Comparison of a neural net-based QSAR algorithm (PCANN) with Hologram- and multiple linear regression-based QSAR...

A QSAR algorithm (PCANN) has been developed and applied to a set of calcium channel blockers which are of special interest because of their role in cardiac disease and also because many of them interact with P-glycoprotein, a membrane protein associated with multidrug resistance to anticancer agents. A database of 46 1,4-dihydropyridines with known Ca2+ channel binding affinities was employed for the present analysis. The QSAR algorithm can be summarized as follows: (1) a set of 90 graph theoretic and information theoretic descriptors representing various structural and topological characteristics was calculated for each of the 1,4-dihydropyridines and (2) principal component analysis (PCA) was used to compress these 90 into the eight best orthogonal composite descriptors for the database. These eight sufficed to explain 96% of the variance in the original descriptor set. (3) Two important empirical descriptors, the Leo-Hansch lipophilic constant and the Hammet electronic parameter, were added to the list of eight. (4) The 10 resulting descriptors were used as inputs to a back-propagation neural network whose output was the predicted binding affinity. (5) The predictive ability of the network was assessed by cross-validation. A comparison of the present approach with two other QSAR approaches (multiple linear regression using the same variables and a Hologram QSAR model) is made and shows that the PCANN approach can yield better predictions, once the right network configuration is identified. The present approach (PCANN) may prove useful for rapid assessment of the potential for biological activity when dealing with large chemical libraries.