Drug discovery
Template:Short description Template:Use dmy dates Template:AI4 In the fields of medicine, biotechnology, and pharmacology, drug discovery is the process by which new candidate medications are discovered.<ref name="fda18">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="fdastep1">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Modern drug discovery involves the identification of screening hits,<ref name="doi.org">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.</ref> medicinal chemistry,<ref>Herrmann, A., Roesner, M., Werner, T. et al. Potent inhibition of HIV replication in primary human cells by novel synthetic polyketides inspired by Aureothin. Sci Rep 10, 1326 (2020). https://doi.org/10.1038/s41598-020-57843-9.</ref> 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.<ref name="fdastep3">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
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.<ref name="Anson2009">Template:Cite news</ref> In 2010, the research and development cost of each new molecular entity was about US$1.8 billion.<ref name="pmid20168317">Template:Cite journal</ref> 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.<ref name="iom">Template:Cite book</ref> 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.<ref name="pmid21395642">Template:Cite journal</ref> 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.
HistoryEdit
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.Template:Cn
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,<ref name="pmid11589663">Template:Cite journal</ref> or phenotypic drug discovery.<ref name="pmid22409666">Template:Cite journal</ref>
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,<ref name="pmid8494337">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> the work of James Black<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> on beta blockers and cimetidine, and the discovery of statins by Akira Endo.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=Watts_2012>Template:Cite journal</ref>
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.Template:Cn
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.<ref name="Swinney_2011">Template:Cite journal</ref>
In the 2020s, qubit and quantum computing started to be used to reduce the time needed to drug discovery.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
TargetsEdit
A "target" is produced within the pharmaceutical industry.<ref name=iom/> 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.<ref name=iom/> 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.<ref name=iom/> In an estimate from 2011, 435 human genome products were identified as therapeutic drug targets of FDA-approved drugs.<ref>Template:Cite journal</ref>
"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.<ref name=fdastep1/> This does not imply that the mechanism of action of drugs that are thought to act through a particular established target is fully understood.<ref name=fdastep1/> 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.<ref name="Jacobson">Template:Cite journal</ref>
Screening and designEdit
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.<ref name=Chen/>
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.<ref name=Chen/> 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.<ref name=Chen/> Cross-screening is useful 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.<ref name=Chen/>
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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.Template:Cn
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<ref name="pmid15109945">Template:Cite journal</ref> (LE) and lipophilic efficiency<ref name="pmid19500981">Template:Cite journal</ref><ref name="pmid17971784">Template:Cite journal</ref> (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,<ref>Template:Cite journal</ref> where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used.<ref name="Chen">Template:Cite journal</ref>
Another method for drug discovery is de novo drug design, in which a prediction is made of the sorts of chemicals that might (e.g.) fit into an active site of the target enzyme. For example, virtual screening and computer-aided drug design are often used to identify new chemical moieties that may interact with a target protein.<ref name="pmid18600572">Template:Cite journal</ref><ref name="pmid18084917">Template:Cite book</ref> Molecular modelling<ref name="pmid19128219">Template:Cite journal</ref> and molecular dynamics simulations can be used as a guide to improve the potency and properties of new drug leads.<ref name="pmid22035460">Template:Cite journal</ref><ref name="pmid22183577">Template:Cite journal</ref><ref>Template:Cite journal</ref>
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)<ref name="pmid15214773">Template:Cite journal</ref><ref name="FragmentBook1">Template:Cite book</ref><ref name="pmid21695633">Template:Cite book</ref><ref name="FragmentBook2">Template:Cite book</ref> and protein-directed dynamic combinatorial chemistry.<ref name="Dynamic_combinatorial_chemistry_in_drug_discovery_bioinorganic_chemistry_and_materials_sciences">Template:Cite book</ref><ref name="pmid27438816">Template:Cite journal</ref><ref name="pmid25706945">Template:Cite journal</ref><ref name="pmid24296754">Template:Cite journal</ref><ref name="Fragment_based_approaches_in_drug_discovery">Template:Cite book</ref> 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.<ref name="pmid23795969">Template:Cite journal</ref><ref name="pmid23202926">Template:Cite journal</ref><ref name="pmid17206823">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> 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 has provided numerous strategies to identify drug targets in these cases.<ref>Template:Cite journal</ref>
