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In the fields of medicine,
biotechnology Biotechnology is a multidisciplinary field that involves the integration of natural sciences and Engineering Science, engineering sciences in order to achieve the application of organisms and parts thereof for products and services. Specialists ...
, and
pharmacology Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...
, drug discovery is the process by which new candidate
medications Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by
serendipitous Serendipity is an unplanned fortunate discovery. The term was coined by Horace Walpole in 1754. The concept is often associated with scientific and technological breakthroughs, where accidental discoveries led to new insights or inventions. Man ...
discovery, as with penicillin. More recently,
chemical libraries A chemical substance is a unique form of matter with constant chemical composition and characteristic properties. Chemical substances may take the form of a single element or chemical compounds. If two or more chemical substances can be com ...
of synthetic
small molecule In molecular biology and pharmacology, a small molecule or micromolecule is a low molecular weight (≤ 1000 daltons) organic compound that may regulate a biological process, with a size on the order of 1 nm. Many drugs are small molecules; ...
s,
natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...
s, or
extract An extract (essence) is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol, oil or water. Extracts may be sold as tinctures or absolutes or dried and powdered. The aromatic principles of ma ...
s were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as
classical pharmacology In the field of drug discovery, classical pharmacology, also known as forward pharmacology, or phenotypic drug discovery (PDD), relies on phenotypic screening (screening in intact cells or whole organisms) of chemical libraries of synthetic small ...
. After
sequencing In genetics and biochemistry, sequencing means to determine the primary structure (sometimes incorrectly called the primary sequence) of an unbranched biopolymer. Sequencing results in a symbolic linear depiction known as a sequence which succ ...
of the
human genome The human genome is a complete set of nucleic acid sequences for humans, encoded as the DNA within each of the 23 distinct chromosomes in the cell nucleus. A small DNA molecule is found within individual Mitochondrial DNA, mitochondria. These ar ...
allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use
high throughput screening High-throughput screening (HTS) is a method for scientific discovery especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling device ...
of large compounds libraries against isolated
biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
s which are hypothesized to be disease-modifying in a process known as
reverse pharmacology 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 thought to be disease modifying will have beneficial t ...
. Hits from these screens are then tested in cells and then in animals for
efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as '' effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made betwee ...
. Modern drug discovery involves the identification of screening hits,Helleboid S, Haug C, Lamottke K, et al. The Identification of Naturally Occurring Neoruscogenin as a Bioavailable, Potent, and High-Affinity Agonist of the Nuclear Receptor RORα (NR1F1). Journal of Biomolecular Screening. 2014;19(3):399–406. https://doi.org/10.1177/1087057113497095.
medicinal chemistry Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with drug design, designing and developing pharmaceutical medication, drugs. Medicinal chemistry involves the identification, ...
, and optimization of those hits to increase the
affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...
,
selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...
(to reduce the potential of side effects), efficacy/
potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of ho ...
,
metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...
stability (to increase the
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
), and oral
bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
. Once a compound that fulfills all of these requirements has been identified, the process of
drug development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regu ...
can continue. If successful,
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s are developed. Modern drug discovery is thus usually a capital-intensive process that involves large investments by
pharmaceutical industry The pharmaceutical industry is a medical industry that discovers, develops, produces, and markets pharmaceutical goods such as medications and medical devices. Medications are then administered to (or self-administered by) patients for curing ...
corporations as well as national governments (who provide grants and
loan guarantee A loan guarantee, in finance, is a promise by one party (the guarantor) to assume the debt obligation of a borrower if that borrower defaults. A guarantee can be limited or unlimited, making the guarantor liable for only a portion or all of the ...
s). 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. In 2010, the
research and development Research and development (R&D or R+D), known in some countries as OKB, experiment and design, is the set of innovative activities undertaken by corporations or governments in developing new services or products. R&D constitutes the first stage ...
cost of each
new molecular entity A new chemical entity (NCE) is, according to the U.S. Food and Drug Administration, a novel, small, chemical molecule drug that is undergoing clinical trials or has received a first approval (not a new use) by the FDA in any other application subm ...
was about US$1.8 billion. 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. 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 The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...
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 A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A ...
, regulatory exclusivity,
marketing Marketing is the act of acquiring, satisfying and retaining customers. It is one of the primary components of Business administration, business management and commerce. Marketing is usually conducted by the seller, typically a retailer or ma ...
, and the need to balance secrecy with communication. Meanwhile, for disorders whose rarity means that no large commercial success or public health effect can be expected, the
orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...
funding process ensures that people who experience those disorders can have some hope of pharmacotherapeutic advances.


