Study of hERG Blockade Mechanism using Structure and Ligand based Computational Methods

Abstract

The hERG potassium ion channel is a voltage gated ion channel. Any change in hERG channel gating leads to alteration in Ik, currents and can develop a condition called long QT syndrome (LQTs) that leads to arrhythmia and ultimately quick death. One of the important reasons for LQTs is the drugs trapping into Herg channel that cause the prolongation of QT interval. A number of drugs, due to this reason, have been restricted or withdrawn from market. An important property of hERG channel is its promiscuous nature that can accommodate chemically diverse drugs to within its binding cavity. The drugs which block hERG channel show two types of behaviour, one in which drugs dissociate from channel after binding at certain pulse rate are called frequency dependent drugs, while those drugs which can't leave the channel at certain pulse rate even after washout are called frequency independent drugs. It was necessary to predict those chemical features of molecules that are involved in showing such behaviour. Therefore, in present project both ligand and structure based computational methods were used to predict the behaviour of the molecules. A database of drugs in the form of chemical structures with standard 3D, energy minimized conformations was used for ligand based studies. Molecular docking of both frequency dependent as well as independent compounds with in the binding cavity was done in closed and open state, for structure based studies. Multivariate analysis have been done by using GRIND technique to analyse, both ligand as well as structure based conformations models. 3D structural features important for frequency independent behaviour, include two hydrogen bond donors (-NH2, -OH) at a distance of 4.0 - 4.4A, while in frequency dependent compounds these features were absent. In open hERG channel, the most common iii interactions observed, as validated by the GRIND methodology, are π- stacking with the Phe656 and /or Tyr652 aromatic moieties while in closed hERG channel, the interactions are more confined to the pore region of the channel. The important residues Tyr623 and Ser624 showed maximum contribution in interactions.