Docking into Symmetric Binding Sites: Problems and Solutions Exemplified on the hERG Potassium Channel

The hERG potassium channel is highly related to severe cardiac side effects. With the technique of homology modelling it is possible to model the homo tetrameric subunits of the hERG channel in the closed and open state, using KcsA and KirBac1.1 as well as MthK and KvAP as templates. Usually only the S5, P, and S6 segments of one subunit are modelled, while the other three subunits are just copies of the first one. This operation results in an artificial symmetry of the hERG channel, so the binding site in the internal part of the channel is also symmetric. This symmetry renders ligand-docking into hERG channel a quite challenging task. In order to investigate the molecular basis of drug trapping/non trapping in the hERG channel we docked a series of propafenone derivatives in a hERG channel homology model of the closed state. Drug trapping was experimentally determined in voltage clamp experiments on Xenopus oocytes.