Rehabilitating drug-induced long-QT promoters: in-silico design of hERG-neutral cisapride analogues with retained pharmacological activity.

ABSTRACT:

Background

The human ether-a-go-go related gene 1 (hERG1), which codes for a potassium ion channel, is a key element in the cardiac delayed rectified potassium current, IKr, and plays an important role in the normal repolarization of the heart's action potential. Many approved drugs have been withdrawn from the market due to their prolongation of the QT interval. Most of these drugs have high potencies for their principal targets and are often irreplaceable, thus "rehabilitation" studies for decreasing their high hERG1 blocking affinities, while keeping them active at the binding sites of their targets, have been proposed to enable these drugs to re-enter the market.

Methods

In this proof-of-principle study, we focus on cisapride, a gastroprokinetic agent withdrawn from the

SUBMITTER: Durdagi S 

PROVIDER: S-EPMC4016140 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature