New Insights into Ion Channels: Predicting hERG-Drug Interactions
Drug-induced long QT syndrome can be a very dangerous side effect of existing and developmental drugs. In this work, a model proposed two decades ago addressing the ion specificity of potassium channels is extended to the human ether-à-gogo gene (hERG). hERG encodes the protein that assembles into t...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/18/10732 |
| _version_ | 1797487210911498240 |
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| author | Michael Fitzpatrick Wempe |
| author_facet | Michael Fitzpatrick Wempe |
| author_sort | Michael Fitzpatrick Wempe |
| collection | DOAJ |
| description | Drug-induced long QT syndrome can be a very dangerous side effect of existing and developmental drugs. In this work, a model proposed two decades ago addressing the ion specificity of potassium channels is extended to the human ether-à-gogo gene (hERG). hERG encodes the protein that assembles into the potassium channel responsible for the delayed rectifier current in ventricular cardiac myocytes that is often targeted by drugs associated with QT prolongation. The predictive value of this model can guide a rational drug design decision early in the drug development process and enhance NCE (New Chemical Entity) retention. Small molecule drugs containing a nitrogen that can be protonated to afford a formal +1 charge can interact with hERG to prevent the repolarization of outward rectifier currents. Low-level ab initio calculations are employed to generate electronic features of the drug molecules that are known to interact with hERG. These calculations were employed to generate structure–activity relationships (SAR) that predict whether a small molecule drug containing a protonated nitrogen has the potential to interact with and inhibit the activity of the hERG potassium channels of the heart. The model of the mechanism underlying the ion specificity of potassium channels offers predictive value toward optimizing drug design and, therefore, minimizes the effort and expense invested in compounds with the potential for life-threatening inhibitory activity of the hERG potassium channel. |
| first_indexed | 2024-03-09T23:44:22Z |
| format | Article |
| id | doaj.art-f898c9127b8346e68ac105b91c79f640 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:44:22Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-f898c9127b8346e68ac105b91c79f6402023-11-23T16:47:04ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181073210.3390/ijms231810732New Insights into Ion Channels: Predicting hERG-Drug InteractionsMichael Fitzpatrick Wempe0Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado—Anschutz Medical Campus, Aurora, CO 80045, USADrug-induced long QT syndrome can be a very dangerous side effect of existing and developmental drugs. In this work, a model proposed two decades ago addressing the ion specificity of potassium channels is extended to the human ether-à-gogo gene (hERG). hERG encodes the protein that assembles into the potassium channel responsible for the delayed rectifier current in ventricular cardiac myocytes that is often targeted by drugs associated with QT prolongation. The predictive value of this model can guide a rational drug design decision early in the drug development process and enhance NCE (New Chemical Entity) retention. Small molecule drugs containing a nitrogen that can be protonated to afford a formal +1 charge can interact with hERG to prevent the repolarization of outward rectifier currents. Low-level ab initio calculations are employed to generate electronic features of the drug molecules that are known to interact with hERG. These calculations were employed to generate structure–activity relationships (SAR) that predict whether a small molecule drug containing a protonated nitrogen has the potential to interact with and inhibit the activity of the hERG potassium channels of the heart. The model of the mechanism underlying the ion specificity of potassium channels offers predictive value toward optimizing drug design and, therefore, minimizes the effort and expense invested in compounds with the potential for life-threatening inhibitory activity of the hERG potassium channel.https://www.mdpi.com/1422-0067/23/18/10732potassium channelhuman ether-à-gogo-related gene (hERG)structure–activity relationships (SAR)ab initio calculationsdrug developmentlong QT syndrome |
| spellingShingle | Michael Fitzpatrick Wempe New Insights into Ion Channels: Predicting hERG-Drug Interactions International Journal of Molecular Sciences potassium channel human ether-à-gogo-related gene (hERG) structure–activity relationships (SAR) ab initio calculations drug development long QT syndrome |
| title | New Insights into Ion Channels: Predicting hERG-Drug Interactions |
| title_full | New Insights into Ion Channels: Predicting hERG-Drug Interactions |
| title_fullStr | New Insights into Ion Channels: Predicting hERG-Drug Interactions |
| title_full_unstemmed | New Insights into Ion Channels: Predicting hERG-Drug Interactions |
| title_short | New Insights into Ion Channels: Predicting hERG-Drug Interactions |
| title_sort | new insights into ion channels predicting herg drug interactions |
| topic | potassium channel human ether-à-gogo-related gene (hERG) structure–activity relationships (SAR) ab initio calculations drug development long QT syndrome |
| url | https://www.mdpi.com/1422-0067/23/18/10732 |
| work_keys_str_mv | AT michaelfitzpatrickwempe newinsightsintoionchannelspredictinghergdruginteractions |