Drug Discovery
Drug discovery is the process through which potential new candidate medicines are identified. This
process involves and has applicability in a wide range of scientific disciplines, including biology,
chemistry, biotechnology and pharmacology.
Historically, drugs were discovered by identifying the active ingredient from traditional remedies
(botanical knowledge about different plant-derived extracts) or by a chance fortunate discovery
(serendipity), as with penicillin.
More recently, chemical libraries which are basically a series of stored chemicals, whether
synthetic small molecules, natural products or extracts, were screened in cells or whole organisms to
identify substances that had a desirable therapeutic effect.
The Human Genome Project (1990-2003) which permitted the sequencing of all of the genes of the
human genome, allowing rapid cloning and synthesis of large quantities of purified proteins, led the
way to using high-throughput screening of large compounds libraries against isolated biological
targets which are hypothesized to be disease-modifying. Hits from these screens are then tested in
cells and then in animals.
Modern drug discovery involves the identification of screening hits and optimization of those hits to
increase the affinity, selectivity, efficacy, metabolic stability, and oral bioavailability. The purpose is
to reduce the potential side effects and to increase the drug half-life. Once the promising candidate
or the molecule that fulfils all of these requirements is identified in the lab, the process of drug
development can continue. It is first subjected to pre-clinical studies or animal studies where
different aspects of the test article are studied. If successful, clinical trials on human participants are
developed. Clinical trials generate data on dosage, safety and efficacy.
Modern drug discovery is thus usually a capital-intensive process that involves large investments
by the pharmaceutical industry as well as national governments. Discovering drugs that may be a
commercial success, or a public health success, involves a complex interaction between investors,
industry, academia, innovative technologies, patent laws, regulatory exclusivity, marketing and the
need to balance secrecy with communication.
History
Medicinal plants, also called medicinal herbs, have been discovered and used in traditional
medicine practices since prehistoric times. The World Health Organization (WHO) defines traditional
medicine as "the sum total of the knowledge, skills, and practices based on the theories, beliefs, and
experiences indigenous to different cultures, whether explicable or not, used in the maintenance of
health as well as in the prevention, diagnosis, improvement or treatment of physical and mental
illness". Humans have remarked ever since ancient times that plants synthesize hundreds of
chemical compounds with potential or established biological activity. The earliest historical records
of herbs are found from the Sumerian civilization, where hundreds of medicinal plants
including opium are listed on clay tablets, c. 3000 BC. The Ebers Papyrus from ancient Egypt, c. 1550
BC, describes over 850 plant medicines. The Greek physician Dioscorides, who worked in the Roman
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army, documented over 1000 recipes for medicines using over 600 medicinal plants in De materia
medica, c. 60 AD; this formed the basis of pharmacopoeias for some 1500 years.
Until the Renaissance, the vast majority of drugs in Western medicine were plant-derived extracts.
This has resulted in a pool of information about the potential of plant species as important sources
of starting materials for drug discovery. Botanical knowledge about
different metabolites and hormones that are produced in different anatomical parts of the plant
(e.g. roots, leaves, and flowers) are crucial for correctly identifying bioactive and pharmacological
plant properties. Drug research sometimes makes use of ethnobotany to search for
pharmacologically active substances, and this approach has yielded hundreds of useful compounds.
These include the common drugs aspirin, digoxin, quinine, and opium.
Classical pharmacology
Historically, substances, whether crude extracts or purified chemicals, were screened for biological
activity without knowledge of the biological target. The idea that the effect of a drug in the human
body is mediated by specific interactions of the drug molecule with biological molecules led
scientists to the conclusion that individual chemicals are required for the biological activity of the
drug. This made for the beginning of the modern era in pharmacology, as pure chemicals, instead of
crude extracts of medicinal plants, became the standard drugs.
Classical (forward) pharmacology traditionally has been the basis for the discovery of new drugs. In
the field of drug discovery, classical pharmacology relies on phenotypic screening (screening in intact
cells or whole organisms) of chemical libraries of synthetic small molecules, natural
products or extracts to identify substances that have a desirable therapeutic effect. The potency,
selectivity, and other properties of these screening hits are optimized to produce candidate drugs.