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, (
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s or
nucleic acid Nucleic acids are large biomolecules that are crucial in all cells and viruses. They are composed of nucleotides, which are the monomer components: a pentose, 5-carbon sugar, a phosphate group and a nitrogenous base. The two main classes of nuclei ...
s 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 Pharmacology is the science of drugs and medications, including a substance's origin, composition, pharmacokinetics, pharmacodynamics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur betwee ...
, as pure chemicals, instead of crude extracts of
medicinal plants Medicinal plants, also called medicinal herbs, have been discovered and used in traditional medicine practices since prehistoric times. Plants synthesize hundreds of chemical compounds for various functions, including Plant defense against h ...
, became the standard drugs. Examples of drug compounds isolated from crude preparations are
morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
, the active agent in opium, and
digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...
, a heart stimulant originating from ''
Digitalis lanata ''Digitalis lanata'', vernacularly often called woolly foxglove or Grecian foxglove, is a species of foxglove, a flowering plant in the plantain family Plantaginaceae. It gets its name due to the woolly indumentum of the leaves. ''D. lanata'', li ...
''. Organic chemistry also led to the synthesis of many of the
natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...
s isolated from biological sources. Historically, substances, whether crude extracts or purified chemicals, were screened for biological activity without knowledge of the
biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
. Only after an active substance was identified was an effort made to identify the target. This approach is known as
classical pharmacology In the field of drug discovery, classical pharmacology, also known as forward pharmacology, or phenotypic drug discovery (PDD), relies on phenotypic screening (screening in intact cells or whole organisms) of chemical libraries of synthetic small ...
, forward pharmacology, or phenotypic drug discovery. 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, the work of James Black on
beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...
s and
cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. With the development of proton pump ...
, and the discovery of
statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...
s by Akira Endo. Another champion of the approach of developing chemical analogues of known active substances was Sir David Jack at Allen and Hanbury's, later
Glaxo GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British multinational pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham, wh ...
, who pioneered the first inhaled selective
beta2-adrenergic agonist Beta2-adrenergic agonists, also known as adrenergic β2 receptor agonists, are a class of drugs that act on the β2 adrenergic receptor. Like other β adrenergic agonists, they cause smooth muscle relaxation. β2 adrenergic agonists' effect ...
for asthma, the first inhaled steroid for asthma,
ranitidine Ranitidine, previously sold under the brand name Zantac among others, is a medication used to decrease stomach acid production. It was commonly used in treatment of peptic ulcer disease, gastroesophageal reflux disease, and Zollinger–Ellis ...
as a successor to cimetidine, and supported the development of the triptans. 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 Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus er ...
) 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 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 thought to be disease modifying will have beneficial t ...
and is the most frequently used approach today. In the 2020s,
qubit In quantum computing, a qubit () or quantum bit is a basic unit of quantum information—the quantum version of the classic binary bit physically realized with a two-state device. A qubit is a two-state (or two-level) quantum-mechanical syste ...
and
quantum computing A quantum computer is a computer that exploits quantum mechanical phenomena. On small scales, physical matter exhibits properties of wave-particle duality, both particles and waves, and quantum computing takes advantage of this behavior using s ...
started to be used to reduce the time needed to drug discovery.


Targets

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. 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. In an estimate from 2011, 435 human genome products were identified as therapeutic drug targets of FDA-approved drugs. "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 In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
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, such as
G-protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large protein family, group of evoluti ...
s (GPCRs) and
protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...
s.


