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

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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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Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors
Takahashi, K., & Yamanaka, S. (2006) · Cell · doi:10.1016/j.cell.2006.07.024 · Cited by 26,673
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (1997) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(96)00423-1 · Cited by 11,484
Extended-Connectivity Fingerprints
Rogers, D. O. W., & Hahn, M. (2010) · Journal of Chemical Information and Modeling · doi:10.1021/ci100050t · Cited by 7,925
The new frontier of genome engineering with CRISPR-Cas9
Doudna, J. A., & Charpentier, E. (2014) · Science · doi:10.1126/science.1258096 · Cited by 7,062
Network pharmacology: the next paradigm in drug discovery
Hopkins, A. L. (2008) · Nature Chemical Biology · doi:10.1038/nchembio.118 · Cited by 4,622
Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Molina, D. M., Jafari, R., Ignatushchenko, M., Seki, T., Larsson, E. A., Dan, C., Sreekumar, L., Cao, Y., & Nordlund, P. (2013) · Science · doi:10.1126/science.1233606 · Cited by 2,261
LigandScout: 3-D Pharmacophores Derived from Protein-Bound Ligands and Their Use as Virtual Screening Filters
Wolber, G., & Langer, T. (2004) · Journal of Chemical Information and Modeling · doi:10.1021/ci049885e · Cited by 1,989
The ChEMBL bioactivity database: an update
Bento, A. P., Gaulton, A., Hersey, A., Bellis, L. J., Chambers, J. K., Davies, M., Krüger, F. A., Light, Y., Mak, L., McGlinchey, S., et al. (2013) · Nucleic Acids Research · doi:10.1093/nar/gkt1031 · Cited by 1,520
Lessons learned from the fate of AstraZeneca's drug pipeline: a five-dimensional framework
Cook, D., Brown, D., Alexander, R., March, R., Morgan, P., Satterthwaite, G., & Pangalos, M. N. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4309 · Cited by 1,344
Concepts and applications of molecular similarity
Johnson, M. A., & Maggiora, G. M. (1990) · Wiley eBooks · Cited by 1,301

Show all 251 references

Research works printed but not linked: 1

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

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Authors: Proschak, E., Stark, H., & Merk, D.
Affiliations: Goethe University Frankfurt (DE)
Heinrich Heine University Düsseldorf (DE)
Corresponding author: Merk, Daniel
ORCID: Proschak, Ewgenij
Stark, Holger
Merk, Daniel
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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Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

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