In the fields of medicine,biotechnology, andpharmacology,drug discovery is the process by which new candidatemedications are discovered.^[1]

Historically, drugs were discovered by identifying the active ingredient from traditional remedies or byserendipitous discovery,as with penicillin. More recently,chemical libraries of syntheticsmall molecules,natural products, orextracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known asclassical pharmacology. Aftersequencing of thehuman genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to usehigh throughput screening of large compounds libraries against isolatedbiological targets which are hypothesized to be disease-modifying in a process known asreverse pharmacology. Hits from these screens are then tested in cells and then in animals forefficacy.^[2]

Modern drug discovery involves the identification of screening hits,^[3]medicinal chemistry,^[4] and optimization of those hits to increase theaffinity,selectivity (to reduce the potential of side effects), efficacy/potency,metabolic stability (to increase thehalf-life), and oralbioavailability. Once a compound that fulfills all of these requirements has been identified, the process ofdrug development can continue. If successful,clinical trials are developed.^[5]

Modern drug discovery is thus usually acapital-intensive process that involves large investments bypharmaceutical industry corporations as well as national governments (who provide grants andloan 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.^[6] In 2010, theresearch and development cost of eachnew molecular entity was about US$1.8 billion.^[7] 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.^[8] 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 theNew 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.^[9] Meanwhile, for disorders whose rarity means that no large commercial success or public health effect can be expected, theorphan drug funding process ensures that people who experience those disorders can have some hope ofpharmacotherapeutic advances.

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 ornucleic 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 inpharmacology, as pure chemicals, instead of crude extracts ofmedicinal plants, became the standard drugs. Examples of drug compounds isolated from crude preparations aremorphine, the active agent in opium, anddigoxin, a heart stimulant originating fromDigitalis lanata. Organic chemistry also led to the synthesis of many of thenatural products isolated from biological sources.^{[citation needed]}

Historically, substances, whether crude extracts or purified chemicals, were screened for biological activity without knowledge of thebiological target. Only after an active substance was identified was an effort made to identify the target. This approach is known asclassical pharmacology, forward pharmacology,^[10] or phenotypic drug discovery.^[11]

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 ofGertrude Elion andGeorge H. Hitchings onpurine metabolism,^[12][13] the work ofJames Black^[14] onbeta blockers andcimetidine, and the discovery ofstatins byAkira Endo.^[15] Another champion of the approach of developing chemical analogues of known active substances wasSir David Jack at Allen and Hanbury's, laterGlaxo, who pioneered the first inhaled selectivebeta2-adrenergic agonist for asthma, the first inhaled steroid for asthma,ranitidine as a successor to cimetidine, and supported the development of the triptans.^[16]

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.^{[citation needed]}

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 asreverse pharmacology and is the most frequently used approach today.^[17]

In the 2020s,qubit andquantum computing started to be used to reduce the time needed to drug discovery.^[18]

A "target" is produced within the pharmaceutical industry.^[8] 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.^[8] 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.^[8] In an estimate from 2011, 435 human genome products were identified as therapeutic drug targets of FDA-approved drugs.^[19]

"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 themechanism 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 asG-protein-coupled receptors (GPCRs) andprotein kinases.^[20]

The process of finding a new drug against a chosen target for a particular disease usually involveshigh-throughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novelGPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (seeantagonist andagonist): if the target is aprotein kinase, the chemicals will be tested for their ability toinhibit that kinase.^[21]

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.^[21] 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.^[21] Cross-screening is useful because the more unrelated targets a compound hits, the more likely that off-targettoxicity will occur with that compound once it reaches the clinic.^[21]

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.^[22][23][24] It is often observed that several compounds are found to have some degree ofactivity, and if these compounds share common chemical features, one or morepharmacophores can then be developed. At this point,medicinal chemists will attempt to usestructure–activity relationships (SAR) to improve certain features of thelead compound:

• increase activity against the chosen target
• reduce activity against unrelated targets
• improve thedruglikeness orADME 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 toin vitro andin vivo testing for activity in the disease model of choice.

Amongst thephysicochemical properties associated with drug absorption include ionization (pKa), and solubility; permeability can be determined byPAMPA andCaco-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) andBlood–brain barrier (BBB) with which there is a high correlation.^{[citation needed]}

A range of parameters can be used to assess the quality of a compound, or a series of compounds, as proposed in theLipinski's Rule of Five. Such parameters include calculated properties such ascLogP to estimate lipophilicity,molecular weight,polar surface area and measured properties, such as potency, in-vitro measurement of enzymaticclearance etc. Some descriptors such asligand efficiency^[25] (LE) andlipophilic efficiency^[26][27] (LiPE) combine such parameters to assessdruglikeness.