Screening and design

The process of finding a new drug against a chosen target for a particular disease usually involves
high-throughput screening High-throughput screening (HTS) is a method for scientific discovery especially used in drug discovery and relevant to the fields of biology, materials science and chemistry. Using robotics, data processing/control software, liquid handling device ...
(HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel
GPCR G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
, compounds will be screened for their ability to inhibit or stimulate that receptor (see
antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
): if the target is a
protein kinase A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them ( phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a f ...
, 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 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 useful because the more unrelated targets a compound hits, the more likely that off-target
toxicity Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacteria, bacterium, or plant, as well as the effect o ...
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. 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 relationship The structure–activity relationship (SAR) is the relationship between the chemical structure of a molecule and its biological activity. This idea was first presented by Alexander Crum Brown and Thomas Richard Fraser at least as early as 1868. Th ...
s (SAR) to improve certain features of the
lead compound A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but ...
: * increase activity against the chosen target * reduce activity against unrelated targets * improve the
druglikeness Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. A druglike molecule has properties such as: * Solubility in both water and fat, as an orally administered d ...
or
ADME ADME is the four-letter abbreviation (acronym) for absorption (pharmacokinetics), ''absorption'', distribution (pharmacology), ''distribution'', ''metabolism'', and ''excretion'', and is mainly used in fields such as pharmacokinetics and pharmacol ...
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 ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
and
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...
testing for activity in the disease model of choice. Amongst the
physicochemical Physical chemistry is the study of macroscopic and microscopic phenomena in chemical systems in terms of the principles, practices, and concepts of physics such as motion, energy, force, time, thermodynamics, quantum chemistry, statistical mecha ...
properties associated with drug absorption include ionization (pKa), and solubility; permeability can be determined by
PAMPA The Pampas (; from Quechuan languages, Quechua 'plain'), also known as the Pampas Plain, are fertile South American low grasslands that cover more than and include the Argentina, Argentine Provinces of Argentina, provinces of Buenos Aires Pro ...
and
Caco-2 Caco-2 (from ''Cancer coli'', "colon cancer") is an immortalized cell line of human colorectal adenocarcinoma cells. It is primarily used as a model of the intestinal epithelial barrier. In culture, Caco-2 cells spontaneously differentiate into ...
. 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 The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
(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 A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...
, polar surface area and measured properties, such as potency, in-vitro measurement of enzymatic clearance etc. Some descriptors such as
ligand efficiency Ligand efficiency is a measurement of the binding energy per atom of a ligand to its binding partner, such as a receptor or enzyme. Ligand efficiency is used in drug discovery research programs to assist in narrowing focus to lead compounds with o ...
(LE) and
lipophilic efficiency Lipophilic efficiency (LiPE), sometimes referred to as ligand-lipophilicity efficiency (LLE) is a parameter used in drug design and drug discovery to evaluate the quality of research compounds, linking potency and lipophilicity in an attempt to es ...
(LiPE) combine such parameters to assess
druglikeness Druglikeness is a qualitative concept used in drug design for how "druglike" a substance is with respect to factors like bioavailability. A druglike molecule has properties such as: * Solubility in both water and fat, as an orally administered d ...
. 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 Drug design, often referred to as rational drug design or simply rational design, is the invention, inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic compound, organi ...
, in which a prediction is made of the sorts of chemicals that might (e.g.) fit into an
active site In biology and biochemistry, the active site is the region of an enzyme where substrate molecules bind and undergo a chemical reaction. The active site consists of amino acid residues that form temporary bonds with the substrate, the ''binding s ...
of the target enzyme. For example,
virtual screening Virtual screening (VS) is a computational technique used in drug discovery to search libraries of small molecules in order to identify those structures which are most likely to bind to a drug target, typically a protein receptor (biochemistry), r ...
and
computer-aided drug design Automation describes a wide range of technologies that reduce human intervention in processes, mainly by predetermining decision criteria, subprocess relationships, and related actions, as well as embodying those predeterminations in machine ...
are often used to identify new chemical moieties that may interact with a target protein.
Molecular modelling Molecular modelling encompasses all methods, theoretical and computational, used to model or mimic the behaviour of molecules. The methods are used in the fields of computational chemistry, drug design, computational biology and materials scien ...
and
molecular dynamics Molecular dynamics (MD) is a computer simulation method for analyzing the Motion (physics), physical movements of atoms and molecules. The atoms and molecules are allowed to interact for a fixed period of time, giving a view of the 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 Chemical space is a concept in cheminformatics referring to the property space spanned by all possible molecules and chemical compounds adhering to a given set of construction principles and boundary conditions. It contains millions of compounds w ...
, to the screening of smaller libraries (maximum a few thousand compounds). These include
fragment-based lead discovery Fragment-based lead discovery (FBLD) also known as fragment-based drug discovery (FBDD) is a method used for finding lead compounds as part of the drug discovery process. Fragments are small organic molecules which are small in size and low in mol ...
(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 In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from Latin ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usuall ...
than hits that are identified from HTS. Further modifications through
organic synthesis Organic synthesis is a branch of chemical synthesis concerned with the construction of organic compounds. Organic compounds are molecules consisting of combinations of covalently-linked hydrogen, carbon, oxygen, and nitrogen atoms. Within the gen ...
into lead compounds are often required. Such modifications are often guided by protein
X-ray crystallography X-ray crystallography is the experimental science of determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to Diffraction, diffract in specific directions. By measuring th ...
of the protein-fragment complex. 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.  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.  In many cases, the exact mechanism of action of hits from these screens is unknown and may require extensive target deconvolution experiments to ascertain. The growth of the field of
chemoproteomics Chemoproteomics (also known as chemical proteomics) entails a broad array of techniques used to identify and interrogate protein-small molecule interactions. Chemoproteomics complements Classical pharmacology, phenotypic drug discovery, a paradigm ...
has provided numerous strategies to identify drug targets in these cases. 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 Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. It includes preclinical research on microorganisms and animals, filing for regu ...
. The best of these is generally called the
lead compound A lead compound (, i.e. a "leading" compound, not to be confused with various compounds of the metallic element lead) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but ...
, while the other will be designated as the "backup". These decisions are generally supported by computational modelling innovations.


