Structure-Based Prediction of hERG-Related Cardiotoxicity: A Benchmark Study

Drug-induced blockade of the human
ether-à-go-go-related
gene (hERG) channel is today considered the main
cause of cardiotoxicity in postmarketing surveillance. Hence, several
ligand-based approaches were developed in the last years and are currently
employed in the early stages of a drug discovery process for in silico cardiac safety assessment of drug candidates.
Herein, we present the first structure-based classifiers able to discern hERG binders from nonbinders. LASSO regularized support
vector machines were applied to integrate docking scores and protein–ligand
interaction fingerprints. A total of 396 models were trained and validated
based on: (i) high-quality experimental bioactivity information returned
by 8337 curated compounds extracted from ChEMBL (version 25) and (ii)
structural predictor data. Molecular docking simulations were performed
using GLIDE and GOLD software programs and four different hERG structural models, namely, the recently published structures
obtained by cryoelectron microscopy (PDB codes: 5VA1 and 7CN1) and
two published homology models selected for comparison. Interestingly,
some classifiers return performances comparable to ligand-based models
in terms of area under the ROC curve (AUCMAX = 0.86 ±
0.01) and negative predictive values (NPVMAX = 0.81 ±
0.01), thus putting forward the herein proposed computational workflow
as a valuable tool for predicting hERG-related cardiotoxicity
without the limitations of ligand-based models, typically affected
by low interpretability and a limited applicability domain. From a
methodological point of view, our study represents the first example
of a successful integration of docking scores and protein–ligand
interaction fingerprints (IFs) through a support vector machine (SVM)
LASSO regularized strategy. Finally, the study highlights the importance
of using hERG structural models accounting for ligand-induced
fit effects and allowed us to select the best-performing protein conformation
(made available in the Supporting Information, SI) to be employed
for a reliable structure-based prediction of hERG-related cardiotoxicity.