Guide Protein Discovery Technologies (Drug Discovery Series)

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The molecules are approximately 12 kD, and can be assessed via NMR. Its 3-D information can be integrated into a small molecule design process. The company presented information on two applications. One involves inhibitors of serine proteases, cathepsin G, elastase, and tryptase, which are all involved in chronic obstructive pulmonary disease and asthma. Most small molecule inhibitors lack good selectivity and have side effects. The company developed fully reversible and selective inhibitors of cathepsin G and elastase exhibiting good ADMET properties.

The second application is the discovery of antagonists of the chemokine receptor, CXCR4, a protein-ligand CPCR initially described as a co-receptor for T-tropic HIV, but recently shown to be an important receptor in angiogenesis, metastasis, and stem cell release. The company expects to bring these compounds into preclinical trials soon, and will also be looking at intracellular protein-protein interaction targets. As an alternative to therapeutic antibodies, Direvo Biotech www. One is the directed evolution of natural proteins, which optimizes existing therapeutic proteins.

The directed evolution platform consists of an ultra high throughput screening process that can handle ,,, individual protein variants per day. Optimization includes efficacy, selectivity, substrate specificity, stability, and yields. Applications include in vitro assays cell-based and pure chemical , assays for solvents, and assays for antibodies and enzymes. NBE is relatively new, but has already been used to develop a new anti-inflammatory protease to inactivate TNF-alpha.

CRC Press Online - Series: Drug Discovery Series

These advantages include: cleaving their target, causing irreversible inactivation; inactivating hundreds to thousands of target proteins with one NBE protease; cost-efficient production via bacteria expression systems that work in vitro; and a production time of only three to six months. Antibodies can only neutralize one target protein, require mammalian expression systems and immunogenicity, and take much longer than six months to create.

The NBE process begins with a library based on the human protease backbone, and then random loops in the protease gene are inserted into specific regions called SDRs Selectivity Determining Regions.

Drug discovery and development process

These are stretches of a few amino acids at certain regions of the protease that can determine and alter its specificity. Then the NBE library is screened for desired specificity, and if necessary, the protease is further optimized for process conditions. Polymedix www. Exclusively licensed from researchers at the University of Pennsylvania, this process involves several computational design tools. This is real-time for the interaction of many molecules with their membrane targets.

Novel Oncology Drug Discovery Strategies

PACE Proteomic-Assisted Computational Engine is a set of algorithms that build nonpeptide backbones from common organic building blocks. Williams S. Ettouati, Pharm. Joseph D. Ma Associate Professor of Clinical Pharmacy.


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Try the Course for Free. Explore our Catalog Join for free and get personalized recommendations, updates and offers. 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. Once a compound that fulfills all of these requirements has been identified, the process of drug development can continue, and, if successful, clinical trials. One or more of these steps may, but not necessarily, involve computer-aided drug design. 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. Small companies have a critical role, often then selling the rights to larger companies that have the resources to run the clinical trials. 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.

The idea that the effect of a drug in the human body is mediated by specific interactions of the drug molecule with biological macromolecules, proteins or nucleic acids in most cases led scientists to the conclusion that individual chemicals are required for the biological activity of the drug.

This made for the beginning of the modern era in pharmacology , as pure chemicals, instead of crude extracts of medicinal plants , became the standard drugs. Examples of drug compounds isolated from crude preparations are morphine , the active agent in opium, and digoxin , a heart stimulant originating from Digitalis lanata.

Organic chemistry also led to the synthesis of many of the natural products isolated from biological sources. Historically, substances, whether crude extracts or purified chemicals, were screened for biological activity without knowledge of the biological target.

Only after an active substance was identified was an effort made to identify the target. This approach is known as classical pharmacology , forward pharmacology, [5] or phenotypic drug discovery. This led to great success, such as the work of Gertrude Elion and George H. Hitchings on purine metabolism , [7] [8] the work of James Black [9] on beta blockers and cimetidine , and the discovery of statins by Akira Endo. 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 leukaemia; pivotal anti-cancer treatments; an anti-malarial; an anti-bacterial; and a treatment for gout.

Cloning of human proteins made possible the screening of large libraries of compounds against specific targets thought to be linked to specific diseases. This approach is known as reverse pharmacology and is the most frequently used approach today. The definition of "target" itself is something argued within the pharmaceutical industry. Generally, the "target" is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-in-development is meant to act on.

However, the distinction between a "new" and "established" target can be made without a full understanding of just what a "target" is.

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This distinction is typically made by pharmaceutical companies engaged in discovery and development of therapeutics. In an estimate from , human genome products were identified as therapeutic drug targets of FDA-approved drugs. This does not imply that the mechanism of action of drugs that are thought to act through a particular established target is fully understood. 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. The majority of targets currently selected for drug discovery efforts are proteins. The process of finding a new drug against a chosen target for a particular disease usually involves high-throughput screening HTS , wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR , compounds will be screened for their ability to inhibit or stimulate that receptor see antagonist and agonist : if the target is a protein kinase , the chemicals will be tested for their ability to inhibit that kinase.

Another important function of HTS is to show how selective the compounds are for the chosen target, as one wants to find a molecule which will interfere with only the chosen target, but not other, related targets. It is very 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.

At this point, medicinal chemists will attempt to use structure-activity relationships SAR to improve certain features of the lead compound :. 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 physico-chemical properties associated with drug absorption include ionization pKa , and solubility; permeability can be determined by PAMPA and Caco PAMPA is attractive as an early screen due to the low consumption of drug and the low cost compared to tests such as Caco-2, gastrointestinal tract GIT and Blood—brain barrier BBB with which there is a high correlation.

A range of parameters can be used to assess the quality of a compound, or a series of compounds, as proposed in the Lipinski's Rule of Five. Such parameters include calculated properties such as cLogP to estimate lipophilicity, molecular weight , polar surface area and measured properties, such as potency, in-vitro measurement of enzymatic clearance etc. Some descriptors such as ligand efficiency [17] LE and lipophilic efficiency [18] [19] LiPE combine such parameters to assess druglikeness. While HTS is a commonly used method for novel drug discovery, it is not the only method.

It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon so-called "me too" drugs. Other methods, such as virtual high throughput screening , where screening is done using computer-generated models and attempting to "dock" virtual libraries to a target, are also often used. Another important method for drug discovery is de novo drug design , in which a prediction is made of the sorts of chemicals that might e. For example, virtual screening and computer-aided drug design are often used to identify new chemical moieties that may interact with a target protein.

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 [26] [27] [28] [29] and protein-directed dynamic combinatorial chemistry. Further modified through organic synthesis into lead compounds are often required.

Such modifications are often guided by protein X-ray crystallography of the protein-fragment complex. 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". Traditionally many drugs and other chemicals with biological activity have been discovered by studying allelopathy — chemicals that organisms create that affect the activity of other organisms in the fight 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.

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. Despite the implied potential, only a fraction of Earth's living species has been tested for bioactivity.