Title:Human Ether-a-Go-Go-Related Gene Channel Blockers and its Structural Analysis for Drug Design
VOLUME: 14 ISSUE: 1
Author(s):N. S. Hari Narayana Moorthy, Maria J. Ramos and Pedro A. Fernandes
Affiliation:REQUIMTE, Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, 687, Rua do Campo Alegre, 4169-007 Porto, Portugal.
Keywords:Acehytisine hydrochloride, anti-arrhythmic drugs, cancer, hERG, QSAR, van der Waals
Abstract:The human ether-a-go-go-related gene (hERG) is a K+ channel protein mainly expressed in the heart and the
nervous systems and its blockade by non-cardiovascular acting drugs resulted in tachycardia and sudden death. In this present
review, we have focused the physicochemical properties responsible for the hERG blocking activity of structurally
different compounds. The reported research works showed that the hydrophobicity on the van der Waals (vdW) surface of
the molecules (aroused from the aromatic ring) necessary for the hERG blocking activity along with topological and electronic
properties. The quinolizidine alkaloids (natural products) such as oxymatrine, sophoridine, sophocarpine and matrine
carry the common molecular structure of O=C=N–C–C–C–N that possessed positive ionotropic effect and hERG
blocking activity. Acehytisine hydrochloride (previously named Guangfu base A) was isolated from the root of Aconitum
coreanum (Levl.), is an anti-arrhythmic drug in phase IV clinical trial. The isoquinoline alkaloid, neferine (Nef) induces a
concentration-dependent decrease in current amplitude (IC50 of 7.419 ΜM). Most of these natural product compounds
contain non-flexible aromatic structures but have significant activity due to the presence of optimum hydrophobicity. Recent
research works revealed that Eag and hERG channels are expressed by a variety of cancer cell lines and tissues. The
Eag channel showed an oncogenic potential while hERG channels are associated with more aggressive tumors and have a
role in mediating invasion. This review concluded that the consideration of physicochemical properties necessary for the
hERG blocking activity will guide to develop novel drugs with less cardiotoxicity.
