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Utilizing Heteroatom Types and Numbers from Extensive Ligand Libraries to Develop Novel hERG Blocker QSAR Models

Safa Haddad1,2, Lalehan Oktay1,2, Ismail Erol1,2

  • 1Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahçeşehir University, Istanbul 34353, Turkey.

ACS Omega
|November 6, 2023
PubMed

Insights

This study identifies key heteroatoms in drug molecules that block the human ether-à-go-go-related gene (hERG) channel, crucial for preventing cardiovascular risks like long QT syndrome (LQTS). Understanding these interactions aids in developing safer medications.

Area of Science:

  • Cardiovascular pharmacology
  • Medicinal chemistry
  • Computational toxicology

Background:

  • The human ether-à-go-go-related gene (hERG) channel is vital for cardiac repolarization.
  • Dysfunctional hERG channels can cause long QT syndrome (LQTS), leading to arrhythmias and sudden cardiac death.
  • Drug-induced hERG channel blockade is a significant safety concern, necessitating careful drug design.

Purpose of the Study:

  • To identify critical heteroatoms in ligands responsible for effective hERG channel blockade.
  • To establish quantitative structure-activity relationship (QSAR) models for predicting hERG channel inhibitory activity.
  • To elucidate the specific roles of heteroatom types and numbers in hERG channel interactions.

Main Methods:

  • Development of ligand-based quantitative structure-activity relationship (QSAR) models using extensive ligand libraries.
  • Application of machine learning techniques, specifically K-nearest partial least squares (KPLS), with eight distinct fingerprints.
  • Utilizing molecular docking, molecular dynamics simulations, and MM/GBSA calculations for detailed interaction analysis.

Main Results:

  • QSAR models effectively identified key structural features, particularly heteroatoms, influencing hERG channel blockage.
  • The KPLS method demonstrated high efficiency in modeling hERG channel activity based on ligand fingerprints.
  • Analysis revealed the significant impact of heteroatom types and numbers on the potency of hERG blockers.

Conclusions:

  • Heteroatoms play a pivotal role in the mechanism of hERG channel blockade by drug ligands.
  • This research provides a quantitative understanding of heteroatom contributions to hERG channel activity.
  • The findings can guide the design of safer drugs with reduced risk of hERG-mediated cardiovascular adverse effects.

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