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Pharmacology is a science of medical drug and medication, including a substance's origin, composition, pharmacokinetics, therapeutic use, and toxicology. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function. If substances have medicinal properties, they are considered pharmaceuticals.
Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In addition, other kinds of proteins include antibodies that protect an organism from infection, and hormones that send important signals throughout the body.
Structural genomics seeks to describe the 3-dimensional structure of every protein encoded by a given genome. This genome-based approach allows for a high-throughput method of structure determination by a combination of experimental and modeling approaches. The principal difference between structural genomics and traditional structural prediction is that structural genomics attempts to determine the structure of every protein encoded by the genome, rather than focusing on one particular protein. With full-genome sequences available, structure prediction can be done more quickly through a combination of experimental and modeling approaches, especially because the availability of large number of sequenced genomes and previously solved protein structures allows scientists to model protein structure on the structures of previously solved homologs.
In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In addition to small molecules, biopharmaceuticals including peptides and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also been developed.
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 devices, and sensitive detectors, high-throughput screening allows a researcher to quickly conduct millions of chemical, genetic, or pharmacological tests. Through this process one can quickly recognize active compounds, antibodies, or genes that modulate a particular biomolecular pathway. The results of these experiments provide starting points for drug design and for understanding the noninteraction or role of a particular location.
World Community Grid (WCG) is an effort to create the world's largest volunteer computing platform to tackle scientific research that benefits humanity. Launched on November 16, 2004, with proprietary Grid MP client from United Devices and adding support for Berkeley Open Infrastructure for Network Computing (BOINC) in 2005, World Community Grid eventually discontinued the Grid MP client and consolidated on the BOINC platform in 2008. In September 2021, it was announced that IBM transferred ownership to the Krembil Research Institute of University Health Network in Toronto, Ontario.
Toxicogenomics is a subdiscipline of pharmacology that deals with the collection, interpretation, and storage of information about gene and protein activity within a particular cell or tissue of an organism in response to exposure to toxic substances. Toxicogenomics combines toxicology with genomics or other high-throughput molecular profiling technologies such as transcriptomics, proteomics and metabolomics. Toxicogenomics endeavors to elucidate the molecular mechanisms evolved in the expression of toxicity, and to derive molecular expression patterns that predict toxicity or the genetic susceptibility to it.
Chemical biology is a scientific discipline between the fields of chemistry and biology. The discipline involves the application of chemical techniques, analysis, and often small molecules produced through synthetic chemistry, to the study and manipulation of biological systems. Although often confused with biochemistry, which studies the chemistry of biomolecules and regulation of biochemical pathways within and between cells, chemical biology remains distinct by focusing on the application of chemical tools to address biological questions.
Chemogenomics, or chemical genomics, is the systematic screening of targeted chemical libraries of small molecules against individual drug target families with the ultimate goal of identification of novel drugs and drug targets. Typically some members of a target library have been well characterized where both the function has been determined and compounds that modulate the function of those targets have been identified. Other members of the target family may have unknown function with no known ligands and hence are classified as orphan receptors. By identifying screening hits that modulate the activity of the less well characterized members of the target family, the function of these novel targets can be elucidated. Furthermore, the hits for these targets can be used as a starting point for drug discovery. The completion of the human genome project has provided an abundance of potential targets for therapeutic intervention. Chemogenomics strives to study the intersection of all possible drugs on all of these potential targets.
Aled Morgan Edwards is the founder and Chief Executive of the Structural Genomics Consortium, a charitable public-private partnership. He is Professor of Medical Genetics and Medical Biophysics at the University of Toronto, Visiting Professor of Chemical Biology at the University of Oxford, and Adjunct Professor at McGill University.
