Gupta S.P. (ed.) Ion Channels and Their Inhibitors
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Ion Channels and Their Inhibitors
.
Satya Prakash Gupta
Editor
Ion Channels
and Their Inhibitors
Editor
Prof. Satya Prakash Gupta
Department of Applied Sciences
Meerut Institute of Engineering and Technology
Meerut 250005
India
spgbits@gmail.com
ISBN 978-3-642-19921-9 e-ISBN 978-3-642-19922-6
DOI 10.1007/978-3-642-19922-6
Springer Heidelberg Dordrecht London New York
Library of Congress Control Number: 2011931782
# Springer-Verlag Berlin Heidelberg 2011
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Preface
As is well known, ion channels are crucial components of living cells. The physio-
logical function of ion channels had been observed long before they were known to
exist. They figure in a wide variety of biological processes that involve changes in
cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport
of nutrients and ions, T-cell activation, and pancreatic b-cell insulin release. Thus
being the crucial components of living cells, ion channels are important targets
of therapeutic agents. Historically, it has been challenging to develop drugs on this
target class. A major issue with target-based ion channel drug development is
identification of good small chemical leads for medicinal chemistry optimization
to clinical candidate status. Thus, enough attention has been paid to the study of
structure and functions of ion channels and their potential inhibitors. The present
book compiles a few important articles authored by eminent workers in the field to
cover some recent advances in the studies on the structure and functions of some
ion channels, e.g., Na
+
,K
+
,Ca
2+
,Cl
, and their inhibitors. The book may be of
great use to the students and scientists working in the area of molecular biology,
biochemistry, physiology, and neurobiology.
The book contains 11 articles in total. Ion channels, in fact, are transmembrane
proteins that selectively allow a given species of ion to pass through them. In
Chap. 1 entitled Structural and Functional Discrimination of Membrane Proteins,
Gromiha et al. discuss all aspects of these membrane proteins right from their
structural discrimination to resulting functi onal discrimination and drug–target
interactions. In Chap. 2, Bois et al. present the pharmacology of hyperpolari-
zation-activated cyclic nucleotide-gated (HCN) channels. HCN channels generate
and/or regulate neuronal and cardiac excitability. Several physiological roles have
been ascribed to HCN channels which are the consequence of their particular
biophysical properties. In Chap. 3 entitled Advanced Molecular Modeling Techni-
ques Applied to Ion Channels Blockers, Hannongbua et al. describe some important
advanced molecular modeling techniques used to design and develop the potent ion
channel blockers. These techniques include 2D-, 3D-, and 4D-QSARs, ADMET
prediction, molecular dynamics simulations, molecular docking, quantum chemical
v
calculations, and QM/MM calculations. These techniques have been widely applied
to the drug design.
Of the various ion channels, sodium ion channels have been of great signifi-
cance. An article on this with the title Advances in Design and Development of
Sodium Channel Blockers has been exclusively written by Zuliani et al. to describe
briefly the recent advances in the development of isoform-specific and state-
selective sodium channel bloc kers and the medicinal chemistry involved, surveying
the emerging therapeutic fields. Abnormal activity of sodium channels is related
to several pathological processes, including card iac arrhythmias, epilepsy, chronic
pain, neurodegenerati ve diseases, and spasticity.
The pota ssium ion channels play no less important role in the human body.
They constitute the important target for the development of antiarrhythmic agents.
Therefore, in Chap. 5, You et al. have presented the development of potassium
channel blockers as antiarrhythmic agents. Although there are a variety of potassi-
um channels, scientists have developed immense interest in human ether-a-go-go-
related gene (hERG) potassium channels due to their involvement in life-threaten-
ing cardiac arrhythmia. Therefore, an article on hERG channels has been presented
by Singh and Sharma to describe their functions and dysfunctions, therapeutic
agents modulating these channels, and associated QT prolongation. In the next
article, Schiesaro and Ecker describe structure- and ligand-based approaches to
develop models which shed light on the molecular basis of hERG channel inhibition
and present an overview on recent approaches for prediction of hERG channel
blockers. In continuation to this, an article on Advances in Structure–Activity
Relationship Studies on Potassium Channel Modulators has been contributed
by Sharma et al., highlighting the mode of functions of potassium ion channel
modulators.
Calcium ions are a ubiquitous second messenger and their entry into the cytosol
is mediated by multiple types of calcium channels, each with a distinct physiologi-
cal role. They constitute an important target to develop drugs against several
cardiovascular and noncardiovascular diseases, such as angina, hypertension,
arrhythmias, asthma, dysmenorrhea, premature labor, cancer, epilepsy, and glauco-
ma. In Chap. 9, therefore, Hadjipavlou-Litina presents a vivid description of
calcium ion channels, their subtypes, and their blockers, with detailed structure–
activity relationships of blockers. N-type voltage-gat ed Ca
2+
channels (NCCs) play
dominant roles in neuropathic pain and cerebral ischemia. An article on this type of
calcium ion channels, therefore, has been presented by Gopi Mohan et al. to mainly
focus on their blockers and the pharmaceutical importance thereof.
Chloride ion channels have been found to play crucial roles in the development
of human diseases, e.g., mutations in the genes encoding Cl
channels lead to a
variety of deleterious diseases in muscle, kidney, bone, and brain, including
myotonia congenita, dystrophia myotonica, cystic fibrosis, osteopetrosis, and epi-
lepsy, and similarly their activation is supposed to be responsible for the progres-
sion of glioma in the brain and the growth of malaria parasite in the red blood cells.
Thus, the study of the structure, function, and blockers of Cl
channels seems to be
of great importance. The last article entitled Chloride Ion Channels: Structure,
vi Preface
Functions and Inhibitors, therefore, has been written by Gupta and Kaur to describe
all important classes of Cl
channels with a detail of their structures, functions, and
inhibitors.
Thus, an attempt has been made to make the book an interesting reading
by selecting the articles of varying taste for all those involved in research on ion
channels and their blockers. As an editor of this book, I have greatly enjoyed
reading all the articles and hope so will do all the readers. I gratef ully acknowledge
the enthusiasm of all the authors for contributing the excellent article s in this book.
Meerut, Uttar Pradesh, India Satya P. Gupta
June 2011
Preface vii
.
Contents
Structural and Functi onal Discrimination of Membrane Proteins ......... 1
M. Michael Gromiha, Yu-Yen Ou, and Shu-An Chen
Pharmacology of Hyperpolarization-Activated Cyclic
Nucleotide-Gated (HCN) Channels .......................................... 33
Patrick Bois, Aurelien Chatelier, Jocelyn Bescond,
and Jean-Franc¸ois Faivre
Advanced Molecular Modeling Techniques Applied
to Ion Channels Blocke rs ..................................................... 53
Supa Hannongbua, Witcha Treesuwan, and Warabhorn Boonyarat
Advances in Design and Development of Sodium
Channel Blockers .............................................................. 79
Valentina Zuliani, Laura Amori, and Mirko Rivara
Potassium Channel Blockers as Antiarrhythmic Agents .................. 117
Qidong You, Qian Yang, and Xiaojian Wang
hERG Potassium Channe ls in Drug Discovery and Development ........ 149
Jitendra N. Singh and Shyam S. Sharma
Prediction of hERG Channel Inhibition Using
In Silico Techniques .......................................................... 191
Andrea Schiesaro and Gerhard F. Ecker
Advances in Structure– Activity Relationship Studies on Potass ium
Channel Modulators ......................................................... 241
Brij K. Sharma, Prithvi Singh, and Yenamandra S. Prabhakar
ix