Recent
Targets in Drug Discovery: A Review
Shweta
Paroha1*, Ravindra Dhar Dubey2 and Subrata Mallick3
1Siddhi Vinayaka
Institute of Technical Sciences, Mangla, Bilaspur, Chhattisgarh, India.
2Institute of
Pharmacy, RITEE, Chhatauna, Mandir Hasaud, Raipur, Chhattisgarh, India.
3School of Pharmaceutical Sciences, Siksha O Anushandhan University,
Bhubneshwar, Orissa, India.
ABSTRACT:
Drug design and drug discovery have critical importance
in human health care. There are various sites for the drug targeting
like cell membrane, intracellular constituents, outside the cell and possibly
antimicrobial action. Receptor as agonist and antagonist, enzymes and pumps,
ion channels, physicochemical action with Lipid, protein or water constituents
of nerve cell membrane are targeted on cell membrane. Various type of nuclear
receptor like Oestrogen, retinoid, vitamin- D,
Glucocorticoid, Thyroid hormone, peroxisome proliferators, liver
receptor etc. are targeted on the intracellular constituents. The
traditional approach of drug discovery involves target identification,
validation, lead search and optimization followed by clinical development
phases. The recent targets for drug action are DNA,
Nuclear Receptors e.g. Retinoid Receptors, Ion Channels e.g. Calcium channel,
Enzymes e.g. Cholinesterase, Receptors e.g. Adenosine Receptor in the present work
different targets of drug action are discussed in brief which is an essential
part during discovery phase of a drug.
KEYWORDS: Drug design, Drug discovery, Receptors,
Targets.
1.
INTRODUCTION:
Drugs usually act on either cellular or genetic chemicals
in the body, known as targets, which are believed to be associated with
disease. Scientists use a variety of techniques to identify and isolate a
target and learn more about its functions and how these influence disease.
Compounds are then identified that have various interactions with drug targets
helpful in treatment of a specific disease.1
New drugs begin in the laboratory with
chemists, scientists and pharmacologists who identify cellular and genetic
factors that play a role in specific diseases. They search for chemical and
biological substances that target these biological markers and are likely to
have drug-like effects. Out of every 5,000 new compounds identified during the
discovery process, only five are considered safe for testing in human volunteers
after preclinical evaluations. After three to six years of further clinical
testing in patients, only one of these compounds is ultimately approved as a
marketed drug for treatment. The following sequence of research activities
begins the process that results in development of new medicines.2
2.
DNA AS TARGETS:
DNA is a long polymer made from repeating units called nucleotides.3,4 In living organisms, DNA does not
usually exist as a single molecule, but instead as a tightly-associated pair of
molecules.5,6 These two long strands entwine like
vines, in the shape of a double
helix. The backbone of the DNA strand is made from
alternating phosphate and sugar
residues.7 The sugar in DNA is 2-deoxyribose,
which is a pentose sugar. The sugars are joined together
by phosphate groups that form phosphodiester bonds
between the third and fifth carbon atoms of adjacent sugar rings. Bonds in a
double helix the direction of the nucleotides in one strand is opposite to
their direction in the other strand. This arrangement of DNA strands is called
antiparallel. The asymmetric ends of DNA strands are referred to as the 5′ (five prime) and 3′ (three prime) ends, with the 5' end
being that with a terminal phosphate group and the 3' end that with a terminal
hydroxyl group. The DNA double helix is stabilized by hydrogen bonds
between the bases attached to the two strands. The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four
bases are attached to the sugar/phosphate to form the complete nucleotide. These bases are classified into two types;
adenine and guanine are fused five- and six-membered heterocyclic compounds
called purines,
while cytosine and thymine are six-membered rings called pyrimidines.8
3. NUCLEAR RECEPTOR AS TARGETS:
In the field of molecular biology, Nuclear Receptors
are a class of proteins found within the interior
of cells that are responsible for sensing the presence of hormones and certain other molecules. In response, these receptors
work in concert with other proteins to regulate the expression of specific genes, thereby controlling the metabolism, development, homeostatic of the organism. Nuclear
receptors have the ability to directly bind to DNA and regulate the expression of adjacent genes; hence these receptors
are classified as transcription factors.9
3.1 Retinoic acid receptors:
