Pharmacophore Refinement and 3D‐QSAR Studies of Histamine H3 Antagonists

Abstract

AbstractMolecular modeling studies were performed to develop a predictive Common Pharmacophore Hypothesis (CPH) and use it for alignment in 3D‐QSAR studies using CoMFA and CoMSIA, with a diverse set of 106 histamine H3 antagonists. A five point CPH with three hydrophobic features, a basic or positive ionizable feature and an acceptor, for pharmacophore‐based alignment of molecules, was derived using PHASE. This hypothesis was selected from a pool, by correlating the observed and estimated activity for the training set and test set of molecules using partial least square analysis. It was found to be comparable to the previously reported hypothesis. The validated pharmacophore hypothesis was used for alignment of molecules in CoMFA and CoMSIA model development. The models so generated showed a good “predictive” r2 value of 0.763 and 0.820 for CoMFA and CoMSIA, respectively. The contour maps of the models were analyzed to give structural insight for activity improvement of future novel histamine H3 antagonists. The CPH can also provide a powerful template for virtual screening and design of new histamine H3 antagonists.