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. 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. A 2007 report 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. Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.


Plant-derived

Many
secondary metabolite Secondary metabolites, also called ''specialised metabolites'', ''secondary products'', or ''natural products'', are organic compounds produced by any lifeform, e.g. bacteria, archaea, fungi, animals, or plants, which are not directly involved ...
s 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 product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical s ...
s have often been used as the starting point for drug discovery.


History

Until the
Renaissance The Renaissance ( , ) is a Periodization, period of history and a European cultural movement covering the 15th and 16th centuries. It marked the transition from the Middle Ages to modernity and was characterized by an effort to revive and sur ...
, 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
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s and
hormone A hormone (from the Ancient Greek, Greek participle , "setting in motion") is a class of cell signaling, signaling molecules in multicellular organisms that are sent to distant organs or tissues by complex biological processes to regulate physio ...
s 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. 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 A regulatory agency (regulatory body, regulator) or independent agency (independent regulatory agency) is a government authority that is responsible for exercising autonomous jurisdiction over some area of human activity in a licensing and regu ...
.


Jasmonates

Jasmonate Jasmonate (JA) and its derivatives are lipid-based plant hormones that regulate a wide range of processes in plants, ranging from growth and photosynthesis to reproductive development. In particular, JAs are critical for plant defense against herb ...
s are important in responses to injury and intracellular signals. They induce apoptosis and protein cascade via proteinase inhibitor, have defense functions, and regulate plant responses to different biotic and abiotic stresses. Jasmonates also have the ability to directly act on
mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
membranes by inducing membrane depolarization via release of
metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
s. Jasmonate derivatives (JAD) are also important in wound response and tissue regeneration in plant cells. They have also been identified to have
anti-aging The anti-aging movement is a social movement devoted to eliminating or reversing aging, or reducing the effects of it. A substantial portion of the attention of the movement is on the possibilities for life extension, but there is also interest i ...
effects on human
epidermal The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermal layer provides a barrier to infection from environmental pathogens and regulates the amount of water relea ...
layer. It is suspected that they interact with
proteoglycan Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan (GAG) chain(s). The point of attachment is a serine (Ser) residue to w ...
s (PG) and
glycosaminoglycan Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case o ...
(GAG)
polysaccharide Polysaccharides (), or polycarbohydrates, are the most abundant carbohydrates found in food. They are long-chain polymeric carbohydrates composed of monosaccharide units bound together by glycosidic linkages. This carbohydrate can react with wat ...
s, which are essential
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
(ECM) components to help remodel the ECM. The discovery of JADs on skin repair has introduced newfound interest in the effects of these plant hormones in therapeutic medicinal application.


Salicylates

Salicylic acid (SA), a
phytohormone Plant hormones (or phytohormones) are signal molecules, produced within plants, that occur in extremely low concentrations. Plant hormones control all aspects of plant growth and development, including embryogenesis, the regulation of organ si ...
, was initially derived from willow bark and has since been identified in many species. It is an important player in
plant immunity Plants are the eukaryotes that form the kingdom Plantae; they are predominantly photosynthetic. This means that they obtain their energy from sunlight, using chloroplasts derived from endosymbiosis with cyanobacteria to produce sugars fro ...
, although its role is still not fully understood by scientists. 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. 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. They have the ability to induce death in
lymphoblast __NOTOC__ A lymphoblast is a modified naive lymphocyte with altered cell morphology. It occurs when the lymphocyte is activated by an antigen and increased in volume by nucleus and cytoplasm growth as well as new mRNA and protein synthesis. The ly ...
ic
leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...
and other human cancer cells. One of the most common drugs derived from salicylates is
aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...
, also known as acetylsalicylic acid, with anti-inflammatory and anti-pyretic properties.