The retinoic acid receptor (RAR) is a type of nuclear receptor
which is activated by both all-trans retinoic acid
and 9-cis retinoic acid.There
are three retinoic acid receptors (RAR), RAR-alpha, RAR-beta, and RAR-gamma encoded by the RARA, RARB, RARG genes respectively. Retinoid is a term for compounds that bind to and activate retinoic acid
receptors members of the nuclear hormone receptor superfamily. The most
important endogenous retinoid is all-trans-retinoic acid. Retinoids
regulate a wide variety of essential biological processes, such as vertebrate
embryonic morphogenesis and organogenesis,cell growth arrest, differentiation
and apoptosis, and homeostasis, as well as their disorders.9
3.2 Vitamin-D Nuclear Receptors:
1,25-dihydroxyvitamin D3
[1,25-(OH)2-D3] or "vitamin D hormone" plays multiple roles in the
regulation of animal metabolism. These are affected in two ways first at the
level of the plasma membrane (by a vitamin D membrane receptor) and second at
the level of gene transcription.9
§
|
The thyroid hormone receptor is a type of nuclear receptor that
is activated by binding thyroid hormone. Amongst
the most important functions of thyroid hormone receptors are regulation of metabolism and heart rate. In addition, they play critical roles in the development of
organisms. There are three forms of the thyroid hormone receptor designated alpha-1, beta-1 and beta-2 that are
able to bind thyroid hormone. There are two TR-alpha receptor splice variants encoded by the THRA gene and two TR-beta isoform splice variants encoded by the THRB gene.9
3.4 Estrogen receptors:
The Estrogen Receptor (ER) is a member of the nuclear hormone
family of intracellular receptors which is
activated by the hormone 17β-estradiol. The main function of the estrogen receptor is as a DNA
binding transcription factor
which regulates gene expression. However the estrogen receptor also has
additional functions independent of DNA binding.10
The glucocorticoid receptor (GR,
or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is a ligand-activated transcription factor
that binds with high affinity to cortisol and other glucocorticoids. The GR is expressed in almost every cell in the body and
regulates either directly or indirectly genes controlling a wide variety of
processes including the development, metabolism, and immune response of the organism.11
3.6 Liver X receptors:
The liver X receptor (LXR) is a
member of the nuclear receptor family of transcription factors.
Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. Since there is no clear
consensus on what the endogenous ligand of LXR is, LXR is referred to as an orphan receptor. Two isoforms of LXR have been identified
and are referred to as LXRα and LXRβ. The liver
X receptors are classified into subfamily 1 (thyroid hormone receptor-like) of the nuclear receptor superfamily, and are given the nuclear receptor nomenclature
symbols NR1H3 (LXRα) and NR1H2 (LXRβ) respectively. Target genes of LXRs are involved in cholesterol and lipid metabolism regulation12
4.
ENZYMES AS TARGETS:
Enzymes are biocatalysts, the catalysts of
life. A catalyst is defined as a substance that increases the velocity or rate
of a chemical reaction without undergoing any change in the overall process.
Enzymes may be defined as biocatalyst synthesized by living cells .They are
protein in nature (exception-RNA acting as ribozyme) colloidal and thermolabile
in character, and specific in their action.
Ion channels are pore-forming proteins
that help to establish and control the small voltage
gradient
across the plasma membrane of all living cells
by allowing the flow of ions
down their electrochemical gradient. They are present
in the membranes that surround all biological
cells. Voltage-gated proton channels openin with depolarization, but
in a strongly pH-sensitive manner. The result is that these channels open only
when the electrochemical gradient is outward, such that their opening will only
allow protons to leave cells. Their function thus appears to be acid extrusion
from cells. Another important function occurs in phagocytes e.g. eosinophils,
neutrophils,
macrophages,
during the respiratory burst.13,14 The Ligand-gated ion channels, also
referred to as LGICs, or ionotropic receptors, are a group of
intrinsic transmembrane ion channels that are opened or closed in response to
binding of a chemical messenger, as opposed to voltage-gated ion channels or stretch-activated ion channels.15 The ion channel
is regulated by a ligand and is usually very selective to
one or more ions like Na+, K+,
Ca2+,
or Cl-.
Such receptors located at synapses convert the chemical signal of presynaptically
released neurotransmitter directly and very quickly into a postsynaptic
electrical signal.
