title: A critical assessment of combined ligand- and structure-based approaches to HERG channel blocker modeling.
abstract: Blockade of human ether-à-go-go related gene (hERG) channel prolongs the duration of the cardiac action potential and is a common reason for drug failure in preclinical safety trials. Therefore, it is of great importance to develop robust in silico tools to predict potential hERG blockers in the early stages of drug discovery and development. Herein we described comprehensive approaches to assess the discrimination of hERG-active and -inactive compounds by combining quantitative structure-activity relationship (QSAR) modeling, pharmacophore analysis, and molecular docking. Our consensus models demonstrated high-predictive capacity and improved enrichment and could correctly classify 91.8% of 147 hERG blockers from 351 inactives. To further enhance our modeling effort, hERG homology models were constructed, and molecular docking studies were conducted, resulting in high correlations (R² = 0.81) between predicted and experimental pIC₅₀s. We expect our unique models can be applied to efficient screening for hERG blockades, and our extensive understanding of the hERG-inhibitor interactions will facilitate the rational design of drugs devoid of hERG channel activity and hence with reduced cardiac toxicities.
authors: Integrated Molecular Discovery Laboratory, Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, 1901 East Rd., Houston, Texas, USA.
authors: Lei
authors: L
authors: Du-Cuny
authors: Lu
authors: L
authors: Chen
authors: Shuxing
authors: S
authors: Zhang
mesh_terms: D000465:Algorithms; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000889:Anti-Arrhythmia Agents; D051638:Ether-A-Go-Go Potassium Channels; D008024:Ligands; D026902:Potassium Channel Blockers