Advancing Torsades de pointes risk prediction: unveiling the role of drug metabolites through molecular docking

This study explores the risk of Torsades de Pointes (TdP) arrhythmia, focusing on the interactions of parent drugs and their metabolites with the Human ether-à-go-go-related gene (hERG) channel, which is crucial in cardiac electrical activity and TdP risk assessment. Using a dual-strategy molecular docking approach with AutoDock Vina and PatchDock, we analyzed clinically relevant ligand pairs: astemizole/desmethylastemizole, terfenadine/fexofenadine, and quetiapine/norquetiapine. Quantitative analysis revealed that high binding affinity does not always correlate with toxicity. For instance, the non-cardiotoxic metabolite fexofenadine exhibited a higher binding affinity (-9.3 kcal/mol) compared to its toxic parent terfenadine (-8.9 kcal/mol), but its safety is explained by physicochemical constraints (zwitterionic nature). Conversely, desmethylastemizole maintained high affinity (-9.2 kcal/mol) with a geometrically "relaxed" fit (Atomic Contact Energy: -338.36), rationalizing its sustained potency. Geometric analysis further distinguished quetiapine as a "steric blocker" (Contact Area: ~588 Ų) causing forced occlusion, whereas its metabolite norquetiapine acted as a specific ligand with a significantly smaller interface area (~417 Ų). These findings highlight the importance of focusing not only on the parent drug but also on metabolites for TdP risk assessment in new drug development. We advocate for an integrated computational framework combining binding energy, geometric complementarity, and physicochemical profiling to enhance the accuracy of early cardiac safety screenings.