6. RECEPTORS AS TARGETS:
In biochemistry,
a receptor is a protein
on the cell membrane or within the cytoplasm
or cell nucleus
that binds to a specific molecule (a ligand), such as a neurotransmitter,
hormone,
or other substance, and initiates the cellular response to the ligand.
Ligand-induced changes in the behavior of receptor proteins result in
physiological changes that constitute the biological actions of the ligands.
The first neurotransmitter system to be
covered will be the cholinergic system. Acetylcholine was one of the first
neurotransmitters to be discovered. Acetylcholine is produced by the synthetic
enzyme choline acetyltransferase which uses acetyl coenzyme A and choline as
substrates for the formation of acetylcholine. Dietary choline and
phosphatidylcholine serve as the sources of free choline for acetylcholine
synthesis. Upon release, acetylcholine is metabolized into choline and acetate
by acetylcholinesterase, and other nonspecific esterases. Acetylcholine release
can be excitatory or inhibitory depending on the type of tissue and the nature
of the receptor with which it interacts.
6.2
5-Hydroxytryptamine receptor 2A:
5-Hydroxytryptamine receptor 2A (5-HT2A) is
a prototypical G protein-coupled serotonin receptor. It is the main molecular target for the
LSD-like hallucinogens (which function as agonists) and for atypical
antipsychotic drugs (which function as antagonists). 5-HT2A receptors have recently
been discovered to be functional co-receptors for the human polyomavirus
JCV. 5-HT2A receptors are highly
enriched in the brain, especially in cortical pyramidal neurons where they
modulate glutamate release and in ventral segmental neurons where they regulate
dopamine release. 5-HT2A receptors also regulate vascular smooth muscle tone,
uterine contraction and platelet aggregation. 5-HT2A receptors activate several
signal transduction cascades including phosphoinositide (PI) hydrolysis,
arachidonic acid (AA) release, activation of Rho/Rac signalling cascades and
ion channel activation.
6.3
Adenosine receptors:
In humans, there are four adenosine
receptors. Each is encoded by a separate gene and has different functions,
although also overlapping. For instance, both A1 receptors and A2a
play roles in the heart, regulating myocardial
oxygen consumption and coronary blood flow. The adenosine receptors (or P1
receptors16)
are a class of purinergic receptors, G-protein coupled receptors with adenosine
as endogenous
ligand.17
6.4 Dopamine receptors:
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are
prominent in the vertebrate central nervous system (CNS). The neurotransmitter
dopamine
is the primary endogenous ligand for dopamine receptors.
There are at least three known endothelin receptors, ETA, ETB1 and ETB2,
all of which are G protein-coupled receptors whose
activation result in elevation of intracellular-free calcium.18 It is associated with ABCD syndrome
and some forms of Waardenburg syndrome.19
6.6 GABA receptors:
The GABA
receptors are a class of receptors that respond to the neurotransmitter
γ-aminobutyric acid (GABA), the chief
inhibitory neurotransmitter in the vertebrate
central nervous system. There are three
classes of GABA receptors; GABAA, GABAB,
and GABAС.
GABAA and GABAС receptors are ligand-gated ion channels (also known as
ionotropic receptors), whereas GABAB receptors are G protein-coupled receptors (also known as
metabotropic receptors).
Fast-responding GABA receptors are members of family of Cys-loop
ligand-gated ion channels.20,21,22
6.7
Glucagon receptors:
The glucagon
receptor is a 62 kDa
peptide
that is activated by glucagon and is a member of the G-protein
coupled family of receptors, coupled to Gs.