Biological Targets and reverse pharmacology
A "target" is produced within the pharmaceutical industry. Generally, the "target" is the naturally
existing cellular or molecular structure involved in the pathology of interest where the drug-in-
development is meant to act. Examples of common classes of biological targets
are proteins (enzymes, ion channels, and receptors) and nucleic acids.
In the field of drug discovery, reverse pharmacology also known as target-based drug
discovery (TDD), a hypothesis is first made that modulation of the activity of a specific protein
target will have beneficial therapeutic effects.
Screening of chemical libraries of small molecules is then used to identify compounds that bind with
high affinity to the target. The hits from these screens are then used as starting points for drug
discovery. This method became popular after the sequencing of the human genome which allowed
the cloning of human proteins that made possible the screening of large libraries of compounds
against specific targets thought to be linked to specific diseases. This method (reverse
pharmacology) is the most frequently used approach in drug discovery today.
Differently than the classical (forward) pharmacology, with the reverse pharmacology approach in
vivo efficacy of identified active (lead) compounds is usually performed in the final drug
discovery stages.
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"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 target is fully understood. Rather, "established"
relates directly to the amount of background information available on a target, in particular
functional information. In general, "new targets" are all those targets that are not "established
targets" but which have been or are the subject of drug discovery efforts. The majority of targets
selected for drug discovery efforts are proteins.
Chemoproteomics and lead compounds
The field of Chemoproteomics has provided numerous strategies to identify drug targets and entails
a broad array of techniques used to identify and interrogate protein-small molecule interactions.
The proteome is the entire set of proteins that is, or can be, expressed by a genome, cell, tissue, or
organism at a certain time. Proteomics is the study of the proteome.
Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead
compounds on the basis of alleviating a disease phenotype, as opposed to target-based drug
discovery (reverse pharmacology), in which lead compounds are designed to interact with
predetermined disease-driving biological targets. As phenotypic drug discovery assays do not
provide confirmation of a compound's mechanism of action, chemoproteomics provides valuable
follow-up strategies to narrow down potential targets and eventually validate
a molecule's mechanism of action. Chemoproteomics also attempts to address the inherent
challenge of drug promiscuity in small molecule drug discovery by analyzing protein-small molecule
interactions on a proteome-wide scale.
A lead compound in drug discovery is a chemical compound that has pharmacological or biological
activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that
requires modification to fit better to the target; lead drugs offer the prospect of being followed by
back-up compounds. The chemical structure of lead components serves as a starting point
for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.
High-throughput screening (HTS) and other methods of drug discovery
High-throughput screening (HTS) is a method for scientific experimentation especially used in drug
discovery that allows a researcher to quickly conduct millions of chemical, genetic, or
pharmacological tests using robotics, data processing/control software, liquid handling devices, and
sensitive detectors. Through this process one can quickly recognize active compounds, antibodies, or
genes that modulate a particular biomolecular pathway. The results of these experiments provide
starting points for drug design and for understanding the noninteraction or role of a particular
location.
Through HTS, large libraries of chemicals are tested for their ability to modify the target. For
example, if the target is a protein receptor, compounds will be screened for their ability to inhibit or
stimulate that receptor (antagonist or agonist): if the target is a protein kinase, the chemicals will be
tested for their ability to inhibit that kinase. Another function of HTS is to show how selective the
compounds are for the chosen target, as one wants to find a molecule which will interfere with only
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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.
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 method for drug discovery is de novo drug design, in which a prediction is made of the sorts
of chemicals that might (e.g.) fit into an active site of the target enzyme. For example, virtual
screening and computer-aided drug design are often used to identify new chemical moieties that
may interact with a target protein. Molecular modelling and molecular dynamics simulations can be
used as a guide to improve the potency and properties of new drug leads.
