Drug discovery

In the fields of medicine, biotechnology and

pharmacology, drug discovery is the process by which
new candidate medications are discovered.[1]

Historically, drugs were discovered by identifying the

active ingredient from traditional remedies or by
serendipitous discovery, as with penicillin. More recently,
chemical libraries of synthetic small molecules, natural
products or extracts were screened in intact cells or
whole organisms to identify substances that had a
desirable therapeutic effect in a process known as
classical pharmacology. After sequencing of the human
genome allowed rapid cloning and synthesis of large
quantities of purified proteins, it has become common
practice to use high throughput screening of large
compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a
process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals
for efficacy.[2]

Modern drug discovery involves the identification of screening hits, medicinal chemistry and optimization of
those hits to increase the affinity, selectivity (to reduce the potential of side effects), efficacy/potency,
metabolic stability (to increase the half-life), and oral bioavailability. Once a compound that fulfills all of these
requirements has been identified, the process of drug development can continue. If successful, clinical trials are
developed.[3]

Modern drug discovery is thus usually a capital-intensive process that involves large investments by
pharmaceutical industry corporations as well as national governments (who provide grants and loan
guarantees). Despite advances in technology and understanding of biological systems, drug discovery is still a
lengthy, "expensive, difficult, and inefficient process" with low rate of new therapeutic discovery.[4] In 2010,
the research and development cost of each new molecular entity was about US$1.8 billion.[5] In the 21st
century, basic discovery research is funded primarily by governments and by philanthropic organizations,
while late-stage development is funded primarily by pharmaceutical companies or venture capitalists.[6] To be
allowed to come to market, drugs must undergo several successful phases of clinical trials, and pass through a
new drug approval process, called the New Drug Application in the United States.

Discovering drugs that may be a commercial success, or a public health success, involves a complex
interaction between investors, industry, academia, patent laws, regulatory exclusivity, marketing and the need
to balance secrecy with communication.[7] Meanwhile, for disorders whose rarity means that no large
commercial success or public health effect can be expected, the orphan drug funding process ensures that
people who experience those disorders can have some hope of pharmacotherapeutic advances.

Contents
History
Targets
Screening and design
Nature as source
Plant-derived
History
Jasmonates
Salicylates
Microbial metabolites
Marine invertebrates
Chemical diversity
Screening
Structural elucidation
New Drug Application
See also
References
Further reading
External links

History
The idea that the effect of a drug in the human body is mediated by specific interactions of the drug molecule
with biological macromolecules, (proteins or nucleic acids in most cases) 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. Examples of drug compounds isolated from crude preparations are morphine, the active agent
in opium, and digoxin, a heart stimulant originating from Digitalis lanata. Organic chemistry also led to the
synthesis of many of the natural products isolated from biological sources.

Historically, substances, whether crude extracts or purified chemicals, were screened for biological activity
without knowledge of the biological target. Only after an active substance was identified was an effort made to
identify the target. This approach is known as classical pharmacology, forward pharmacology,[8] or
phenotypic drug discovery.[9]

Later, small molecules were synthesized to specifically target a known physiological/pathological pathway,
avoiding the mass screening of banks of stored compounds. This led to great success, such as the work of
Gertrude Elion and George H. Hitchings on purine metabolism,[10][11] the work of James Black[12] on beta
blockers and cimetidine, and the discovery of statins by Akira Endo.[13] Another champion of the approach of
developing chemical analogues of known active substances was Sir David Jack at Allen and Hanbury's, later
Glaxo, who pioneered the first inhaled selective beta2-adrenergic agonist for asthma, the first inhaled steroid
for asthma, ranitidine as a successor to cimetidine, and supported the development of the triptans.[14]

Gertrude Elion, working mostly with a group of fewer than 50 people on purine analogues, contributed to the
discovery of the first anti-viral; the first immunosuppressant (azathioprine) that allowed human organ
transplantation; the first drug to induce remission of childhood leukemia; pivotal anti-cancer treatments; an
anti-malarial; an anti-bacterial; and a treatment for gout.