The Structural Genomics Consortium (SGC) is a public-private-partnership focusing on elucidating the functions and disease relevance of all proteins encoded by the human genome, with an emphasis on those that are relatively understudied. The SGC places all its research output into the public domain without restriction and does not file for patents and continues to promote open science. Two recent publications revisit the case for open science. Founded in 2003, and modelled after the Single Nucleotide Polymorphism Database (dbSNP) Consortium, the SGC is a charitable company whose Members comprise organizations that contribute over $5,4M Euros to the SGC over a five-year period. The Board has one representative from each Member and an independent Chair, who serves one 5-year term. The current Chair is Anke Müller-Fahrnow (Germany), and previous Chairs have been Michael Morgan (U.K.), Wayne Hendrickson (U.S.A.), Markus Gruetter (Switzerland) and Tetsuyuki Maruyama (Japan). The founding and current CEO is Aled Edwards (Canada). The founding Members of the SGC Company were the Canadian Institutes of Health Research, Genome Canada, the Ontario Research Fund, GlaxoSmithKline and Wellcome Trust. The current Members comprise Bayer Pharma AG, Bristol Myers Squibb, Boehringer Ingelheim, the Eshelman Institute for Innovation, Genentech, Genome Canada, Janssen, Merck KGaA, Pfizer, and Takeda.
Computational Resources for Drug Discovery (CRDD) is one of the important silico modules of Open Source for Drug Discovery (OSDD). The CRDD web portal provides computer resources related to drug discovery on a single platform. It provides computational resources for researchers in computer-aided drug design, a discussion forum, and resources to maintain a wiki related to drug discovery, predict inhibitors, and predict the ADME-Tox property of molecules. One of the major objectives of CRDD is to promote open source software in the field of chemoinformatics and pharmacoinformatics.
ChEMBL or ChEMBLdb is a manually curated chemical database of bioactive molecules with drug inducing properties. It is maintained by the European Bioinformatics Institute (EBI), of the European Molecular Biology Laboratory (EMBL), based at the Wellcome Trust Genome Campus, Hinxton, UK.
Chemical genetics is the investigation of the function of proteins and signal transduction pathways in cells by the screening of chemical libraries of small molecules. Chemical genetics is analogous to classical genetic screen where random mutations are introduced in organisms, the phenotype of these mutants is observed, and finally the specific gene mutation (genotype) that produced that phenotype is identified. In chemical genetics, the phenotype is disturbed not by introduction of mutations, but by exposure to small molecule tool compounds. Phenotypic screening of chemical libraries is used to identify drug targets or to validate those targets in experimental models of disease. Recent applications of this topic have been implicated in signal transduction, which may play a role in discovering new cancer treatments. Chemical genetics can serve as a unifying study between chemistry and biology. The approach was first proposed by Tim Mitchison in 1994 in an opinion piece in the journal Chemistry & Biology entitled "Towards a pharmacological genetics".
Computer Atlas of Surface Topography of Proteins (CASTp) aims to provide comprehensive and detailed quantitative characterization of topographic features of protein, is now updated to version 3.0. Since its release in 2006, the CASTp server has ≈45000 visits and fulfills ≈33000 calculation requests annually. CASTp has been proven as a confident tool for a wide range of researches, including investigations of signaling receptors, discoveries of cancer therapeutics, understanding of mechanism of drug actions, studies of immune disorder diseases, analysis of protein–nanoparticle interactions, inference of protein functions and development of high-throughput computational tools. This server is maintained by Jie Liang's lab in University of Illinois at Chicago.
Chemoproteomics entails a broad array of techniques used to identify and interrogate protein-small molecule interactions. Chemoproteomics complements phenotypic drug discovery, a paradigm that aims to discover lead compounds on the basis of alleviating a disease phenotype, as opposed to target-based drug discovery, in which lead compounds are designed to interact with predetermined disease-driving biological targets. As phenotypic drug discovery assays do not provide confirmation of a compound's mechanism of action, chemoproteomics provides valuable follow-up strategies to narrow down potential targets and eventually validate a molecule's mechanism of action. Chemoproteomics also attempts to address the inherent challenge of drug promiscuity in small molecule drug discovery by analyzing protein-small molecule interactions on a proteome-wide scale. A major goal of chemoproteomics is to characterize the interactome of drug candidates to gain insight into mechanisms of off-target toxicity and polypharmacology.
The Chemical Probes Portal is an open, online resource whose purpose is to identify and make available high quality chemical probes for use in biological research and drug discovery. While chemical probes can be valuable tools to elucidate signal transduction pathways and to validate new drug targets, many of the probes that are in use are not selective and therefore can give very misleading results.
