Polypharmacology

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Polypharmacology is the design or use of pharmaceutical agents that act on multiple targets or disease pathways. [1]

Despite scientific advancements and an increase of global R&D spending, drugs are frequently withdrawn from markets. This is primarily due to their side effects or toxicities. Drug molecules often interact with multiple targets and the unintended drug-target interactions can cause side effects. Polypharmacology remains to be one of the major challenges in drug development, and it opens novel avenues to rationally design the next generation of more effective but less toxic therapeutic agents. [2] Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. [3] [4]

It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that "hits" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. [5] In contrast, chemical biology continues to be a reductionist discipline, still regarding chemical probes as highly selective small molecules that enable the modulation and study of one specific target. Chemical biology cannot continue to overlook the existence of polypharmacologytext[ according to whom? ] and its urge to become a more holistic discipline that looks at the use of tool compounds from a systems perspective. [6] The use of chemoproteomics offers strategies to develop a more holistic understanding of the proteome-wide range of targets a drug interacts with. [7]

The primordial idea of polypharmacology was first proposed in 2004 by Bryan Roth. [8] He reasoned that most common central nervous system disorders are polygenic in origin, and attempts to develop more effective treatments for diseases such as schizophrenia and depression by discovering drugs selective for single molecular targets ('magic bullets') have been largely unsuccessful. He therefore proposed a proof of concept that designing selectively non-selective drugs (that is, 'magic shotguns') that interact with several molecular targets will lead to new and more effective medications for a variety of central nervous system disorders.

A similar concept was independently proposed in the year of 2006 by Professor Zhiguo Wang [9] who used the term 'single agent–multiple targets' (SAMT) to describe the same principle as 'magic shotguns' and his research team provided the first experimental evidence for the feasibility, effectiveness and advantages of SAMT, specifically the 'complex decoy oligodeoxynucleotides technology cdODN' attacking multiple target transcription factors, in the treatment of xenograft breast cancer in mice. Subsequently, Wang's team extended the SAMT to designing single agent that can act on multiple miRNAs targeting cancer cells and cardiac pacemaker channel genes and calcium channel genes as a new therapeutic approach. [10] [11] [12] Wang has published two monographs on polypharmacology:<Polypharmacology: Principles and Methodologies> [13] and <Anti-Aging Polypharmacology> [14] Wang's work is now categorized as 'Epigenetic Polypharmacology' or 'Targeted Polypharmacology', a branch of Polypharmacology. [15] In 2008, Professor Keven Shokat and his colleagues described a single compound that blocks the proliferation of tumor cells by direct inhibition of oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases and termed it 'multitargeted drug' along with the concept of 'Polypharmacology'. [16] Since then, Polypharmacology has become a new branch of Pharmacology discipline and research field as well as one of the new direction and strategies for drug development. [17]

See also

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<span class="mw-page-title-main">Drug discovery</span> Pharmaceutical procedure

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.

<span class="mw-page-title-main">Drug design</span> Invention of new medications based on knowledge of a biological target

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<span class="mw-page-title-main">High-throughput screening</span> Drug discovery technique

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.

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<span class="mw-page-title-main">Mechanism of action</span> Biochemical interaction through which a drug produces its pharmacological effect

In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there.

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<span class="mw-page-title-main">Ming-Ming Zhou</span>

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Phenotypic screening is a type of screening used in biological research and drug discovery to identify substances such as small molecules, peptides, or RNAi that alter the phenotype of a cell or an organism in a desired manner. Phenotypic screening must be followed up with identification and validation, often through the use of chemoproteomics, to identify the mechanisms through which a phenotypic hit works.

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<span class="mw-page-title-main">Classical pharmacology</span> Drug discovery by phenotypic screening

In the field of drug discovery, classical pharmacology, also known as forward pharmacology, or phenotypic drug discovery (PDD), relies on phenotypic screening of chemical libraries of synthetic small molecules, natural products or extracts to identify substances that have a desirable therapeutic effect. Using the techniques of medicinal chemistry, the potency, selectivity, and other properties of these screening hits are optimized to produce candidate drugs.

<span class="mw-page-title-main">Targeted covalent inhibitors</span>

Targeted covalent inhibitors (TCIs) or Targeted covalent drugs are rationally designed inhibitors that bind and then bond to their target proteins. These inhibitors possess a bond-forming functional group of low chemical reactivity that, following binding to the target protein, is positioned to react rapidly with a proximate nucleophilic residue at the target site to form a bond.

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.

A proteolysis targeting chimera (PROTAC) is a heterobifunctional molecule composed of two active domains and a linker, capable of removing specific unwanted proteins. Rather than acting as a conventional enzyme inhibitor, a PROTAC works by inducing selective intracellular proteolysis. PROTACs consist of two covalently linked protein-binding molecules: one capable of engaging an E3 ubiquitin ligase, and another that binds to a target protein meant for degradation. Recruitment of the E3 ligase to the target protein results in ubiquitination and subsequent degradation of the target protein via the proteasome. Because PROTACs need only to bind their targets with high selectivity, there are currently many efforts to retool previously ineffective inhibitor molecules as PROTACs for next-generation drugs.