Cloning of human proteins made possible the screening of large libraries of compounds against specific targets
thought to be linked to specific diseases. This approach is known as reverse pharmacology and is the most
frequently used approach today.[15]
Targets
A "target" is produced within the pharmaceutical industry.[6] 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.[6] 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 the discovery and development of therapeutics.[6] In an estimate from 2011, 435 human genome
products were identified as therapeutic drug targets of FDA-approved drugs.[16]

"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.[2] This does not imply that the mechanism of action of drugs that are thought to act through a
particular established target is fully understood.[2] 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, such as G-protein-coupled
receptors (GPCRs) and protein kinases.[17]

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, as one
wants 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 unlikely that a perfect drug candidate will emerge from these early screening runs. One of the first steps is
to screen for compounds that are unlikely to be developed into drugs; for example compounds that are hits in
almost every assay, classified by medicinal chemists as "pan-assay interference compounds", are removed at
this stage, if they were not already removed from the chemical library.[18][19][20] It is 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 compound:

increase activity against the chosen target

reduce activity against unrelated targets
improve the druglikeness 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.
Amongst the physicochemical properties associated with drug absorption include ionization (pKa), and
solubility; permeability can be determined by PAMPA and Caco-2. PAMPA is attractive as an early screen due
to the low consumption of drug and the low cost compared to tests such as Caco-2, gastrointestinal tract (GIT)
and Blood–brain barrier (BBB) with which there is a high correlation.

A range of parameters can be used to assess the quality of a compound, or a series of compounds, as proposed
in the Lipinski's Rule of Five. Such parameters include calculated properties such as cLogP to estimate
lipophilicity, molecular weight, polar surface area and measured properties, such as potency, in-vitro
measurement of enzymatic clearance etc. Some descriptors such as ligand efficiency[21] (LE) and lipophilic
efficiency[22][23] (LiPE) combine such parameters to assess druglikeness.

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 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.[24][25] Molecular modelling[26] and molecular dynamics simulations can be used as a guide to
improve the potency and properties of new drug leads.[27][28][29]

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)[30][31][32][33] and protein-directed
dynamic combinatorial chemistry.[34][35][36][37][38] 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. Further
modifications through organic synthesis into lead compounds are often required. Such modifications are often
guided by protein X-ray crystallography of the protein-fragment complex.[39][40][41] The advantages of these
approaches are that they allow more efficient screening and the compound library, although small, typically
covers a large chemical space when compared to HTS.

Phenotypic screens have also provided new chemical starting points in drug discovery.[42][43] 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. Smaller screening sets are often used for these screens,
especially when the models are expensive or time-consuming to run.[44] In many cases, the exact mechanism
of action of hits from these screens is unknown and may require extensive target deconvolution experiments to
ascertain.

Once a lead compound 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". These important
decisions are generally supported by computational modelling innovations. [45][46][47]

Nature as source
Traditionally, many drugs and other chemicals with biological activity have been discovered by studying
chemicals that organisms create to affect the activity of other organisms for survival.[48]
Despite the rise of combinatorial chemistry as an integral part of lead discovery process, natural products still
play a major role as starting material for drug discovery.[49] A 2007 report[50] found that of the 974 small
molecule new chemical entities developed between 1981 and 2006, 63% were natural derived or semisynthetic
derivatives of natural products. For certain therapy areas, such as antimicrobials, antineoplastics,
antihypertensive and anti-inflammatory drugs, the numbers were higher. In many cases, these products have
been used traditionally for many years.

Natural products may be useful as a source of novel chemical structures for modern techniques of development
of antibacterial therapies.[51]

Plant-derived

Many secondary metabolites produced by plants have potential therapeutic medicinal properties. These
secondary metabolites contain, bind to, and modify the function of proteins (receptors, enzymes, etc.).
Consequently, plant derived natural products have often been used as the starting point for drug
discovery.[52][53][54][55]

History

Until the Renaissance, the vast majority of drugs in Western medicine were plant-derived extracts.[56] This has
resulted in a pool of information about the potential of plant species as important sources of starting materials
for drug discovery.[57] 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.[57][58] Identifying new drugs and getting them approved for
market has proved to be a stringent process due to regulations set by national drug regulatory agencies.[59]

Jasmonates

Jasmonates are important in responses to injury and intracellular

signals. They induce apoptosis [60][61] and protein cascade via
proteinase inhibitor,[60] have defense functions,[62] and regulate plant
responses to different biotic and abiotic stresses.[62][63] Jasmonates
also have the ability to directly act on mitochondrial membranes by
inducing membrane depolarization via release of metabolites.[64]

