Development of Safe Drugs: The hERG Challenge

Subha Kalyaanamoorthy; Khaled H. Barakat

doi:10.1002/med.21445

journal article May 03, 2017

Development of Safe Drugs: The hERG Challenge

Subha Kalyaanamoorthy

Khaled H. Barakat

Medicinal Research Reviews Vol. 38 No. 2 pp. 525-555 · Wiley

View at Publisher Save 10.1002/med.21445

Abstract

AbstractDrug‐induced blockade of human ether‐a‐go‐go‐related gene (hERG) remains a major impediment in delivering safe drugs to the market. Several drugs have been withdrawn from the market due to their severe cardiotoxic side effects triggered by their off‐target interactions with hERG. Thus, identifying the potential hERG blockers at early stages of lead discovery is fast evolving as a standard in drug design and development. A number of in silico structure‐based models of hERG have been developed as a low‐cost solution to evaluate drugs for hERG liability, and it is now agreed that the hERG blockers bind at the large central cavity of the channel. Nevertheless, there is no clear convergence on the appropriate drug binding modes against the channel. The proposed binding modes differ in their orientations and interpretations on the role of key residues in the channel. Such ambiguities in the modes of binding remain to be a significant challenge in achieving efficient computational predictive models and in saving many important already Food and Drug Administration approved drugs. In this review, we discuss the spectrum of reported binding modes for hERG blockers, the various in silico models developed for predicting a drug's affinity to hERG, and the known successful optimization strategies to avoid off‐target interactions with hERG.

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References

Details

Published: May 03, 2017
Vol/Issue: 38(2)
Pages: 525-555
License: View

Authors

S

Subha Kalyaanamoorthy

Faculty of Pharmacy and Pharmaceutical Sciences University Of Alberta Edmonton Alberta Canada

K

Khaled H. Barakat

Faculty of Pharmacy and Pharmaceutical Sciences University Of Alberta Edmonton Alberta Canada; Li Ka Shing Institute of Virology University of Alberta Edmonton Alberta Canada; Li Ka Shing Applied Virology Institute University of Alberta Edmonton Alberta Canada

Funding

Natural Sciences and Engineering Research Council of Canada

Cite This Article

Subha Kalyaanamoorthy, Khaled H. Barakat (2017). Development of Safe Drugs: The hERG Challenge. Medicinal Research Reviews, 38(2), 525-555. https://doi.org/10.1002/med.21445

Development of Safe Drugs: The hERG Challenge

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