In medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed. Medicine is the branch of health science and the sector of public life concerned with maintaining or restoring human health through the study, diagnosis, treatment and possible prevention of disease and injury. ... The structure of insulin Biotechnology is a technology based on biology, especially when used in agriculture, food science, and medicine. ... Pharmacology (in Greek: pharmacon (φάρμακον) meaning drug, and logos (λόγος) meaning science) is the study of how chemical substances interact with living systems. ... Oral medication A medication is a licenced drug taken to cure or reduce symptoms of an illness or medical condition. ...

In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. A new approach has been to understand how disease and infection are controlled at the molecular and physiological level and to target specific entities based on this knowledge. Look up Serendipity in Wiktionary, the free dictionary For other uses, see Serendipity (disambiguation). ... Contagious redirects here. ... An infection is the detrimental colonization of a host organism by a foreign species. ... Molecular biology is the study of biology at a molecular level. ... Physiology (in Greek physis = nature and logos = word) is the study of the mechanical, physical, and biochemical functions of living organisms. ...

The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy. Once a compound has shown its value in these tests, it will begin the process of drug development prior to clinical trials. It has been suggested that this article or section be merged into Pharmacology. ... In medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is a research study. ...

Despite advances in technology and understanding of biological systems, drug discovery is still a long process with low rate of new therapeutic discovery. Information on the human genome, its sequence and what it encodes has been hailed as a potential windfall for drug discovery, promising to virtually eliminate the bottleneck in therapeutic targets that has been one limiting factor on the rate of therapeutic discovery.^[1] However, data indicates that "new targets" as opposed to "established targets" are more prone to drug discovery project failure in general.^[2] This data corroborates some thinking underlying a pharmaceutical industry trend beginning at the turn of the twenty-first century and continuing today which finds more risk aversion in target selection among multi-national pharmaceutical companies.^[3]

Targets: New and Established

The definition of "target" itself is something debated within the pharmaceutical industry. 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 discovery and development of small molecule therapeutics.

"Established targets" are those for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. This does not imply that the mechanism of action of drugs that are thought to act through a particular established targets is fully understood. Rather, "established" relates directly to the amount of background information available on a target, in particular functional information. The more such information is available, the less investment is (generally) required to develop a therapeutic directed against the target. The process of gathering such functional information is called "target validation" in pharmaceutical industry parlance. Established targets also include those that the pharmaceutical industry has had experience mounting drug discovery campaigns against in the past; such a history provides information on the chemical feasibility of developing a small molecular therapeutic against the target and can provide licensing opportunities and freedom-to-operate indicators with respect to small molecule therapeutic candidates. Wikipedia does not yet have an article with this exact name. ...

In general, "new targets" are all those targets that are not "established targets" but which have been or are the subject of drug discovery campaigns. These typically include newly discovered proteins, or proteins whose function has now become clear as a result of basic scientific research. A representation of the 3D structure of myoglobin, showing coloured alpha helices. ...

The majority of targets currently selected for drug discovery efforts are proteins. Two classes predominate: G-protein-coupled receptors (or GPCRs) and protein kinases. The seven transmembrane α-helix structure of a G-protein-coupled receptor. ... A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). ...

Screening and Design

The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (see antagonist and agonist): if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase. It has been suggested that Virtual_high_throughput_screening be merged into this article or section. ... In cell biology, G-protein-coupled receptors (also known as GPCRs, seven transmembrane receptors, heptahelical receptors, or 7TM receptors) are transmembrane receptors that transduce an extracellular signal (ligand binding) into an intracellular signal (G protein activation). ... Antagonists In medicine and biology, a receptor antagonist is a substance that inhibits the normal physiological function of a receptor. ... Agonists An agonist is a substance that binds to a receptor and triggers a response in the cell. ... A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). ... An enzyme inhibitor is a molecule that binds to an enzyme and decreases its rate of reaction. ...

Another important function of HTS is to show how selective the compounds are for the chosen target. The ideal is to find a molecule which will interfere with only the chosen target, but not other, related targets. To this end, other screening runs will be made to see whether the "hits" against the chosen target will interfere with other related targets - this is the process of cross-screening. Cross-screening is important, because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic. The skull and crossbones is a common symbol for toxicity. ...