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 asvirtual high throughput screening,^[28] where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used.^[21]

Another method for drug discovery isde novodrug design, in which a prediction is made of the sorts of chemicals that might (e.g.) fit into anactive site of the target enzyme. For example,virtual screening andcomputer-aided drug design are often used to identify new chemical moieties that may interact with a target protein.^[29][30]Molecular modelling^[31] andmolecular dynamics simulations can be used as a guide to improve the potency and properties of new drug leads.^[32][33][34]

There is also a paradigm shift in the drug discovery community to shift away from HTS, which is expensive and may only cover limitedchemical space, to the screening of smaller libraries (maximum a few thousand compounds). These includefragment-based lead discovery (FBDD)^{[35][36][37][38]} andprotein-directed dynamic combinatorial chemistry.^{[39][40][41][42][43]} The ligands in these approaches are usually much smaller, and they bind to the target protein with weakerbinding affinity than hits that are identified from HTS. Further modifications throughorganic synthesis into lead compounds are often required. Such modifications are often guided by proteinX-ray crystallography of the protein-fragment complex.^[44][45][46] 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.^[47][48]  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.^[49]  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 ofchemoproteomics has provided numerous strategies to identify drug targets in these cases.^[50]

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 fordrug development. The best of these is generally called thelead compound, while the other will be designated as the "backup". These decisions are generally supported by computational modelling innovations.^[51][52][53]

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.^[55]

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.^[56] A 2007 report^[57] found that of the 974 small molecule new chemical entities developed between 1981 and 2006, 63% were natural derived orsemisynthetic derivatives of natural products. For certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive and anti-inflammatory drugs, the numbers were higher.^{[citation needed]}

Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.^[58]

Manysecondary 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 derivednatural products have often been used as the starting point for drug discovery.^{[59][60][61][62][3]}

Until theRenaissance, the vast majority of drugs in Western medicine were plant-derived extracts.^[63] This has resulted in a pool of information about the potential of plant species as important sources of starting materials for drug discovery.^[64] Botanical knowledge about differentmetabolites andhormones 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.^[64][65] Identifying new drugs and getting them approved for market has proved to be a stringent process due to regulations set by national drugregulatory agencies.^[66]

Jasmonates are important in responses to injury and intracellular signals. They induce apoptosis^[67][68] and protein cascade viaproteinase inhibitor,^[67] have defense functions,^[69] and regulate plant responses to differentbiotic and abiotic stresses.^[69][70] Jasmonates also have the ability to directly act onmitochondrial membranes by inducing membrane depolarization via release ofmetabolites.^[71]

Jasmonate derivatives (JAD) are also important in wound response and tissueregeneration in plant cells. They have also been identified to haveanti-aging effects on humanepidermal layer.^[72] It is suspected that they interact withproteoglycans (PG) andglycosaminoglycan (GAG)polysaccharides, which are essentialextracellular matrix (ECM) components to help remodel the ECM.^[73] The discovery of JADs on skin repair has introduced newfound interest in the effects of these plant hormones in therapeutic medicinal application.^[72]

Salicylic acid (SA), aphytohormone, was initially derived from willow bark and has since been identified in many species. It is an important player inplant immunity, although its role is still not fully understood by scientists.^[74] 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.^[74] 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.^[67] They have the ability to induce death inlymphoblasticleukemia and other human cancer cells.^[67] One of the most common drugs derived from salicylates isaspirin, also known as acetylsalicylic acid, with anti-inflammatory andanti-pyretic properties.^[74][75]

Some drugs used in modern medicine have been discovered in animals or are based on compounds found in animals. For example, theanticoagulant drugs,hirudin and its syntheticcongener,bivalirudin, are based onsaliva chemistry of theleech,Hirudo medicinalis.^[76] Used to treattype 2 diabetes,exenatide was developed fromsaliva compounds of theGila monster, a venomouslizard.^[77]

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 ispenicillin in bacterial cultures contaminated byPenicillium fungi in 1928.^{[citation needed]}

Marine environments are potential sources for new bioactive agents.^[78]Arabinosenucleosides 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.^{[citation needed][dubious –discuss]} For example, the cone snail toxinziconotide, 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 arebryostatin-like compounds, under investigation as anti-cancer therapy.^{[citation needed]}

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.^[57] This has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs or natural products. Thechemoinformatics concept chemical diversity, depicted as distribution of compounds in thechemical 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.^[56] 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 andchirality are well-established factors inmedicinal 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.^{[citation needed]}

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.^{[citation needed]}

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 theNational Cancer Institute, which started in the 1960s.Paclitaxel was identified from Pacific yew treeTaxus 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 forKaposi's sarcoma. Early in the 21st century,Cabazitaxel (made bySanofi, a French firm), another relative oftaxol has been shown effective againstprostate 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 involvesethnobotany, the study of the general use of plants in society, andethnopharmacology, an area inside ethnobotany, which is focused specifically on medicinal uses.

Artemisinin, an antimalarial agent from sweet wormtreeArtemisia annua, used in Chinese medicine since 200BC is one drug used as part ofcombination therapy for multiresistantPlasmodium falciparum.

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.^[79]

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 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.

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.^[80] 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.^[80]

• Drug discovery

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