Killer factor for a molecule to be a drug - hERG Channel Inhibition

Guest Post – Jagmohan Singh Saini

The whole drug discovery and development process is very time-consuming and expensive. It is now recognized that besides poor ADME (Absorption, distribution, metabolism, and excretion), cardiac toxicity is one of the killer factors for a molecule to be a drug. In recent years, several blockbuster drugs have been withdrawn from the market because of reports of sudden cardiac deaths. In all cases, long QT syndrome, characterized by the prolongation of the QT interval in ECG was responsible.

The prolonged duration of the cardiac action potential can be traced to one specific mechanism: blockage of Ikr current in the heart. This current is conducted by tetrameric pores with the individual subunit encoded by human ether-à-go-go related gene (hERG). Blockage of hERG K+ channel is widely regarded as a prominent cause of drug induced QT prolongation making early detection of compounds with this undesirable side effect an important objective in the pharmaceutical Industry.

Perhaps owing to the unique shape of the ligand-binding site and its hydrophobic character, the hERG channel has been shown to interact with pharmaceuticals of widely varying structure, often at concentrations similar to the levels of on-target activity of the respective compounds. The homology model of hERG Channel clearly shows that and Phe656 and Tyr652 appeared to be the primary interaction points. The current consensus implicates Phe656 in π-stacking interactions with the ligands, whereas Tyr652 is thought to participate in a cation–π interaction with the protonated basic nitrogen present in most of the reported hERG blockers.

Structural model of hERG channels. (a) Key elements of hERG channel topology illustrated using the X-ray structure of KvAP. Two of the four subunits comprising the tetrameric channel are shown. (b) Model of the pore portion of hERG channel. The P-S6 fragment is shown for a dimer. Aromatic residues Phe656 and Tyr652 are critical for hERG block by most known small-molecule ligands. Polar residues Thr623 and Ser624 modulate the binding potency for a number of reported hERG blockers.

A hERG blocker is represented schematically based on published evidence. One or two hydrophobes interact with Phe656, a positive charge is stabilized by cation–π interaction with Tyr652. The generally hydrophobic tail contains an acceptor able to interact with the polar residues on the loop that connects the pore helix to the selectivity filter.