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References

  1. ↑ "Polypharmacology". PubMed. MeSH. Retrieved May 6, 2017.
  2. ↑ Reddy, A. Srinivas; Zhang, Shuxing (2013). "Polypharmacology: drug discovery for the future". Expert Rev Clin Pharmacol. 6 (1): 41–47. doi:10.1586/ecp.12.74. PMC   3809828 . PMID   23272792.
  3. ↑ Matera, Carlo; Pucci, Luca; Fiorentini, Chiara; Fucile, Sergio; Missale, Cristina; Grazioso, Giovanni; Clementi, Francesco; Zoli, Michele; De Amici, Marco; Gotti, Cecilia; Dallanoce, Clelia (2015). "Bifunctional compounds targeting both D 2 and non-α7 nACh receptors: Design, synthesis and pharmacological characterization". European Journal of Medicinal Chemistry. 101: 367–383. doi:10.1016/j.ejmech.2015.06.039. ISSN   0223-5234. PMID   26164842.
  4. ↑ Matera, Carlo; Bono, Federica; Pelucchi, Silvia; Collo, Ginetta; Bontempi, Leonardo; Gotti, Cecilia; Zoli, Michele; De Amici, Marco; Missale, Cristina; Fiorentini, Chiara; Dallanoce, Clelia (2019). "The novel hybrid agonist HyNDA-1 targets the D3R-nAChR heteromeric complex in dopaminergic neurons". Biochemical Pharmacology. 163: 154–168. doi:10.1016/j.bcp.2019.02.019. hdl: 2434/678632 . ISSN   0006-2952. PMID   30772268. S2CID   73466944.
  5. ↑ Anighoro, Andrew; Bajorath, Jürgen; Rastelli, Giulio (2014). "Polypharmacology: Challenges and Opportunities in Drug Discovery". J Med Chem. 57 (19): 7874–87. doi:10.1021/jm5006463. PMID   24946140.
  6. ↑ Antolin, A.A. (2014). The Impact of polypharmacology on chemical biology (Doctoral Thesis). Barcelona: Universitat Pompeu Fabra. Departament de Ciències Experimentals i de la Salut. hdl:10803/329012.
  7. ↑ Moellering, Raymond E.; Cravatt, Benjamin F. (January 2012). "How Chemoproteomics Can Enable Drug Discovery and Development". Chemistry & Biology. 19 (1): 11–22. doi:10.1016/j.chembiol.2012.01.001. ISSN   1074-5521. PMC   3312051 . PMID   22284350.
  8. ↑ Roth BL, Sheffler DJ, Kroeze WK (2004). "Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia". Nature Reviews. Drug Discovery. 3 (4): 353–9. doi:10.1038/nrd1346. PMID   15060530. S2CID   20913769.
  9. ↑ Gao, Huanhuan; Xiao, Jiening; Sun, Qiang; Lin, Huixian; Bai, Yunlong; Yang, Long; Yang, Baofeng; Wang, Huizhen; Wang, Zhiguo (2006-11-01). "A Single Decoy Oligodeoxynucleotides Targeting Multiple Oncoproteins Produces Strong Anticancer Effects". Molecular Pharmacology. 70 (5): 1621–1629. doi:10.1124/mol.106.024273. ISSN   0026-895X. PMID   16936227. S2CID   10019690.
  10. ↑ Lu, Yanjie; Xiao, Jiening; Lin, Huixian; Bai, Yunlong; Luo, Xiaobin; Wang, Zhiguo; Yang, Baofeng (Feb 2009). "A single anti-microRNA antisense oligodeoxyribonucleotide (AMO) targeting multiple microRNAs offers an improved approach for microRNA interference". Nucleic Acids Research. 37 (3): e24. doi:10.1093/nar/gkn1053. ISSN   1362-4962. PMC   2647303 . PMID   19136465.
  11. ↑ Wang, Zhiguo (2009). MicroRNA Interference Technologies. doi:10.1007/978-3-642-00489-6. ISBN   978-3-642-00488-9.
  12. ↑ Wang, Zhiguo (2011). "The concept of multiple-target anti-miRNA antisense oligonucleotide technology". MicroRNA and Cancer. Methods in Molecular Biology. Vol. 676. pp. 51–57. doi:10.1007/978-1-60761-863-8_4. ISBN   978-1-60761-862-1. ISSN   1940-6029. PMID   20931389.
  13. ↑ Wang, Zhiguo; Yang, Baofeng (2022). "Polypharmacology: Principles and Methodologies". Springer Nature (Switzerland AG). ISBN   978-3-031-04998-9.
  14. ↑ Wang, Zhiguo (2024). "Anti-Aging Polypharmacology". Cambridge Scholars Publishing (UK). ISBN   978-1-0364-0680-6.
  15. ↑ Tomaselli, D.; Lucidi, A.; Rotili, D.; Mai, A. (2020). "Epigenetic polypharmacology: A new frontier for epi-drug discovery. | wizdom.ai - intelligence for everyone". Medicinal Research Reviews. 40 (1): 190–244. doi:10.1002/MED.21600. PMC   6917854 . PMID   31218726.
  16. ↑ Apsel, Beth; Blair, Jimmy A.; Gonzalez, Beatriz; Nazif, Tamim M.; Feldman, Morri E.; Aizenstein, Brian; Hoffman, Randy; Williams, Roger L.; Shokat, Kevan M.; Knight, Zachary A. (Oct 2008). "Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases". Nature Chemical Biology. 4 (11): 691–699. doi:10.1038/nchembio.117. ISSN   1552-4469. PMC   2880455 . PMID   18849971.
  17. ↑ Reddy, A Srinivas; Zhang, Shuxing (2013-01-01). "Polypharmacology: drug discovery for the future". Expert Review of Clinical Pharmacology. 6 (1): 41–47. doi:10.1586/ecp.12.74. ISSN   1751-2433. PMC   3809828 . PMID   23272792.
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