The DOI matches its Crossref record; 26 of the 26 references it cites were found in a registry or an index.
Quantifying the chameleonic properties of macrocycles and other high-molecular-weight drugs
Open accessAbstract
Key to the pharmaceutical utility of certain macrocyclic drugs is a “chameleonic” ability to change their conformation to expose polar groups in aqueous solution, but bury them when traversing lipid membranes. Based on analysis of the structures of 20 macrocyclic compounds that are approved oral drugs, we propose that good solubility requires a topological polar surface area (TPSA, in Å2) of ≥0.2 × MW. Meanwhile, good passive membrane permeability requires a molecular (i.e. 3D) PSA in nonpolar environments of ≤140 Å2. We show that one or other of these limits is almost invariably violated for compounds with MW > 600 Da., suggesting that some degree of chameleonic behavior is required for most high MW oral drugs.
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Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(00)00129-0 · Cited by 18,139
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 11,385
Molecular properties that influence the oral bioavailability of drug candidates
Veber, D. F., Johnson, S. R., Cheng, H.-Y., Smith, B. R., Ward, K. W., & Kopple, K. D. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm020017n · Cited by 8,420
Amidon, G. L., Lennernäs, H., Shah, V. P., & Crison, J. R. (1995) · Pharmaceutical Research · doi:10.1023/a:1016212804288 · Cited by 5,430
An inhibitor of Bcl-2 family proteins induces regression of solid tumours
Oltersdorf, T., Elmore, S. W., Shoemaker, A. R., Armstrong, R. C., Augeri, D. J., Belli, B. A., Bruncko, M., Deckwerth, T. L., Dinges, J., Hajduk, P. J., et al. (2005) · Nature · doi:10.1038/nature03579 · Cited by 3,416
Ertl, P., Rohde, B., & Selzer, P. (2000) · Journal of Medicinal Chemistry · doi:10.1021/jm000942e · Cited by 3,084
ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor
Tse, C., Shoemaker, A. R., Adickes, J., Anderson, M. G., Chen, J., Jin, S., Johnson, E. F., Marsh, K. C., Mitten, M. J., Nimmer, P., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5836 · Cited by 1,992
The exploration of macrocycles for drug discovery — an underexploited structural class
Driggers, E. M., Hale, S. P., Lee, J., & Terrett, N. K. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2590 · Cited by 1,370
Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates
Doak, B. C., Over, B., Giordanetto, F., & Kihlberg, J. (2014) · Chemistry & Biology · doi:10.1016/j.chembiol.2014.08.013 · Cited by 835
The impact of natural products upon modern drug discovery
Ganesan, A. (2008) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2008.03.016 · Cited by 646
Cited by
Orally Absorbed Cyclic Peptides
Nielsen, D. S., Shepherd, N. E., Xu, W., Lucke, A. J., Stoermer, M. J., & Fairlie, D. P. (2017) · Chemical Reviews · doi:10.1021/acs.chemrev.6b00838 · Cited by 445
How Big Is Too Big for Cell Permeability?
Matsson, P., & Kihlberg, J. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00237 · Cited by 303
RNA Display Methods for the Discovery of Bioactive Macrocycles
Huang, Y., Wiedmann, M. M., & Suga, H. (2019) · Chemical Reviews · doi:10.1021/acs.chemrev.8b00430 · Cited by 298
Solution Conformations Shed Light on PROTAC Cell Permeability
Atilaw, Y., Poongavanam, V., Svensson Nilsson, C., Nguyen, D., Giese, A., Meibom, D., Erdelyi, M., & Kihlberg, J. (2021) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.0c00556 · Cited by 208
GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf
Zhang, Z., Gao, R., Hu, Q., Peacock, H., Peacock, D. M., Dai, S., Shokat, K. M., & Suga, H. (2020) · ACS Central Science · doi:10.1021/acscentsci.0c00514 · Cited by 124
Metadata
- Authors
- Whitty, A., Zhong, M., Viarengo, L., Beglov, D., Hall, D. R., & Vajda, S.
- Venue
- Drug Discovery Today
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 21
- Issue
- 5
- Pages
- 712-717
- ISSN
- 1359-6446 (ISSN-L)
- OpenAlex
- W2279263454
- Cited by
- 285
- References
- 26
- FWCI
- 11.68
- Type
- journal article
- Language
- en
- Open access
- green
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