Paper Citing NAMD - Abstract
Schmidtke, Peter; Ciantar, Marine; Theret, Isabelle; Ducrott, Pierre
Dynamics of hERG Closure Allow Novel Insights into hERG Blocking by Small Molecules
JOURNAL OF CHEMICAL INFORMATION AND MODELING, 54:2320-2333, AUG 2014
Today, drug discovery routinely uses experimental assays to determine very early if a lead compound can yield certain types of off-target activity. Among such off targets is hERG. The ion channel plays a primordial role in membrane repolarization and altering its activity can cause severe heart arrhythmia and sudden death. Despite routine tests for hERG activity, rather little information is available for helping medicinal chemists and molecular modelers to rationally circumvent hERG activity. In this article novel insights into the dynamics of hERG channel closure are described. Notably, helical pairwise closure movements have been observed. Implications and relations to hERG inactivation are presented. Based on these dynamics novel insights on hERG blocker placement are presented, compared to literature, and discussed. Last, new evidence for horizontal ligand positioning is shown in light of former studies on hERG blockers.
