Developing novel hERG blocker models using heteroatom type and numbers from extensive ligand libraries

The voltage-gated potassium channel, KV11.1, encoded by the human Ether-à-go-go, Related Gene (hERG) is crucial for the membrane repolarization of the action potential. The period of ventricular repolarization is prolonged when this hERG1 channel is inhibited causing long QT syndrome which, results in severe cardiovascular disorders. Various drugs binding indiscriminately to the intracavitary binding site in the pore domain of hERG channels cause a similar malfunction called drug induced LQTS. The inhibition of hERG has become the major reason for drug withdrawals. Identifying key interactions for effective hERG channel blockade is essential in preventing undesired channel blocks. In this study, our goal is to build ligand-based models based on heteroatom types and numbers from extensive ligand libraries that contain data on the chemical constitution of ligands and their associated hERG channel blockage (i.e., pIC50 values). QSAR models were developed to analyze the key structural components influencing compound activity, with the KPLS method emerging as the most efficient, facilitating the construction of models based on eight distinct fingerprints. Then, the influence of heteroatoms on the activity of the hERG blockers was investigated in detail, which demonstrated the involvement of some heteroatoms. By quantifying the effect of the heteroatoms on the pIC50 activity, 6 pairs of compounds were selected for Glide SP and Glide XP docking. The resulting poses were used in molecular dynamics simulations and Prime-MM/GBSA calculations per residue for deeper study and analysis. Keywords: hERG channels, Heteroatoms, Cardiotoxicity, Molecular docking, MD simulations