Jasmonate derivatives (JAD) are also important in wound response

and tissue regeneration in plant cells. They have also been identified
to have anti-aging effects on human epidermal layer.[65] It is Chemical structure of methyl
suspected that they interact with proteoglycans (PG) and jasmonate (JA).
glycosaminoglycan (GAG) polysaccharides, which are essential
extracellular matrix (ECM) components to help remodel the ECM.[66]
The discovery of JADs on skin repair has introduced newfound interest in the effects of these plant hormones
in therapeutic medicinal application.[65]

Salicylates

Salicylic acid (SA), a phytohormone, was initially derived from willow bark and has since been identified in
many species. It is an important player in plant immunity, although its role is still not fully understood by
scientists.[67] They are involved in disease and immunity responses in plant and animal tissues. They have
salicylic acid binding proteins (SABPs) that have shown to affect
multiple animal tissues.[67] The first discovered medicinal
properties of the isolated compound was involved in pain and
fever management. They also play an active role in the
suppression of cell proliferation.[60] They have the ability to
induce death in lymphoblastic leukemia and other human cancer
cells.[60] One of the most common drugs derived from salicylates
is aspirin, also known as acetylsalicylic acid, with anti-
inflammatory and anti-pyretic properties.[67][68]

Chemical structure of acetylsalicylic acid,

Microbial metabolites more commonly known as Aspirin.

Microbes compete for living space and nutrients. To survive in

these conditions, many microbes have developed abilities to prevent competing species from proliferating.
Microbes are the main source of antimicrobial drugs. Streptomyces isolates have been such a valuable source
of antibiotics, that they have been called medicinal molds. The classic example of an antibiotic discovered as a
defense mechanism against another microbe is penicillin in bacterial cultures contaminated by Penicillium
fungi in 1928.

Marine invertebrates

Marine environments are potential sources for new bioactive agents.[69] Arabinose nucleosides discovered
from marine invertebrates in 1950s, demonstrated for the first time that sugar moieties other than ribose and
deoxyribose can yield bioactive nucleoside structures. It took until 2004 when the first marine-derived drug
was approved. For example, the cone snail toxin ziconotide, also known as Prialt treats severe neuropathic
pain. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-
inflammatory use and pain. One class of these agents are bryostatin-like compounds, under investigation as
anti-cancer therapy.

Chemical diversity

As above mentioned, combinatorial chemistry was a key technology enabling the efficient generation of large
screening libraries for the needs of high-throughput screening. However, now, after two decades of
combinatorial chemistry, it has been pointed out that despite the increased efficiency in chemical synthesis, no
increase in lead or drug candidates has been reached.[50] This has led to analysis of chemical characteristics of
combinatorial chemistry products, compared to existing drugs or natural products. The chemoinformatics
concept chemical diversity, depicted as distribution of compounds in the chemical space based on their
physicochemical characteristics, is often used to describe the difference between the combinatorial chemistry
libraries and natural products. The synthetic, combinatorial library compounds seem to cover only a limited
and quite uniform chemical space, whereas existing drugs and particularly natural products, exhibit much
greater chemical diversity, distributing more evenly to the chemical space.[49] The most prominent differences
between natural products and compounds in combinatorial chemistry libraries is the number of chiral centers
(much higher in natural compounds), structure rigidity (higher in natural compounds) and number of aromatic
moieties (higher in combinatorial chemistry libraries). Other chemical differences between these two groups
include the nature of heteroatoms (O and N enriched in natural products, and S and halogen atoms more often
present in synthetic compounds), as well as level of non-aromatic unsaturation (higher in natural products). As
both structure rigidity and chirality are well-established factors in medicinal chemistry known to enhance
compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourably
to today's combinatorial chemistry libraries as potential lead molecules.
Screening

Two main approaches exist for the finding of new bioactive chemical entities from natural sources.

The first is sometimes referred to as random collection and screening of material, but the collection is far from
random. Biological (often botanical) knowledge is often used to identify families that show promise. This
approach is effective because only a small part of the earth's biodiversity has ever been tested for
pharmaceutical activity. Also, organisms living in a species-rich environment need to evolve defensive and
competitive mechanisms to survive. Those mechanisms might be exploited in the development of beneficial
drugs.

