A two-state homology model of the hERG K+ channel: application to ligand binding.
Homology models based on available K+ channel structures have been used to construct a multiple state representation of the hERG cardiac K+ channel. These states are used to capture the flexibility of the channel. We show that this flexibility is essential in order to correctly model the binding affinity of a set of diverse ligands. Using this multiple state approach, a binding affinity model was constructed for set of known hERG channel binders. The predicted pIC50s are in good agreement with experiment (RMSD: 0.56 kcal/mol). In addition, these calculations provide structures for the bound ligands that are consistent with published mutation studies. These computed ligand bound complex structures can be used to guide synthesis of analogs with reduced hERG liability.
Rajamani
Ramkumar
R
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, PO Box 776, Welsh and McKean Roads, Spring House, PA 19477-0776, USA.
Tounge
Brett A
BA
Li
Jian
J
Reynolds
Charles H
CH
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D008954:Models, Biological; D008958:Models, Molecular; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D024642:Potassium Channels, Voltage-Gated