Prediction of TdP Arrhythmia Risk Through Molecular Simulations of Conformation-specific Drug Interactions with the hERG K⁺, Na_v1.5, and Ca_v1.2 Channels.

ABSTRACT: Unintended block of cardiac ion channels, particularly hERG (K_v11.1), remains a key concern in drug development as disruption of ion channel function can lead to deadly arrhythmia. To assess proarrhythmic risk, we investigated how drugs interact with hERG in its open and inactivated states and whether drug interactions with other cardiac channels like Na_v1.5 and Ca_v1.2 mitigate that risk. Using cryo-EM structures, we modeled open and inactivated conformations of these channels with Rosetta and AlphaFold. We then applied Site Identification by Ligand Competitive Saturation (SILCS), a physics-based pre-computed ensemble docking method, to predict drug binding affinities. SILCS leverages molecular simulation-generated free energy maps for high-throughput docki

SUBMITTER: Rouen KC 

PROVIDER: S-EPMC12485723 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature