Target
Discovery and Validation: Advances in Molecular Pharmacology
Dibyajyoti Saha*1, Mayukh Jana2
Supradip Mandal2
1School of Pharmacy, Chouksey Engineering College, Lal
Khadan, Masturi Road,
Bilaspur-495004,C.G.
2Bharat Technology, Banitabla, Uluberia,
Howrah-711316
ABSTRACT:
The molecular pharmacology involving aspects of
biological, medical and pharmaceutical sciences. It is concerned with invention, discovery, design,
identification and preparation of biologically active compounds, the study of
their metabolism, the interpretation of their mode of action at the molecular
level. The physiology based drug discovery follows physiological readouts and
by contrast, the road of target based drugs discovery begins with identifying
the function of a possible therapeutic target and its role in disease. The
validation of a molecular target in vitro usually proceeds
the validation of a therapeutic concept in vivo; together this defines its
clinical potential. The present article gives disease mechanisms of target
discovery and outline of target validation with its pathways.
KEYWORDS: Target discovery, Target validation, Molecular target,
Disease genes, Molecular pharmacology.
INTRODUCTION:
Drug
discovery and development can broadly follow two different paradigms:
physiology based drug discovery and target-based discovery. The main difference
between this two paradigms lies in the time point at
which the drug target is actually identified1. The disease mechanism defines the possible causes of
the particular disorder, as well as the phenotype of the disease. Target
validation requires a demonstration that a molecular target is critically
involved in a disease process, and that modulation of the target is likely to
have a therapeutic effect.
TARGET DISCOVERY – DISEASE MECHANISM:
Understanding
the disease mechanism directs research and formulates a possible treatment to
show or reverse the disease process. It also predicts a change of the disease
pattern and its implications2.
The various types of disease mechanisms are defect in distinct genes – genetic
disorders; infection by bacteria, fungi or viruses; immune/autoimmune disease; multicasual disease; trauma and acute disease based on
injury or organ failure3.
TARGET DISCOVERY – DISEASE GENES:
Disease genes have identified based on hereditary
patterns even before the knowledge of the DNA sequences of the human genome.
Following
an original founder mutation, these genetically inherited diseases run in
families; examples include phenylketonuria, cystic
fibrosis, Huntington disease, fanconi’s anemia, autosomal dominant familial Alzheimer’s (FAD). The specific
gene defects or mutations that bring about a hereditary disorder have been
identified for a number of diseases. Progress in DNA sequencing technology has
enabled a rapid identification of disease genes through genetic screening.
Early intervention is possible for a limited number of hereditary diseases. A
large fraction of disease, however, is not based on the mutation of a single
gene, but rather on a number of genes that together determine a person’s risk
of developing a particular disease4.
Environmental factors such as diet, toxic exposures, trauma, stress and other
life experiences are assumed to interact with genetic susceptibility factors to
result in disease. Thus, drug targets may include molecular pathways related to
environmental factors5.
TARGET DISCOVERY – TARGET TYPE AND
“DRUGABILITY”
Target
for therapeutic intervention can be broadly classified into these categories:
Receptors; Proteins and enzymes; DNA; RNA and ribosomal targets.
The
“drugability” of a given target is defined either by
how well a therapeutic, such as small molecule drugs or antibodies, can access
the target, or by the efficacy a therapeutic can actually achieve. A long list
a parameters influences drugability of a given
target; this include cellular location, development of resistance, transport
mechanisms such as export pumps, side effects, toxicity, etc6.
TARGET VALIDATION:
Target
validation involves studies in interact animals or disease related cell based
models that can provide information about the integrative response of an
organism to a pharmacological intervention and thereby help to predict the
possible profile of new drugs in patients7.
The
action and interaction of genes and their gene products is complex. Research
aimed to define pathways that control and regulate processes in living
organisms provides valuable information for drug discovery8. The knowledge of pathways allows definition and
separate targeting of upstream and downstream targets. Inhibition or modulation
of selected targets could lead to the same therapeutic with fewer side effects
or better drugablity9.
CONCLUSION:
Some
target classes (e.g. G-protein coupled receptors - GPCRs) have been
successfully targeted, and a sizeable number of drugs prescribed today hit this
particular class. Therefore, the GPCR target type is considered drugable.
Lastly,
the knowledge of pathways and their relation to each other helps researchers
understand side effect profiles. Identification of one disease target can lead
to a number of alternative drug targets in the same pathway and increase the
possibilities for a novel therapeutic. Examples include the drug acting on the
cholesterol synthesis pathways10.
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Received on 05.03.2011 Accepted
on 08.05.2011
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Asian J.
Pharm. Ana.
1(2): April-June 2011; Page 27-28