Polypharmacology

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Despite scientific advancements and an increase of global R&D spending, drugs are frequently withdrawn from markets.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 and its urge to become a more holistic discipline that looks at the use of tool compounds from a systems perspective.[6]

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. ISSN 0006-2952.
  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.
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