hERG Blockade Prediction by Combining Site Identification by Ligand Competitive Saturation and Physicochemical Properties by Himanshu Goel Wenbo Yu & Alexander D. MacKerell Jr

Author:Himanshu Goel, Wenbo Yu & Alexander D. MacKerell, Jr.
Format: pdf
Tags: The human ether-a-go-go-related gene (hERG) potassium channel is a well-known contributor to drug-induced cardiotoxicity and therefore is an extremely important target when performing safety assessments of drug candidates. Ligand-based approaches in connection with quantitative structure active relationships (QSAR) analyses have been developed to predict hERG toxicity. The availability of the recent published cryogenic electron microscopy (cryo-EM) structure for the hERG channel opened the prospect of using structure-based simulation and docking approaches for hERG drug liability predictions. In recent times, the idea of combining structure- and ligand-based approaches for modeling hERG drug liability has gained momentum offering improvements in predictability when compared to ligand-based QSAR practices alone. The present article demonstrates uniting the structure-based SILCS (site-identification by ligand competitive saturation) approach in conjunction with physicochemical properties to develop predictive models for hERG blockade. This combination leads to improved model predictability based on Pearson’s R and percent correct (represents rank-ordering of ligands) metric for different validation sets of hERG blockers involving a diverse chemical scaffold and wide range of pIC50 values. The inclusion of the SILCS structure-based approach allows determination of the hERG region to which compounds bind and the contribution of different chemical moieties in the compounds to the blockade, thereby facilitating the rational ligand design to minimize hERG liability., SILCS; hERG channel; physicochemical properties; multiple linear regression; FragMaps


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