It is very unlikely that a perfect drug candidate will emerge from these early screening runs. It is more 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 molecules: It has been suggested that this article or section be merged with Bioactivity. ... A pharmacophore is a three-dimensional substructure of a molecule that carries (phoros) the essential features responsible for a drugs (pharmacon) biological activity. ... Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. ... QSAR (quantitative structure-activity relationship, sometimes the A stands also for affinity = reactivity) is the quantitative correlation of the biological (ecological, toxicological or pharmacological) activity to the structure of chemical compounds, which allows the prediction of the so-called drug efficacy of a structurally related compound. ...

• increase activity against the chosen target
• reduce activity against unrelated targets
• improve the "drug-like" 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. ADME is an acronym in pharmacokinetics and pharmacology for Absorption, Distribution, Metabolism, and Excretion, and describes the disposition of a pharmaceutical compound within an organism. ... Wiktionary has a definition of: In vitro In vitro (Latin: within glass) means within a test tube, or, more generally, outside a living organism or cell. ... In vivo (Latin for (with)in the living). ...

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. Secondary metabolites, also known as natural products, are those products (chemical compounds) of metabolism that are not essential for normal growth, development or reproduction of an organism. ... It has been suggested that this article or section be merged with High-throughput_screening. ...

Another important method for drug discovery is drug design, whereby the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemicals that might (eg.) fit into an active site. Novel pharmacophores can emerge very rapidly from these exercises. Drug design is the approach of finding drugs by design, based on their biological targets. ... The active site of an enzyme is the binding site where catalysis occurs. ...

Once a lead molecule 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". It has been suggested that this article or section be merged into Pharmacology. ...

See also

• Drug development
• Pre-clinical development
• Protein structure prediction
• Drug design
• Rational drug design
• Bioinformatics
• Cheminformatics
• Biomedical informatics
• Orphan drug
• Pharmaceutical company
• Physiologically-based pharmacokinetic modelling
• Pharmacogenetics

It has been suggested that this article or section be merged into Pharmacology. ... Activities that need to be performed and results to be obtained a before a clinical trial in humans can begin. ... Protein structure prediction is one of the most significant technologies pursued by computational structural biology and theoretical chemistry. ... Drug design is the approach of finding drugs by design, based on their biological targets. ... Drug design is the approach of finding drugs by design, based on what the drug is targeting. ... Map of the human X chromosome (from the NCBI website). ... Cheminformatics is the use of computer and informational techniques, applied to a range of problems in the field of chemistry. ... Biomedical informatics encompasses both medical informatics (or healthcare informatics) and bioinformatics. ... In America, an orphan drug is any drug developed under the Orphan Drug Act of 1983, a federal law concerning rare diseases (orphan diseases), defined as diseases affecting fewer than 200,000 people in the United States. ... A pharmaceutical company, or drug company, is a company licensed to discover, develop, market and distribute drugs. ... Physiologically-based pharmacokinetic modelling (PBPK) is a mathematical modelling technique for human health risk assessment and investigation of toxicity. ... The terms pharmacogenomics and pharmacogenetics tend to be used interchangeably, and a precise, consensus definition of either remains elusive. ...

External links

• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
• Food and Drug Administration (FDA)
• CDER Drug and Biologic Approval Reports
• Pharmaceutical Research and Manufacturers of America (PhRMA)
• European Medicines Agency (EMEA)
• Pharmaceuticals and Medical Devices Agency (PMDA)
• WHO Model List of Essential Medicines
• Innovation and Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products - FDA
• Priority Medicines for Europe and the World Project "A Public Health Approach to Innovation" - WHO
• Drug Discovery Blog
• Prediction of ADME/Tox Properties in Drug Discovery

References

• Shayne Cox Gad (2005), Drug Discovery Handbook, Wiley-Interscience, ISBN 0-471-21384-5
• Madsen U. (2002), Textbook of Drug Design and Discovery, CRC, ISBN 0-415-28288-8

Notes

1. ↑  this requires substantiation with one or more reputable sources from the time of enthusiasm following "completion" of the human genome sequence
2. ↑  Drug Discovery & Development, October 2005, Trend Watch: Success Rate by Discovery Phase, New and Established Target Projects
3. ↑  Personal communication. this requires substantiation with one or more reputable sources reporting on industry trends in 2003–2005