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Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators
One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K(+), Ca(2+) and Na(+) currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156305/ https://www.ncbi.nlm.nih.gov/pubmed/25191697 http://dx.doi.org/10.1371/journal.pone.0105553 |
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author | Guo, Jiqing Durdagi, Serdar Changalov, Mohamed Perissinotti, Laura L. Hargreaves, Jason M. Back, Thomas G. Noskov, Sergei Y. Duff, Henry J. |
author_facet | Guo, Jiqing Durdagi, Serdar Changalov, Mohamed Perissinotti, Laura L. Hargreaves, Jason M. Back, Thomas G. Noskov, Sergei Y. Duff, Henry J. |
author_sort | Guo, Jiqing |
collection | PubMed |
description | One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K(+), Ca(2+) and Na(+) currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4–S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs. |
format | Online Article Text |
id | pubmed-4156305 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41563052014-09-09 Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators Guo, Jiqing Durdagi, Serdar Changalov, Mohamed Perissinotti, Laura L. Hargreaves, Jason M. Back, Thomas G. Noskov, Sergei Y. Duff, Henry J. PLoS One Research Article One of the main culprits in modern drug discovery is apparent cardiotoxicity of many lead-candidates via inadvertent pharmacologic blockade of K(+), Ca(2+) and Na(+) currents. Many drugs inadvertently block hERG1 leading to an acquired form of the Long QT syndrome and potentially lethal polymorphic ventricular tachycardia. An emerging strategy is to rely on interventions with a drug that may proactively activate hERG1 channels reducing cardiovascular risks. Small molecules-activators have a great potential for co-therapies where the risk of hERG-related QT prolongation is significant and rehabilitation of the drug is impractical. Although a number of hERG1 activators have been identified in the last decade, their binding sites, functional moieties responsible for channel activation and thus mechanism of action, have yet to be established. Here, we present a proof-of-principle study that combines de-novo drug design, molecular modeling, chemical synthesis with whole cell electrophysiology and Action Potential (AP) recordings in fetal mouse ventricular myocytes to establish basic chemical principles required for efficient activator of hERG1 channel. In order to minimize the likelihood that these molecules would also block the hERG1 channel they were computationally engineered to minimize interactions with known intra-cavitary drug binding sites. The combination of experimental and theoretical studies led to identification of functional elements (functional groups, flexibility) underlying efficiency of hERG1 activators targeting binding pocket located in the S4–S5 linker, as well as identified potential side-effects in this promising line of drugs, which was associated with multi-channel targeting of the developed drugs. Public Library of Science 2014-09-05 /pmc/articles/PMC4156305/ /pubmed/25191697 http://dx.doi.org/10.1371/journal.pone.0105553 Text en © 2014 Guo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Guo, Jiqing Durdagi, Serdar Changalov, Mohamed Perissinotti, Laura L. Hargreaves, Jason M. Back, Thomas G. Noskov, Sergei Y. Duff, Henry J. Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators |
title | Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators |
title_full | Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators |
title_fullStr | Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators |
title_full_unstemmed | Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators |
title_short | Structure Driven Design of Novel Human Ether-A-Go-Go-Related-Gene Channel (hERG1) Activators |
title_sort | structure driven design of novel human ether-a-go-go-related-gene channel (herg1) activators |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4156305/ https://www.ncbi.nlm.nih.gov/pubmed/25191697 http://dx.doi.org/10.1371/journal.pone.0105553 |
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