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the free encyclopedia
In
medicine,
biotechnology and
pharmacology, drug
discovery is the process by
which
drugs are discovered and/or
designed.
In the past most drugs have
been discovered either by
identifying the active ingredient
from traditional remedies or by
serendipitous discovery. A new
approach has been to understand
how
disease and
infection are controlled at
the
molecular and
physiological level and to
target specific entities based on
this knowledge.
The process of drug discovery
involves the identification of
candidates, synthesis,
characterization, screening, and
assays for therapeutic efficacy.
Once a compound has shown its
value in these tests, it will
begin the process of
drug development prior to
clinical trials.
Despite advances in technology
and understanding of biological
systems, drug discovery is still a
long process with low rate of new
therapeutic discovery. Information
on the human genome, its sequence
and what it encodes has been
hailed as a potential windfall for
drug discovery, promising to
virtually eliminate the bottleneck
in therapeutic targets that has
been one limiting factor on the
rate of therapeutic discovery.[1]
However, data indicates that "new
targets" as opposed to
"established targets" are more
prone to drug discovery project
failure in general.[2]
This data corroborates some
thinking underlying a
pharmaceutical industry trend
beginning at the turn of the
twenty-first century and
continuing today which finds more
risk aversion in target selection
among multi-national
pharmaceutical companies.[3]
Targets: New and Established
The definition of "target"
itself is something debated within
the pharmaceutical industry.
However, the distinction between a
"new" and "established" target can
be made without a full
understanding of just what a
"target" is. This distinction is
typically made by pharmaceutical
companies engaged in discovery and
development of small molecule
therapeutics.
"Established targets" are those
for which there is a good
scientific understanding,
supported by a lengthy publication
history, of both how the target
functions in normal physiology and
how it is involved in human
pathology. This does not imply
that the
mechanism of action of drugs
that are thought to act through a
particular established targets is
fully understood. Rather,
"established" relates directly to
the amount of background
information available on a target,
in particular functional
information. The more such
information is available, the less
investment is (generally) required
to develop a therapeutic directed
against the target. The process of
gathering such functional
information is called "target
validation" in pharmaceutical
industry parlance. Established
targets also include those that
the pharmaceutical industry has
had experience mounting drug
discovery campaigns against in the
past; such a history provides
information on the
chemical feasibility of
developing a small molecular
therapeutic against the target and
can provide licensing
opportunities and
freedom-to-operate indicators with
respect to small molecule
therapeutic candidates.
In general, "new targets" are
all those targets that are not
"established targets" but which
have been or are the subject of
drug discovery campaigns. These
typically include newly discovered
proteins, or proteins whose
function has now become clear as a
result of basic scientific
research.
The majority of targets
currently selected for drug
discovery efforts are proteins.
Two classes predominate:
G-protein-coupled receptors
(or GPCRs) and
protein kinases.
Screening and Design
The process of finding a new
drug against a chosen target for a
particular disease usually
involves
high-throughput screening (HTS),
wherein large libraries of
chemicals are tested for their
ability to modify the target. For
example, if the target is a novel
GPCR, compounds will be
screened for their ability to
inhibit or stimulate that receptor
(see
antagonist and
agonist): if the target is a
protein kinase, the chemicals
will be tested for their ability
to inhibit that kinase.
Another important function of
HTS is to show how selective the
compounds are for the chosen
target. The ideal is to find a
molecule which will interfere with
only the chosen target, but not
other, related targets. To this
end, other screening runs will be
made to see whether the "hits"
against the chosen target will
interfere with other related
targets - this is the process of
cross-screening.
Cross-screening is important,
because the more unrelated targets
a compound hits, the more likely
that off-target
toxicity will occur with that
compound once it reaches the
clinic.
It is very unlikely that a
perfect drug candidate will emerge
from these early screening runs.
It is more often observed that
several compounds are found to
have some degree of
activity, and if these
compounds share common chemical
features, one or more
pharmacophores can then be
developed. At this point,
medicinal chemists will
attempt to use
structure-activity relationships
(SAR) to improve certain features
of the lead molecules:
- increase activity against
the chosen target
- reduce activity against
unrelated targets
- improve the "drug-like" or
ADME properties of the
molecule.
This process will require
several iterative screening runs,
during which, it is hoped, the
properties of the new molecular
entities will improve, and allow
the favoured compounds to go
forward to
in vitro and
in vivo testing for activity
in the disease model of choice.
While HTS is a commonly used
method for novel drug discovery,
it is not the only method. It is
often possible to start from a
molecule which already has some of
the desired properties. Such a
molecule might be extracted from a
natural product or even be a
drug on the market which could be
improved upon (so-called "me too"
drugs). Other methods, such as
virtual high throughput screening,
where screening is done using
computer-generated models and
attempting to "dock" virtual
libraries to a target, are also
often used.
Another important method for
drug discovery is
drug design, whereby the
biological and physical properties
of the target are studied, and a
prediction is made of the sorts of
chemicals that might (eg.) fit
into an
active site. Novel
pharmacophores can emerge very
rapidly from these exercises.
Once a lead molecule series has
been established with sufficient
target potency and selectivity and
favourable drug-like properties,
one or two compounds will then be
proposed for
drug development. The best of
these is generally called the
"lead" compound, while the other
will be designated as the
"backup".
Notes and references
-
↑ this
requires substantiation with one
or more reputable sources from
the time of enthusiasm following
"completion" of the human genome
sequence
-
↑ Drug
Discovery & Development, October
2005, Trend Watch: Success
Rate by Discovery Phase, New and
Established Target Projects
-
↑ Personal
communication. this requires
substantiation with one or more
reputable sources reporting on
industry trends in 2003–2005
