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Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities

Munawar, S; Windley, MJ; Tse, EG; Todd, MH; Hill, AP; Vandenberg, JI; Jabeen, I; (2018) Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities. Frontiers in Pharmacology , 9 (1035) p. 1035. 10.3389/fphar.2018.01035. Green open access

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Abstract

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.

Type: Article
Title: Experimentally Validated Pharmacoinformatics Approach to Predict hERG Inhibition Potential of New Chemical Entities
Location: Switzerland
Open access status: An open access version is available from UCL Discovery
DOI: 10.3389/fphar.2018.01035
Publisher version: https://doi.org/10.3389/fphar.2018.01035
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: GRIND, hERG inhibitors, long QT syndrom, molecular docking, patch clamp, pharmcophore, trosade de pointes
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharma and Bio Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/10061485
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