Assessing hERG Pore Models As Templates for Drug Docking Using Published Experimental Constraints: The Inactivated State in the Context of Drug Block

Abstract

Many structurally and therapeutically diverse drugs interact with the human heart K+ channel hERG by binding within the K+ permeation pathway of the open channel, leading to drug-induced ‘long QT syndrome’. Drug binding to hERG is often stabilized by inactivation gating. In the absence of a crystal structure, hERG pore homology models have been used to characterize drug interactions. Here we assess potentially inactivated states of the bacterial K+ channel, KcsA, as templates for inactivated state hERG pore models in the context of drug binding using computational docking. Although Flexidock and GOLD docking produced low energy score poses in the models tested, each method selected a MthK K+ channel-based model over models based on the putative inactivated state KcsA structures for each of the 9 drugs tested. The variety of docking poses found indicates that an optimal arrangement for drug binding of aromatic side chains in the hERG pore can be achieved in several different configurations. This plasticity of the drug “binding site” is likely to be a feature of the hERG inactivated state. The results demonstrate that experimental data on specific drug interactions can be used as structural constraints to assess and refine hERG homology models.

hERG Potassium Channel Blockade by the HCN Channel Inhibitor Bradycardic Agent Ivabradine

“…42 The modest effect of the hERG S624A mutation (Figure 6) and lack of close proximity of the drug to S624 in docking simulations (Figure 7) are consistent with an indirect role for this residue in ivabradine binding to hERG. 23 Sequence alignment of HCN4 and hERG (Figure 7D) shows tyrosine (Y) residues at homologous positions (Y652 hERG; Y506 HCN4) and proximate phenylalanine residues (F656 hERG; F509 HCN4), though HCN4 has an isoleucine at the homologous position (I510) of F656. The Y506A, F509A, and I510A mutations have been shown to impair markedly ivabradine inhibition of HCN4, with docking simulations to open WT HCN4 channels identifying the drug adopting a bent configuration and stacking interactions between the benzazepinone and benzocylobutane moieties of the drug and Y506 and F509 aromatic side chains.…”

Development of Safe Drugs: The hERG Challenge

“…Thus, the authors of this study postulated that, in the T623A mutant hERG channel, the Tyr652 residue (in the absence of Thr623) might orient itself in an unfavorable way, such that it destabilizes the drug binding. Another study by Dempsey et al . also reported the lack of direct interactions between the drugs and the Thr623 residue of the hERG channel.…”

In Silico Prediction of hERG Inhibition

“…The crystal structure of the potassium channel from Streptomyces lividans KcsA [91] is the most widely used template for building models of the hERG [44,85,88,[96][97][98][99][100][101]. However, the crystal structure of KcsA is in the closed state, but the pore domain is more likely to be in the open state for compounds to enter [44].…”