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or withdrawn from market.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.
