Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities
The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinforma...
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doaj-751cb4f962a644c8aad52cc7eabe09d52020-11-24T23:46:40ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122018-09-01910.3389/fphar.2018.01035405191Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical EntitiesSaba Munawar0Saba Munawar1Monique J. Windley2Edwin G. Tse3Matthew H. Todd4Adam P. Hill5Jamie I. Vandenberg6Ishrat Jabeen7Research Center for Modeling and Simulation, National University of Science and Technology, Islamabad, PakistanVictor Chang Cardiac Research Institute, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Sydney, NSW, AustraliaSchool of Chemistry, The University of Sydney, Sydney, NSW, AustraliaSchool of Chemistry, The University of Sydney, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Sydney, NSW, AustraliaVictor Chang Cardiac Research Institute, Sydney, NSW, AustraliaResearch Center for Modeling and Simulation, National University of Science and Technology, Islamabad, PakistanThe hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinformatics strategy using combined ligand and structure based models for the prediction of hERG inhibition potential (IC50) of new chemical entities (NCEs) during early stages of drug design and development. Integrated GRid-INdependent Descriptor (GRIND) models, and lipophilic efficiency (LipE), ligand efficiency (LE) guided template selection for the structure based pharmacophore models have been used for virtual screening and subsequent hERG activity (pIC50) prediction of identified hits. Finally selected two hits were experimentally evaluated for hERG inhibition potential (pIC50) using whole cell patch clamp assay. Overall, our results demonstrate a difference of less than ±1.6 log unit between experimentally determined and predicted hERG inhibition potential (IC50) of the selected hits. This revealed predictive ability and robustness of our models and could help in correctly rank the potency order (lower μM to higher nM range) against hERG.https://www.frontiersin.org/article/10.3389/fphar.2018.01035/fullhERG inhibitorstrosade de pointeslong QT syndrompharmcophoreGRINDmolecular docking |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Saba Munawar Saba Munawar Monique J. Windley Edwin G. Tse Matthew H. Todd Adam P. Hill Jamie I. Vandenberg Ishrat Jabeen |
spellingShingle |
Saba Munawar Saba Munawar Monique J. Windley Edwin G. Tse Matthew H. Todd Adam P. Hill Jamie I. Vandenberg Ishrat Jabeen Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities Frontiers in Pharmacology hERG inhibitors trosade de pointes long QT syndrom pharmcophore GRIND molecular docking |
author_facet |
Saba Munawar Saba Munawar Monique J. Windley Edwin G. Tse Matthew H. Todd Adam P. Hill Jamie I. Vandenberg Ishrat Jabeen |
author_sort |
Saba Munawar |
title |
Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities |
title_short |
Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities |
title_full |
Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities |
title_fullStr |
Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities |
title_full_unstemmed |
Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities |
title_sort |
experimentally validated pharmacoinformatics approach to predict herg inhibition potential of new chemical entities |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2018-09-01 |
description |
The hERG (human ether-a-go-go-related gene) encoded potassium ion (K+) channel plays a major role in cardiac repolarization. Drug-induced blockade of hERG has been a major cause of potentially lethal ventricular tachycardia termed Torsades de Pointes (TdPs). Therefore, we presented a pharmacoinformatics strategy using combined ligand and structure based models for the prediction of hERG inhibition potential (IC50) of new chemical entities (NCEs) during early stages of drug design and development. Integrated GRid-INdependent Descriptor (GRIND) models, and lipophilic efficiency (LipE), ligand efficiency (LE) guided template selection for the structure based pharmacophore models have been used for virtual screening and subsequent hERG activity (pIC50) prediction of identified hits. Finally selected two hits were experimentally evaluated for hERG inhibition potential (pIC50) using whole cell patch clamp assay. Overall, our results demonstrate a difference of less than ±1.6 log unit between experimentally determined and predicted hERG inhibition potential (IC50) of the selected hits. This revealed predictive ability and robustness of our models and could help in correctly rank the potency order (lower μM to higher nM range) against hERG. |
topic |
hERG inhibitors trosade de pointes long QT syndrom pharmcophore GRIND molecular docking |
url |
https://www.frontiersin.org/article/10.3389/fphar.2018.01035/full |
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