Computer Simulations of Structure–Activity Relationships for hERG Channel Blockers
| Autor: | Anna Stary-Weinzinger, Bert L. de Groot, Göran Wallin, Johan Åqvist, Lars Boukharta, Henrik Keränen |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Indoles Protein Conformation hERG Molecular Dynamics Simulation Pharmacology Ligands Biochemistry Inhibitory Concentration 50 Structure-Activity Relationship Predictive Value of Tests Potassium Channel Blockers Humans Computer Simulation Channel blocker biology Protein Stability Chemistry Imidazoles Reproducibility of Results Ether-A-Go-Go Potassium Channels Potassium channel Blockade Drug development Structural Homology Protein biology.protein Antipsychotic Agents Protein Binding |
| Zdroj: | Biochemistry |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/bi200173n |
| Popis: | The hERG potassium channel is of major pharmaceutical importance, and its blockade by various compounds, potentially causing serious cardiac side effects, is a major problem in drug development. Despite the large amounts of existing biochemical data on blockade of hERG by drugs and druglike compounds, relatively little is known regarding the structural basis of binding of blockers to the channel. Here, we have used a recently developed homology model of hERG to conduct molecular docking experiments with a series of channel blockers, followed by molecular dynamics simulations of the complexes and evaluation of binding free energies with the linear interaction energy method. The calculations yield a remarkably good agreement with experimental binding affinities and allow for a rationalization of three-dimensional structure-activity relationships in terms of a number of key interactions. Two main interaction regions of the channel are thus identified with implications for further mutagenesis experiments and design of new compounds. |
| Databáze: | OpenAIRE |
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