There is also a paradigm shift in the drug discovery community to shift away from HTS, which is
expensive and may only cover limited chemical space, to the screening of smaller libraries
(maximum a few thousand compounds). These include fragment-based lead discovery (FBDD)
and protein-directed dynamic combinatorial chemistry. The ligands in these approaches are usually
much smaller, and they bind to the target protein with weaker binding affinity than hits that are
identified from HTS.
Phenotypic screens have also provided new chemical starting points in drug discovery. A variety of
models have been used including yeast, zebrafish, worms, immortalized cell lines, primary cell lines,
patient-derived cell lines and whole animal models. These screens are designed to find compounds
which reverse a disease phenotype such as death, protein aggregation, mutant protein expression,
or cell proliferation as examples in a more holistic cell model or organism.
Preclinical development
In drug development, preclinical development, also termed preclinical studies or nonclinical
studies, is a stage of research that begins before clinical trials (testing in humans) and during which
important feasibility, iterative testing and drug safety data are collected, typically in laboratory
animals. The main goals of preclinical studies are to determine a starting, safe dose for first-in-
human study and assess potential toxicity of the product.
Each class of product may undergo different types of preclinical research. For instance, drugs may
undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics (what the
body does to the drug) (PK), ADME (absorption, distribution, metabolism, and excretion),
and toxicology testing. Typically, both in vitro and in vivo tests will be performed. Studies of drug
toxicity include which organs are targeted by that drug, as well as if there are any long-
term carcinogenic effects or toxic effects causing illness.
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Clinical trials
Clinical trials are experiments or observations done in clinical research. Such research studies of
new drugs on human participants are designed to answer specific questions about the drugs and
known interventions that warrant further study and comparison. Clinical trials generate data on
dosage, safety and efficacy. They are conducted only after they have received health
authority/ethics committee approval in the country where approval of the therapy is sought. Costs
for clinical trials can range into the billions of dollars per approved drug. The sponsor may be a
governmental organization or a pharmaceutical, biotechnology or medical device company.
The sponsor designs the trial in coordination with a panel of expert clinical investigators, including
what alternative or existing treatments to compare to the new drug and what type(s) of patients
might benefit. If the sponsor cannot obtain enough test subjects at one location investigators at
other locations are recruited to join the study.
During the trial, investigators recruit subjects with the predetermined characteristics, administer the
treatment(s) and collect data on the subjects' health for a defined time period. Data include
measurements such as vital signs, concentration of the study drug in the blood or tissues, changes to
symptoms, and whether improvement or worsening of the condition targeted by the study drug
occurs. The researchers send the data to the trial sponsor, who then analyzes the pooled data
using statistical tests.
Only 10 percent of all drugs started in human clinical trials become approved drugs.
There are two goals to testing medical treatments: to learn whether they work well enough, called
"efficacy" or "effectiveness"; and to learn whether they are safe enough, called "safety". Neither is
an absolute criterion; both safety and efficacy are evaluated relative to how the treatment is
intended to be used, what other treatments are available, and the severity of the disease or
condition. The benefits must outweigh the risks. For example, many drugs to treat cancer have
severe side effects that would not be acceptable for an over-the-counter pain medication, yet the
cancer drugs have been approved since they are used under a physician's care and are used for a
life-threatening condition.
Clinical trials are conducted to collect data regarding the safety and efficacy of new drug and device
development. They are conducted in a series of phases, each designed to address a separate
purpose:
Phase I: Researchers test a new drug or treatment in a small group of people (20-80) for the
first time to evaluate its safety, determine a safe dosage range, and identify side effects.
Phase II: The study drug or treatment is given to a larger group of people (100-300) to see if
it is effective and to further evaluate its safety.
Phase III: The study drug or treatment is given to large groups of people (1,000-3,000) to
confirm its effectiveness, monitor side effects, compare it to commonly used treatments,
and collect information that will allow the drug or treatment to be used safely.
Phase IV: Post marketing studies delineate additional information including the drug's risks,
benefits, and optimal use.
