1. Pre-Discovery
Pre-discovery Understand the disease before any
potential new medicine can be discovered, scientists work to understand the
disease to be treated as well as possible, and to unravel the underlying cause
of the condition.
They try to understand how the genes are altered,
how that affects the proteins they encode and how those proteins interact with
each other in living cells, how those affected cells change the specific tissue
they are in and finally how the disease affects the entire patient. This
knowledge is the basis for treating the problem.
Researchers from government, academia and industry
all contribute to this knowledge base. However, even with new tools and
insights, this research takes many years of work and, too often, leads to
frustrating dead ends. And even if the research is successful, it will take
many more years of work to turn this basic understanding of what causes a
disease into a new treatment.
2. Target
Identification Choose a molecule to target with a drug
Once they have enough understanding of
the underlying cause of a disease, pharmaceutical researchers select a “target”
for a potential new medicine.
A target is generally a single
molecule, such as a gene or protein, which is involved in a particular disease.
Even at this early stage in drug discovery it is critical that researchers pick
a target that is “drugable,” i.e., one that can potentially interact with and
be affected by a drug molecule.
3. Target Validation
Test the target and confirm its role in
the disease After choosing a potential target, scientists must show that it
actually is involved in the disease and can be acted upon by a drug.
Target validation is crucial to help
scientists avoid research paths that look promising, but ultimately lead to
dead ends. Researchers demonstrate that a particular target is relevant to the
disease being studied through complicated experiments in both living cells and
in animal models of disease.
4. Drug Discovery
Find a promising molecule (a “lead
compound”) that could become a drug Armed with their understanding of the
disease, scientists are ready to begin looking for a drug.
They search for a molecule, or “lead
compound,” that may act on their target to alter the disease course. If
successful over long odds and years of testing, the lead compound can
ultimately become a new medicine.
There are a few ways to find a lead compound:
Nature: Until recently, scientists usually turned to nature to find
interesting compounds for fighting disease. Bacteria found in soil and moldy
plants both led to important new treatments, for example. Nature still offers
many useful substances, but now there are other ways to approach drug
discovery.
De novo: Thanks to advances in chemistry, scientists can also create
molecules from scratch. They can use sophisticated computer modeling to predict
what type of molecule may work.
High-throughput Screening: This process is the most common way that
leads are usually found. Advances in robotics and computational power allow
researchers to test hundreds of thousands of compounds against the target to
identify any that might be promising. Based on the results, several lead
compounds are usually selected for further study.
Biotechnology: Scientists can also genetically
engineer living systems to produce disease-fighting biological molecules
5. Early Safety
Tests
Perform initial tests on promising
compounds Lead compounds go through a series of tests to provide an early
assessment of the safety of the lead compound.
Scientists test Absorption,
Distribution, Metabolism, Excretion and Toxicological (ADME/Tox) properties, or
“pharmacokinetics,” of each lead.
Successful drugs must be:
- Absorbed into the bloodstream,
- Distributed to the proper site of action in the body,
- Metabolized efficiently and effectively,
- Successfully excreted from the body
- Demonstrated to be not toxic.
These studies help researchers
prioritize lead compounds early in the discovery process. ADME/Tox studies are
performed in living cells, in animals and via computational models.
6. Lead Optimization
Alter the structure of lead candidates
to improve properties Lead compounds that survive the initial screening are
then “optimized,” or altered to make them more effective and safer. By changing
the structure of a compound, scientists can give it different properties.
For example, they can make it less
likely to interact with other chemical pathways in the body, thus reducing the
potential for side effects.
Hundreds of different variations or
“analogues” of the initial leads are made and tested.
Teams of biologists and chemists work
together closely:
The biologists test the effects of
analogues on biological systems while the chemists take this information to
make additional alterations that are then retested by the biologists. The
resulting compound is the candidate drug. Even at this early stage, researchers
begin to think about how the drug will be made, considering formulation (the
recipe for making a drug, including inactive ingredients used to hold it
together and allow it to dissolve at the right time), delivery mechanism (the
way the drug is taken – by mouth, injection, inhaler) and large-scale
manufacturing (how you make the drug in large quantities).
7. Preclinical
Testing
Lab and animal testing to determine if
the drug is safe enough for human testing. With one or more optimized compounds
in hand, researchers turn their attention to testing them extensively to
determine if they should move on to testing in humans.
Scientists carry out in vitro and in
vivo tests.
In vitro tests are experiments
conducted in the lab, usually carried out in test tubes and beakers (“vitro” is
“glass” in Latin) and in vivo studies are those in living cell cultures
and animal models (“vivo” is “life” in Latin).
Scientists try to understand how the
drug works and what its safety profile looks like. The U.S. Food and Drug
Administration (FDA) require extremely thorough testing before the candidate
drug can be studied in humans.
During this stage researchers also must
work out how to make large enough quantities of the drug for clinical trials.
Techniques for making a drug in the lab on a small scale do not translate
easily to larger production. This is the first scale up. The drug will need to
be scaled up even more if it is approved for use in the general patient
population.
At the end of several years of
intensive work, the discovery phase concludes. After starting with
approximately 5,000 to 10,000 compounds, scientists now have win no wed the
group down to between one and five molecules, “candidate drugs,” which will be
studied in clinical trials.
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