Dynamics of hERG Closure Allow Novel Insights into hERG Blocking by Small Molecules

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.