State-specific binding thermodynamics predicts ligand efficacy across ion-channel families.
Predicting ligand efficacy is a critical challenge in drug discovery, as a target's functional response is often determined by the way a ligand shifts conformational equilibria between different functional states, a process that is particularly intricate in ion channels. We classify ligands based on the difference of their binding free energies on putative active and inactive conformations,…
Predicting how a drug interacts with an ion channel is a key challenge in drug development, as the response is influenced by how the drug alters the channel's conformation between different functional states. The researchers analyzed 78 pairs of proteins and their associated ligands, spanning six ion channels from four distinct structural families: GluA2, GABAAR {rho}1, 3{beta}4 nAChR, 5-HT3AR, TRPML1, and KCNQ2.
By calculating the binding free energies using a method called free energy perturbation (FEP), they were able to classify the ligands based on their predicted difference in binding energy between active and inactive conformations of the ion channels. This approach was capable of accurately identifying both agonists and antagonists, regardless of whether the channels exhibited large or minor structural variations, even at sites facing the membrane.
Furthermore, the study revealed that the local conformations within the binding pocket of the ligand play a crucial role in determining its efficacy, even when the overall state of the ion channel is uncertain. This research suggests that examining the state-specific binding thermodynamics of ion channels can provide a reliable method for studying the mechanisms of action of various channels and for advancing the discovery of new drugs with specific functional properties, going beyond mere affinity measurements.
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