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Cited by 555Computational Drug Discovery MethodsProtein Degradation and InhibitorsHeterocyclic Compound Synthesis and Bioactivity

The DOI matches its Crossref record; 251 of the 251 references it cites were found in a registry or an index.

Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

Proschak, Ewgenij, Stark, Holger, Merk, Daniel·2019·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.8b00760
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Abstract

Multitargeting compounds comprising activity on more than a single biological target have gained remarkable relevance in drug discovery owing to the complexity of multifactorial diseases such as cancer, inflammation, or the metabolic syndrome. Polypharmacological drug profiles can produce additive or synergistic effects while reducing side effects and significantly contribute to the high therapeutic success of indispensable drugs such as aspirin. While their identification has long been the result of serendipity, medicinal chemistry now tends to design polypharmacology. Modern in vitro pharmacological methods and chemical probes allow a systematic search for rational target combinations and recent innovations in computational technologies, crystallography, or fragment-based design equip multitarget compound development with valuable tools. In this Perspective, we analyze the relevance of multiple ligands in drug discovery and the versatile toolbox to design polypharmacology. We conclude that despite some characteristic challenges remaining unresolved, designed polypharmacology holds enormous potential to secure future therapeutic innovation.

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Crossref · 10.1021/acs.jmedchem.8b00760

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  1. Glen R. C., 2006, IDrugs, 9, 199

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Metadata

Authors
Proschak, E., Stark, H., & Merk, D.
Affiliations
  • Goethe University Frankfurt (DE)
  • Heinrich Heine University Düsseldorf (DE)
Corresponding author
Merk, Daniel
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2018-07-23
Volume
62
Issue
2
Pages
420-444
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.8b00760
OpenAlex
W2884740260
Cited by
498
References
251
Citations by year
2026: 51 · 2025: 56 · 2024: 74 · 2023: 60 · 2022: 86 · 2021: 64 · 2020: 67 · 2019: 39 · 2018: 1
FWCI
35.15
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • Publikationsdatenbank der Fraunhofer-Gesellschaft (Fraunhofer-Gesellschaft) (submittedVersion)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
Funders
  • Eidgen?ssische Technische Hochschule Z?rich (16-2 FEL-07)
  • Deutsche Forschungsgemeinschaft (SFB1039, PR1405/2-2, PR1405/4-1)
  • European Cooperation in Science and Technology (CA15135)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
  • Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
Keywords
polypharmacology, multi-target drug design, drug discovery, chemical probes, fragment-based design, crystallography, computer-aided drug design, complex diseases, drug synergy, side effect reduction
MeSH terms
Machine Learning, Animals, Chemistry, Pharmaceutical, Humans, Ligands, Structure-Activity Relationship, Drug Design, Crystallography, X-Ray, Models, Animal, Metabolic Networks and Pathways

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