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 decisions are generally supported by computational modelling innovations.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
Nature as sourceEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.<ref>Template:Citation</ref>
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.<ref name="pmid12546556">Template:Cite journal</ref> A 2007 report<ref name="pmid17309302">Template:Cite journal</ref> 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.Template:Citation needed
Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.<ref name="pmid16881035">Template:Cite journal</ref>
Plant-derivedEdit
Template:Further 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="doi.org"/>
HistoryEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Until the Renaissance, the vast majority of drugs in Western medicine were plant-derived extracts.<ref name=":5">Template:Cite book</ref> This has resulted in a pool of information about the potential of plant species as important sources of starting materials for drug discovery.<ref name="ahn2">Template:Cite journal</ref> 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.<ref name="ahn2" /><ref name=":4">Template:Cite journal</ref> 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.<ref name=":10">Template:Cite journal</ref>
JasmonatesEdit
Jasmonates are important in responses to injury and intracellular signals. They induce apoptosis<ref name=":0">Template:Cite journal</ref><ref name=":3">Template:Cite journal</ref> and protein cascade via proteinase inhibitor,<ref name=":0" /> have defense functions,<ref name=":1">Template:Cite journal</ref> and regulate plant responses to different biotic and abiotic stresses.<ref name=":1" /><ref>Template:Cite journal</ref> Jasmonates also have the ability to directly act on mitochondrial membranes by inducing membrane depolarization via release of metabolites.<ref name="pmid15753398">Template:Cite journal</ref>
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.<ref name=":11">Template:Cite journal</ref> It is suspected that they interact with proteoglycans (PG) and glycosaminoglycan (GAG) polysaccharides, which are essential extracellular matrix (ECM) components to help remodel the ECM.<ref>Template:Cite journal</ref> The discovery of JADs on skin repair has introduced newfound interest in the effects of these plant hormones in therapeutic medicinal application.<ref name=":11" />
SalicylatesEdit
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.<ref name=":8">Template:Cite journal</ref> 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.<ref name=":8" /> 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.<ref name=":0" /> They have the ability to induce death in lymphoblastic leukemia and other human cancer cells.<ref name=":0" /> One of the most common drugs derived from salicylates is aspirin, also known as acetylsalicylic acid, with anti-inflammatory and anti-pyretic properties.<ref name=":8" /><ref name=":9">Template:Cite book</ref>
Animal-derivedEdit
Some drugs used in modern medicine have been discovered in animals or are based on compounds found in animals. For example, the anticoagulant drugs, hirudin and its synthetic congener, bivalirudin, are based on saliva chemistry of the leech, Hirudo medicinalis.<ref name="taylor">Template:Cite journal</ref> Used to treat type 2 diabetes, exenatide was developed from saliva compounds of the Gila monster, a venomous lizard.<ref name="shy">Template:Cite journal</ref>
Microbial metabolitesEdit
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.Template:Citation needed
Marine invertebratesEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Marine environments are potential sources for new bioactive agents.<ref name="pmid15039835">Template:Cite journal</ref> 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.Template:Citation needed {{ safesubst:#invoke:Unsubst||date=__DATE__ |$B= Template:Fix }} 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.Template:Citation needed
Chemical diversityEdit
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.<ref name="pmid17309302"/> 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.<ref name="pmid12546556"/> 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.Template:Cn
ScreeningEdit
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.Template:Cn
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.
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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
Structural elucidationEdit
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.
New Drug ApplicationEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} 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.<ref name="fdastep4">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="fdastep4" />
See alsoEdit
ReferencesEdit
Further readingEdit
External linksEdit
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