Animal-derived

Some drugs used in modern medicine have been discovered in animals or are based on compounds found in animals. For example, the
anticoagulant An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which ...
drugs,
hirudin Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches (such as ''Hirudo medicinalis'') that has a blood anticoagulant property. This is essential for the leeches' habit of feeding on blood, since it keeps a h ...
and its synthetic congener,
bivalirudin Bivalirudin, sold under the brand names Angiomax and Angiox, among others, is a specific and reversible direct thrombin inhibitor (DTI). Chemically, it is a synthetic congener of the naturally occurring drug hirudin, found in the saliva of t ...
, are based on
saliva Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...
chemistry of the
leech Leeches are segmented parasitism, parasitic or Predation, predatory worms that comprise the Class (biology), subclass Hirudinea within the phylum Annelida. They are closely related to the Oligochaeta, oligochaetes, which include the earthwor ...
, ''
Hirudo medicinalis ''Hirudo medicinalis'', or the European medicinal leech, is one of several species of leeches used as medicinal leeches. Other species of ''Hirudo'' sometimes also used as medicinal leeches include ''Hirudo orientalis, H. orientalis'', ''Hirudo ...
''. Used to treat
type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
, exenatide was developed from
saliva Saliva (commonly referred as spit or drool) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which ...
compounds of the
Gila monster The Gila monster (''Heloderma suspectum'', ) is a species of venomous lizard native to the Southwestern United States and the northwestern Mexico, Mexican state of Sonora. It is a heavy, slow-moving reptile, up to long, and it is the only ve ...
, a venomous
lizard Lizard is the common name used for all Squamata, squamate reptiles other than snakes (and to a lesser extent amphisbaenians), encompassing over 7,000 species, ranging across all continents except Antarctica, as well as most Island#Oceanic isla ...
.


Microbial metabolites

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 Penicillins (P, PCN or PEN) are a group of beta-lactam antibiotic, β-lactam antibiotics originally obtained from ''Penicillium'' Mold (fungus), moulds, principally ''Penicillium chrysogenum, P. chrysogenum'' and ''Penicillium rubens, P. ru ...
in bacterial cultures contaminated by ''
Penicillium ''Penicillium'' () is a genus of Ascomycota, ascomycetous fungus, fungi that is part of the mycobiome of many species and is of major importance in the natural environment, in food spoilage, and in food and drug production. Some members of th ...
'' fungi in 1928.