A collection of plant, animal and microbial samples from rich ecosystems can potentially give rise to novel
biological activities worth exploiting in the drug development process. One example of successful use of this
strategy is the screening for antitumor agents by the National Cancer Institute, which started in the 1960s.
Paclitaxel was identified from Pacific yew tree Taxus brevifolia. Paclitaxel showed anti-tumour activity by a
previously undescribed mechanism (stabilization of microtubules) and is now approved for clinical use for the
treatment of lung, breast, and ovarian cancer, as well as for Kaposi's sarcoma. Early in the 21st century,
Cabazitaxel (made by Sanofi, a French firm), another relative of taxol has been shown effective against
prostate cancer, also because it works by preventing the formation of microtubules, which pull the
chromosomes apart in dividing cells (such as cancer cells). Other examples are: 1. Camptotheca (Camptothecin
· Topotecan · Irinotecan · Rubitecan · Belotecan); 2. Podophyllum (Etoposide · Teniposide); 3a.
Anthracyclines (Aclarubicin · Daunorubicin · Doxorubicin · Epirubicin · Idarubicin · Amrubicin · Pirarubicin ·
Valrubicin · Zorubicin); 3b. Anthracenediones (Mitoxantrone · Pixantrone).

The second main approach involves ethnobotany, the study of the general use of plants in society, and
ethnopharmacology, an area inside ethnobotany, which is focused specifically on medicinal uses.

Artemisinin, an antimalarial agent from sweet wormtree Artemisia annua, used in Chinese medicine since
200BC is one drug used as part of combination therapy for multiresistant Plasmodium falciparum.

Structural elucidation

The elucidation of the chemical structure is critical to avoid the re-discovery of a chemical agent that is already
known for its structure and chemical activity. Mass spectrometry is a method in which individual compounds
are identified based on their mass/charge ratio, after ionization. Chemical compounds exist in nature as
mixtures, so the combination of liquid chromatography and mass spectrometry (LC-MS) is often used to
separate the individual chemicals. Databases of mass spectras for known compounds are available and can be
used to assign a structure to an unknown mass spectrum. Nuclear magnetic resonance spectroscopy is the
primary technique for determining chemical structures of natural products. NMR yields information about
individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecule's
architecture.

New Drug Application

When a drug is developed with evidence throughout its history of research to show it is safe and effective for
the intended use in the United States, the company can file an application – the New Drug Application (NDA)
– to have the drug commercialized and available for clinical application.[70] NDA status enables the FDA to
examine all submitted data on the drug to reach a decision on whether to approve or not approve the drug
candidate based on its safety, specificity of effect, and efficacy of doses.[70]
See also
Antitarget
Bioinformatics
Biomedical informatics
Cheminformatics
Drug discovery hit to lead
Drug metabolism
Fragment-based drug discovery
High content screening
Pharmacogenetics
Pharmacognosy
Physiologically-based pharmacokinetic modelling
Pre-clinical development
Protein-directed dynamic combinatorial chemistry
Discovery and development of proton pump inhibitors
Discovery and development of melatonin receptor agonists
Discovery and development of nucleoside and nucleotide reverse transcriptase inhibitors
Discovery and development of Bcr-Abl tyrosine kinase inhibitors
Discovery and development of antiandrogens
Discovery and development of cephalosporins
Retrometabolic drug design

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Further reading
Gad SC (2005). Drug Discovery Handbook. Hoboken, N.J: Wiley-Interscience/J. Wiley.
ISBN 978-0-471-21384-0.
Madsen U, Krogsgaard-Larsen P, Liljefors T (2002). Textbook of Drug Design and Discovery.
Washington, DC: Taylor & Francis. ISBN 978-0-415-28288-8.
Rasmussen N (2014). Gene Jockeys: Life Science and the rise of Biotech Enterprise (https://bo
oks.google.com/books?id=tTE_AwAAQBAJ). Baltimore: Johns Hopkins University Press.
ISBN 978-1-42141-340-2.

External links
Drug Discovery (https://curlie.org//Science/Biology/Bioinformatics/Products_and_Services/Drug_Discovery/)
at Curlie
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