Prediction of Pgp-ATPase interaction and rhodamine 123 efflux inhibitory activities of propafenone analogs using PLS statistics

A method for the prediction of ATPase interaction and rhodamine 123 efflux inhibitory activity of propafenone analogs using multivariate partial least squares projections (PLS) analysis was investigated. Molecular descriptors were calculated using Dragon and ChemSketch software. Good statistical models were observed for both ATPase interactions and efflux inhibitory activities, resulting in R2 values ranging from 0.894 to 0.990 and Q2 values ranging from 0.858 to 0.969. The root mean squared error of prediction (RMSEp) values for the external test sets ranged from 0.189 to 0.253. Moriguchi octanol-water partition coefficient (MLOGP) was not selected as a descriptor for ATPase interaction but it was a significant descriptor for efflux inhibitory activity. Since different molecular properties were selected to describe ATPase interaction and rhodamine 123 efflux inhibitory activity, together with the relatively low correlation between log(1/Ka) and log(1/EC50), R2 of 0.69, these two properties may not be well associated and other factors besides ATPase interaction are probably involved with the efflux inhibition.