Structure-based classifiers integrating docking scores and protein-ligand interaction fingerprints achieved an area under the ROC curve of 0.86 for predicting hERG-related cardiotoxicity.
Integrating docking scores with protein-ligand interaction fingerprints using machine learning provides a highly accurate structure-based method for predicting hERG-related cardiotoxicity.
Effect estimate: AUC 0.86
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.
Creanza et al. (Fri,) conducted a other in hERG-related cardiotoxicity (n=8,337). Structure-based classifiers integrating docking scores and protein-ligand interaction fingerprints vs. Classifiers based on docking scores alone was evaluated on Area under the ROC curve (AUC) for discerning hERG binders from nonbinders (AUC 0.86). Structure-based classifiers integrating docking scores and protein-ligand interaction fingerprints achieved an area under the ROC curve of 0.86 for predicting hERG-related cardiotoxicity.