Characterization of small-molecule ligands

Structural characterization of ligand binding is an essential process in structure-based drug design. Experimental structure determination of protein-ligand complexes at atomic resolution is often not possible due to the flexibility of the ligands or receptors. In these cases, computational modeling and molecular dynamics simulations are particularly useful, providing additional molecular insight into the inhibitory and activation mechanisms.

Very recently, we identified a class of negatively charged activators (NCAs) to open a series of  K⁺ channels, including many two-pore domain K⁺ (K2P) channels, voltage-gated hERG channels, and Ca²⁺-activated big-conductance potassium (BK)-type channels. Functional analysis, X-ray crystallography, and molecular dynamics simulations revealed that the NCAs bind to similar sites below the selectivity filter, increase pore and selectivity filter K⁺ occupancy, and open the filter gate. These results uncovered an unrecognized polypharmacology among K⁺ channel activators and highlight a filter gating machinery that is conserved across different families of K⁺ channels with implications for rational drug design (Schewe* and Sun* et al., Science, 2019).