Assessing hERG pore models as templates for drug docking using published experimental constraints: the inactivated state in the context of drug block.
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.
School of Biochemistry, Medical Sciences Building, University of Bristol , University Walk, Bristol BS8 1TD, U.K.
Christopher E
CE
Dempsey
Dominic
D
Wright
Charlotte K
CK
Colenso
Richard B
RB
Sessions
Jules C
JC
Hancox
D000595:Amino Acid Sequence; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006220:Haloperidol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D016062:Porosity; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
D051638:Ether-A-Go-Go Potassium Channels; D004364:Pharmaceutical Preparations; D026902:Potassium Channel Blockers; D000644:Quaternary Ammonium Compounds; D006220:Haloperidol