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Calculation of absolute binding free energies between the hERG channel and structurally diverse drugs

Tatsuki Negami1, Mitsugu Araki2, Yasushi Okuno2

  • 1Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-8657, Japan.

Scientific Reports
|November 14, 2019
PubMed

Insights

This study predicts drug binding to the human ether-a-go-go-related gene (hERG) channel using computational methods. The findings enable accurate prediction of drug affinity, crucial for preventing cardiac arrhythmia.

Area of Science:

  • Biophysics
  • Computational Chemistry
  • Pharmacology

Background:

  • The human ether-a-go-go-related gene (hERG) channel is vital for cardiac repolarization.
  • Drug-induced blockade of hERG channels can cause fatal cardiac arrhythmias.
  • Understanding drug-hERG interactions is essential for cardiovascular safety.

Purpose of the Study:

  • To elucidate the binding mechanisms between hERG channels and diverse drugs using in silico approaches.
  • To develop a predictive model for drug affinity to the hERG channel.

Main Methods:

  • Utilized cryo-electron microscopy structure of the hERG channel.
  • Performed molecular docking simulations to predict drug-channel complexes.
  • Calculated absolute binding free energies using the MP-CAFEE method.

Main Results:

  • Generated accurate complex structures of hERG channel and various drugs.
  • MP-CAFEE calculations showed strong correlation with experimental binding data.
  • Developed a regression equation for predicting drug-hERG affinity.

Conclusions:

  • In silico methods can accurately predict drug binding affinity to the hERG channel.
  • This approach aids in identifying potential cardiotoxic drugs early in development.
  • Facilitates safer drug discovery by assessing hERG channel interactions.

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