Stimulation of the receptor results in activation of adenylate
cyclase and increased levels of intracellular
cAMP. Glucagon receptors
are mainly expressed in liver and in kidney with lesser amounts found in heart, adipose
tissue, spleen,
thymus,
adrenal
glands, pancreas, cerebral
cortex, and gastrointestinal tract. The glucagon receptor family is a group of
closely related G-protein coupled receptors.23
The metabotropic
glutamate receptors, or mGluRs,
are a type of glutamate receptor which is active through an
indirect metabotropic process. They are members of
the group C family of G-protein-coupled receptors, or GPCRs.24
The mGluRs perform a variety of functions in the central and
peripheral nervous systems: for example, they are involved in learning,
memory,
anxiety,
and the perception of pain.25
They are found in pre- and postsynaptic neurons in synapses
of the hippocampus,
cerebellum,and
the cerebral cortex, as well as other parts of the brain and in peripheral
tissues.26
Like other metabotropic receptors, mGluRs have seven transmembrane domains that span the cell
membrane. Unlike ionotropic receptors, metabotropic receptors
are not directly linked to ion channels, but may affect them by activating
biochemical cascades. In addition to producing excitatory and inhibitory postsynaptic potentials,
mGluRs serve to modulate the function of other receptors (such as NMDA
receptors), changing the synapse's
excitability.27
6.9
Neuropeptide Y
receptors are receptors for Neuropeptide
Y. They are all G-protein coupled receptors, coupling to Gi.There
are five known mammalian neuropeptide y receptors designated Y1
through Y5. Four neuropeptide y receptors each encoded by a
different gene have been identified in humans, they are Y1 - NPY1R,
Y2 - NPY2R, Y4 - PPYR1, Y5 - NPY5R.
The neuropeptide Y receptors act as receptors for NPY, PYY and pancreatic polypeptide which are a closely
related group of peptide.
6.10
Opioid receptors:
Opioid receptors are a group of G-protein coupled receptors with opioids as ligands. The endogenous
opioids
are dynorphins,
enkephalins,
endorphins,
endomorphins and nociceptin/orphanin FQ.
6.11
Somatostatin receptors:
There are five known somatostatin receptorsthat are targeted
for the drug action SST1 (SSTR1), SST2 (SSTR2), SST3 (SSTR3), SST4 (SSTR4), SST5 (SSTR5).
7. HORMONES AS TARGETS:
A Hormone is a
chemical messenger that carries a signal from
one cell
(or group of cells) to another via the blood. All multicellular organisms produce hormones.
In general, hormones regulate the function of their target cells, i.e., cells
that express a receptor for the hormone. The action, or net effect of hormones
is determined by a number of factors including its pattern of secretion and the
response of the receiving tissue - the signal transduction response. Most hormones
initiate a cellular response by initially combining with either a specific intracellular
or cell membrane associated receptor protein. A cell may have several
different receptors that recognize the same hormone and activate different signal transduction pathways, or alternatively
different hormones and their receptors may invoke the same biochemical pathway.
For many hormones, including most protein hormones,
the receptor is membrane associated and embedded in the plasma
membrane at the surface of the cell. The interaction of hormone and
receptor typically triggers a cascade of secondary effects within the cytoplasm
of the cell, often involving phosphorylation
or dephosphorylation of various other cytoplasmic proteins, changes in ion channel
permeability, or increased concentrations of intracellular molecules that may
act as secondary messengers (e.g. cyclic AMP).
Some protein hormones also interact with intracellular
receptors located in the cytoplasm or nucleus
by an intracrine
mechanism. For hormones such as steroid
or thyroid hormones, their receptors are located intracellularly
within the cytoplasm
of their target cell. In order to bind their receptors these hormones must
cross the cell membrane. The combined hormone-receptor complex
then moves across the nuclear membrane into the nucleus of the cell, where it
binds to specific DNA sequences, effectively amplifying or
suppressing the action of certain genes, and affecting protein
synthesis However, it has been shown that not all steroid receptors
are located intracellularly, some are plasma
membrane associated.28
8. CONCLUSION:
Drug design and drug discovery are becomes very
convenient by using “recent targets in drug discovery”.The main goal of this
discovery are to predict biological activity and to concern structural
information of drug design. This approach deals with typically individual genes
or gene product. Now-a-days the process of drug discovery utilizes the
technologies such as genomics, proteomics and bioinformatics in target
identification, as well as downstream process such as target validation, lead
discovery, lead optimization and clinical development. The principle targets
for drug action are DNA, Receptors, Ion channels, Enzymes and Hormones. By
using these techniques, it will be very easy for present and future generation
to do research on drug design and drug discovery.
9.
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Received on 08.10.2010
Accepted on 10.11.2010
© A&V Publication all right reserved
Research J. Pharmacology and
Pharmacodynamics. 3(1): Jan. –Feb. 2011, 5-9
