Three-dimensional quantitative structure-permeability relationship analysis for a series of inhibitors of rhinovirus replication

Multiple three-dimensional quantitative structure-activity relationship (3D -QSAR) approaches were applied to predicting passive Caco-2 permeability fo r a series of 28 inhibitors of rhinovirus replication. Catalyst, genetic fu nction approximation (GFA) with MS-WHIM descriptors. CoMFA, and VolSurf wer e all used for generating 3D-quantitative structure permeability relationsh ips utilizing a training set of 19 molecules. Each of these approaches was then compared using a test set of nine molecules not present in the trainin g set. Statistical parameters for the test set predictions (r(2) and leave- one-out q(2)) were used to compare the models. It was found that the Cataly st pharmacophore model as the most predictive (test set of predicted versus observed permeability, r(2) = 0.94). This model consisted of a hydrogen bo nd acceptor, hydrogen bond donor, and ring aromatic feature with a training set correlation of r(2) = 0.83. The CoMFA model consisted of three compone nts with an r(2) value of 0.96 and produced good predictions for the test s et (r(2) = 0.84). VolSurf resulted in an r(2) value of 0.76 and good predic tions For the test set (r(2) = 0.83). Test set predictions with GFA/WHIM de scriptors (r(2) = 0.46) were inferior when compared with the Catalyst, CoMF A, and VolSurf model predictions in this evaluation. In Summary it would ap pear that the 3D techniques have considerable value in predicting passive p ermeability for a congeneric series of molecules, representing a valuable a sset for drug discovery.