Molecular glue refers to a class of chemical compounds or molecules that play a crucial role in binding and stabilizing protein-protein interactions in biological systems. These molecules act as "glue" by enhancing the affinity between proteins, ultimately influencing various cellular processes. Molecular glue compounds have gained significant attention in the fields of drug discovery, chemical biology, and fundamental research due to their potential to modulate protein interactions, and thus, impact various cellular pathways. They have unlocked avenues in medicine previously thought to be “undruggable.”
Angela N. Koehler is an American biochemist who is the Karl Van Tassel (1925) Career Development Professor of Chemical Biology at the Broad Institute. Her research considers the development of chemical tools to understand transcriptional regulation, and the design of next-generation pharmaceuticals.
References
- ↑ Carter AJ, Kraemer O, Zwick M, Mueller-Fahrnow A, Arrowsmith CH, Edwards AM (November 2019). "Target 2035: probing the human proteome". Drug Discovery Today. 24 (11): 2111–2115. doi: 10.1016/j.drudis.2019.06.020 . PMID 31278990.
- ↑ Mullard A (September 2019). "A probe for every protein". Nature Reviews. Drug Discovery. 18 (10): 733–736. doi:10.1038/d41573-019-00159-9. PMID 31570852.
- ↑ Lowe D (September 20, 2019). "Probes For Everything". Science . Retrieved April 22, 2021.
- ↑ Rubinstein YR, Robinson PN, Gahl WA, Avillach P, Baynam G, Cederroth H, et al. (October 2020). "The case for open science: rare diseases". JAMIA Open. 3 (3): 472–486. doi:10.1093/jamiaopen/ooaa030. PMC 7660964 . PMID 33426479.
- ↑ Fleming N (May 2018). "How artificial intelligence is changing drug discovery". Nature. 557 (7707): S55–S57. doi: 10.1038/d41586-018-05267-x . PMID 29849160.
- ↑ Savage N (2021-05-27). "Tapping into the drug discovery potential of AI". Biopharma Dealmakers. doi: 10.1038/d43747-021-00045-7 . ISSN 2730-6275.
- ↑ Satz AL, Kuai L, Peng X (May 2021). "Selections and screenings of DNA-encoded chemical libraries against enzyme and cellular targets". Bioorganic & Medicinal Chemistry Letters. 39: 127851. doi: 10.1016/j.bmcl.2021.127851 . PMID 33631371.
- 1 2 Ackloo S, Al-awar R, Amaro RE, Arrowsmith CH, Azevedo H, Batey RA, et al. (2022-02-15). "CACHE (Critical Assessment of Computational Hit-finding Experiments): A public–private partnership benchmarking initiative to enable the development of computational methods for hit-finding". Nature Reviews Chemistry: 1–9. doi: 10.1038/s41570-022-00363-z . ISSN 2397-3358. PMC 9246350 .
- ↑ Müller S, Ackloo S, Al Chawaf A, Al-Lazikani B, Antolin A, Baell JB, et al. (January 2022). "Target 2035 - update on the quest for a probe for every protein". RSC Medicinal Chemistry. 13 (1): 13–21. doi:10.1039/D1MD00228G. PMC 8792830 . PMID 35211674.
- ↑ Kozlov M (February 2022). "NIH issues a seismic mandate: share data publicly". Nature. 602 (7898): 558–559. doi: 10.1038/d41586-022-00402-1 . PMID 35173323.
- ↑ "Best practises for validating chemical probes".
- ↑ "Chemical Probes as Essential Tools for Biological Discovery". CellPress Webninar.
- ↑ Quinlan RB, Brennan PE (June 2021). "Chemogenomics for drug discovery: clinical molecules from open access chemical probes". RSC Chemical Biology. 2 (3): 759–795. doi: 10.1039/D1CB00016K . PMC 8341094 . PMID 34458810.
- ↑ "Target 2035 – Pharmacological modulators for all human proteins" (PDF). target2035.net.
- ↑ Müller S, Ackloo S, Al Chawaf A, Al-Lazikani B, Antolin A, Baell JB, et al. (January 2022). "Target 2035 - update on the quest for a probe for every protein". RSC Medicinal Chemistry. 13 (1): 13–21. doi: 10.1039/D1MD00228G . PMID 35211674.