Marine invertebrates

Marine environments are potential sources for new bioactive agents.
Arabinose Arabinose is an aldopentose – a monosaccharide containing five carbon atoms, and including an aldehyde (CHO) functional group. Properties For biosynthetic reasons, most saccharides are almost always more abundant in nature as the "D"-form, o ...
nucleosides Nucleosides are glycosylamines that can be thought of as nucleotides without a phosphate group. A nucleoside consists simply of a nucleobase (also termed a nitrogenous base) and a five-carbon sugar (ribose or 2'-deoxyribose) whereas a nucleotide ...
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 Ziconotide, sold under the brand name Prialt, also called intrathecal ziconotide (ITZ) because of its administration route, is an atypical analgesic agent for the amelioration of severe and chronic pain. Derived from '' Conus magus'', a cone sn ...
, 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 Bryostatins are a group of macrolide lactones from (bacterial symbionts of) the marine organism ''Bugula neritina'' that were first collected and provided to JL Hartwell’s anticancer drug discovery group at the National Cancer Institute (NCI) by ...
-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. This has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs or natural products. The
chemoinformatics Cheminformatics (also known as chemoinformatics) refers to the use of physical chemistry theory with computer and information science techniques—so called "''in silico''" techniques—in application to a range of descriptive and prescriptive pr ...
concept chemical diversity, depicted as distribution of compounds in the
chemical space Chemical space is a concept in cheminformatics referring to the property space spanned by all possible molecules and chemical compounds adhering to a given set of construction principles and boundary conditions. It contains millions of compounds w ...
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. 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 Chirality () is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable fro ...
are well-established factors in
medicinal chemistry Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with drug design, designing and developing pharmaceutical medication, drugs. Medicinal chemistry involves the identification, ...
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 The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health (NIH), which is one of eleven agencies that are part of the U.S. Department of Health and Human Services. ...
, which started in the 1960s.
Paclitaxel Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered b ...
was identified from Pacific yew tree ''
Taxus brevifolia ''Taxus brevifolia'', the Pacific yew or western yew, is a species of tree in the yew family Taxaceae native to the Pacific Northwest of North America. It is a small evergreen conifer, thriving in moisture and otherwise tending to take the form o ...
''. 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 Kaposi's sarcoma (KS) is a type of cancer that can form masses on the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limite ...
. Early in the 21st century, Cabazitaxel (made by
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
, a French firm), another relative of
taxol Paclitaxel, sold under the brand name Taxol among others, is a chemotherapy medication used to treat ovarian cancer, esophageal cancer, breast cancer, lung cancer, Kaposi's sarcoma, cervical cancer, and pancreatic cancer. It is administered by ...
has been shown effective against
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
, 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 Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the Bark (botany), bark of ''Camptotheca acuminata'' (� ...
·
Topotecan Topotecan, sold under the brand name Hycamtin among others, is a chemotherapeutic agent medication that is a topoisomerase inhibitor. It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the ...
·
Irinotecan Irinotecan, sold under the brand name Camptosar among others, is an anti-cancer medication used to treat colon cancer and small cell lung cancer. For colon cancer it is used either alone or with fluorouracil. For small cell lung cancer it is ...
· Rubitecan · Belotecan); 2. Podophyllum (
Etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...
· Teniposide); 3a. Anthracyclines ( Aclarubicin ·
Daunorubicin Daunorubicin, also known as daunomycin, is a chemotherapy medication used to treat cancer. Specifically it is used for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and Kaposi's sarcoma. I ...
·
Doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
·
Epirubicin Epirubicin is an anthracycline drug used for chemotherapy. It can be used in combination with other medications to treat breast cancer in patients who have had surgery to remove the tumor. It is marketed by Pfizer under the trade name Ellence in ...
·
Idarubicin Idarubicin or 4-demethoxydaunorubicin is an anthracycline antileukemic drug. It inserts itself into DNA and prevents DNA unwinding by interfering with the enzyme topoisomerase II. It is an analog of daunorubicin, but the absence of a methoxy gro ...
· Amrubicin · Pirarubicin ·
Valrubicin Valrubicin (''N''-trifluoroacetyladriamycin-14-valerate, trade name Valstar) is a chemotherapy drug used to treat bladder cancer. Valrubicin is a semisynthetic analog of the anthracycline doxorubicin, and is administered by infusion directly into ...
· Zorubicin); 3b. Anthracenediones (
Mitoxantrone Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent. Uses Mitoxantrone is used to treat certain types of cancer, mostly acute myeloid leukemia. It improves th ...
· Pixantrone). The second main approach involves
ethnobotany Ethnobotany is an interdisciplinary field at the interface of natural and social sciences that studies the relationships between humans and plants. It focuses on traditional knowledge of how plants are used, managed, and perceived in human socie ...
, the study of the general use of plants in society, and
ethnopharmacology Ethnomedicine is a study or comparison of the traditional medicine based on bioactive compounds in plants and animals and practiced by various ethnic groups, especially those with little access to western medicines, e.g., indigenous peoples. The ...
, an area inside ethnobotany, which is focused specifically on medicinal uses.
Artemisinin Artemisinin () and its semisynthetic derivatives are a group of drugs used in the treatment of malaria due to ''Plasmodium falciparum''. It was discovered in 1972 by Tu Youyou, who shared the 2015 Nobel Prize in Physiology or Medicine for he ...
, an antimalarial agent from sweet wormtree '' Artemisia annua'', used in Chinese medicine since 200BC is one drug used as part of
combination therapy In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...
for multiresistant ''
Plasmodium falciparum ''Plasmodium falciparum'' is a Unicellular organism, unicellular protozoan parasite of humans and is the deadliest species of ''Plasmodium'' that causes malaria in humans. The parasite is transmitted through the bite of a female ''Anopheles'' mos ...
''. Additionally, since machine learning has become more advanced, virtual screening is now an option for drug developers. AI algorithms are being used to perform virtual screening of chemical compounds, which involves predicting the activity of a compound against a specific target. By using machine learning algorithms to analyse large amounts of chemical data, researchers can identify potential new drug candidates that are more likely to be effective against a specific disease. Algorithms, such as Nearest-Neighbour classifiers, RF, extreme learning machines, SVMs, and deep neural networks (DNNs), are used for VS based on synthesis feasibility and can also predict in vivo activity and toxicity.


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 Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a ''mass spectrum'', a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used ...
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 spectra 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. 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.


See also


References


Further reading

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External links

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