Biomedical Engineering Reference
In-Depth Information
1
Introduction
The ensemble of properties, which describe absorption, distribution, metabolism,
elimination and toxicity (ADMET) are of utmost importance for the drug discovery
process. In light of the studies on antitarget proteins responsible for poor ADMET
properties of drug candidates, many high-throughput methods have been developed
for early identification of compounds with a bad ADMET profile. In the past
decade, many strategies were developed to screen libraries of compounds and to
assess the risk of a bad ADMET profile. There is overwhelming evidence that the
inhibition of the hERG potassium channel is directly correlated with a lethal
arrhythmia called Torsade de Points. Thus, the discovery of unwanted interactions
between compounds under development and the hERG channel is a killing criteria.
One of the main challenges of antitarget proteins such as hERG, cytochrome P-450,
P-glycoprotein and serum albumin is their polyspecificity. Even though the binding
sites of many hERG blockers were indentified through docking into homology
models, the molecular basis of the hERG polyspecificity is not clear yet. Due to the
lack of crystal structures, ligand-based approaches were developed to predict the
hERG activity of candidate compounds. Recent studies show that a combination of
different methodologies, such as 2D- and 3D-QSAR with pharmacophore modeling
and classification algorithms was quite successful and might be a powerful tool in
the in silico screening of compound libraries. In this chapter, we will present
selected in silico models developed to predict hERG channel blockers.
2 Long QT Syndrome
The cardiac action potential is composed of five phases. Phase 0 is characterized by
rapid depolarization due to an inward Na
þ
current. This phase is followed first by an
initial short repolarization (phase 1) due to an outward K
þ
current and then by a
plateau (phase 2), which is characterized by a slow repolarization rate. During the
plateau phase, an inward Ca
2+
current is balanced by an outward K
þ
current. In
phase 3 of the cardiac action potential, the rapid and the slow delayed rectifier K
þ
(
I
Kr
and
I
Ks
, respectively) determine the repolarization of the myocyte with its
membrane potential to the resting state (phase 4). A long cardiac action potential
is a safeguard mechanism that prevents the onset of potentially dangerous
arrhythmias. However, this mechanism is not perfect, as a delay of cardiac repolar-
ization prolongs the QT time.
Through the electrocardiogram is possible to register the electrical activity of the
heart. The P wave registers the atrial depolarization, followed by the QRS complex,
which registers the ventricular depolarization. The T wave finally corresponds
to the ventricular repolarization. During the interval between the Q and T waves
(QT interval), which is a measure of repolarization duration, the heart is refractory
to new excitations. A delay in ventricular repolarization is registered in the ECG as
