Towards high-resolution modeling of small molecule-ion channel interactions

Ion channels are critical drug discovery targets for a wider range of pathologies, such as epilepsy, chronic pain, itch, autoimmunity, and cardiac arrhythmias. To develop effective and safe therapeutics, it is necessary to design small molecules with high potency and selectivity for specific ion channel subtypes. There has been increasing implementation of structure-guided drug design for the development of small molecules targeting ion channels. We evaluated the performance of two Rosetta ligand docking methods, RosettaLigand and GALigandDock, on structures of known ligand-cation channel complexes. Ligands were docked to voltage-gated sodium (NaV), voltage-gated calcium (CaV), and transient receptor potential vanilloid (TRPV) channel families. For each test case, RosettaLigand and GALigandDock methods were able to frequently sample a ligand binding pose within 1-2 Å root mean square deviation (RMSD) relative to the native ligand-channel structure. However, RosettaLigand and GALigandDock scoring functions cannot consistently identify native drug binding poses as top-scoring models. Our study reveals that the proper scoring criteria for RosettaLigand and GALigandDock modeling of ligand-ion channel complexes should be assessed on a case-by-case basis using sufficient ligand and receptor interface sampling, knowledge about state specific interactions of the ion channel and inherent receptor site flexibility that could influence ligand binding.