Paper Citing NAMD - Abstract
Pietra, Francesco
Putative Binding Sites, and Pathways to Them, for Amidine and Guanidine Current Inhibitors on Acid-Sensing Ion Channels (ASIC). A Theoretical Approach with hASIC1a Homology Model
CHEMISTRY & BIODIVERSITY, 9:331-351, FEB 2012
Central inhibition of the acid-sensing hASIC1a channel, acting upstream of the opiate system, might serve to treat any type of pain, avoiding the unwanted addiction problems of the opioid drugs. To this end, inhibition of hASIC1a channel by PcTx1, a peptide from the Trinidad chevron tarantula, is under development. New inhibitors of the hASIC1a channel are also being sought, in the hope of further modulating the activity, from which antiplasmodial amidine and guanidine phenyl drugs have emerged as promising candidates. However, how such current inhibition takes place remains obscure from the molecular point of view, hindering any further progress in developing drugs. Therefore, the nature of the binding sites, and how they are reached by the amidine-guanidine drugs, was investigated here via automated docking and molecular dynamics with hASIC1a homology models. This study has revealed that this ion channel is rich in binding sites, and that flexible drugs, such as nafamostat, may penetrate it in a snake-like elongated conformation. Then, crawling like a snake through temporary holes in the protein, nafamostat either simply flips, or changes to a high-energy folded conformation to become adapted to the shape of the binding site.
