Paper Citing NAMD - Abstract
Yang, Qian; Du, Lupei; Tsai, Keng-Chang; Wang, Xiaojian; Li, Minyong; You, Qidong
Pharmacophore Mapping for Kv1.5 Potassium Channel Blockers
QSAR & COMBINATORIAL SCIENCE, 28:59-71, JAN 2009
The ultra-rapid delayed rectifier potassium current (I(Kur)), encoded by Kv1.5 gene, is a selective target for the treatment of Atrial Fibrillation (AF). Based on the chemical structures of Kv1.5 potassium channel blockers, a pharmacophore model of Kv1.5 was developed using HypoGen algorithm implemented in Catalyst 4.11 package. The most predictive hypothesis, Hypo1, obtained from 40 training, set molecules, consists of one aromatic ring, two hydrophobic points and a hydrogen bond acceptor. This pharmacophore. model was validated by test set prediction and Fischer's randomization test, and all validation results suggested a good and reliable pharmacophore model with statistical significance. In order to validate the reliability, the best active compounds in the training and test set, compounds 1 and 41, were docked into the active site of Kv1.5 homology model, respectively. The pharmacophore conformations of these two compounds were highly similar with their docking conformations, in the meanwhile the common features of hypothesis also have good mapping with the binding profile proposed by molecular docking. Therefore, our pharmacophore efforts would be readily applicable for studies of molecular mechanism of Kv1.5 potassium channel blockers and for providing a rational approach in the molecular design targeting Kv1.5.
