How Big Is Too Big for Cell Permeability?
Open accessAbstract
Understanding how to design cell permeable ligands for intracellular targets that have difficult binding sites, such as protein-protein interactions, would open vast opportunities for drug discovery. Interestingly, libraries of cyclic peptides displayed a steep drop-off in membrane permeability at molecular weights above 1000 Da and it appears likely that this cutoff constitutes an upper size limit also for more druglike compounds. However, chemical space from 500 to 1000 Da remains virtually unexplored and represents a vast opportunity for those prepared to venture into new territories of drug discovery.
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In drug development, 500 Da is often quoted as the maximum molecular weight parameter, but molecules with higher molecular weights can be absorbed, and the limits of oral bioavailability appear to extend to about MW ≤ 1000 Da.
“In the development of new drugs, 500 Da is often quoted as the maximum molecular weight parameter. However, it has been observed that molecules with higher molecular weights are also capable of being absorbed, and the limits of oral bioavailability appear to extend to about MW ≤ 1000 Da [70,71,72].”
From The EU’s Per- and Polyfluoroalkyl Substances (PFAS) Ban: A Case of Policy over Science (2023) · cites this paper as [72]
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- Authors
- Matsson, P., & Kihlberg, J.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Kihlberg, Jan
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-02-24
- Volume
- 60
- Issue
- 5
- Pages
- 1662-1664
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2590560529
- Cited by
- 303
- References
- 13
- Citations by year
- 2026: 44 · 2025: 37 · 2024: 40 · 2023: 48 · 2022: 44 · 2021: 39 · 2020: 22 · 2019: 8 · 2018: 13 · 2017: 8
- FWCI
- 10.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- membrane permeability, molecular weight, cyclic peptides, protein-protein interaction, drug-like molecules, chemical space
- MeSH terms
- Cell Membrane Permeability, Humans, Molecular Weight
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