore, the A3 binding affinity increases with decrease of lipophilicity of the compounds and in the presence of methyl or ethyl substituent at R position. Again, the binding affinity decreases in the presence of tert-butyloxy group at R position. When factor scores were used as predictor variables in principal component regression analysis, the resulted model showed 87.0% predicted variance and 89.5% explained variance. The data set was also modeled using genetic function approximation (GFA) technique. The best two equations derived from GFA show better predicted variance values (0.753 and 0.739) than that found in case of the best equation derived from FA. However, considerable intercorrelation was found between two predictor variables in case of GFA derived equations. GFA derived equations show importance of Wang-Ford charges of different atoms of the thiazole/thiadiazole nucleus and phenyl ring (S9, X8 and C2, the effects of the first two being predominant) along with similar impact of lipophilicity and R group on the binding affinity as found in case of the FA derived relation.