The DOI matches its Crossref record; 17 of the 17 references it cites were found in a registry or an index.
How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets
Abstract
To improve discovery of drugs for difficult targets, the opportunities of chemical space beyond the rule of 5 (bRo5) were examined by retrospective analysis of a comprehensive set of structures for complexes between drugs and clinical candidates and their targets. The analysis illustrates the potential of compounds far beyond rule of 5 space to modulate novel and difficult target classes that have large, flat, and groove-shaped binding sites. However, ligand efficiencies are significantly reduced for flat- and groove-shape binding sites, suggesting that adjustments of how to use such metrics are required. Ligands bRo5 appear to benefit from an appropriate balance between rigidity and flexibility to bind with sufficient affinity to their targets, with macrocycles and nonmacrocycles being found to have similar flexibility. However, macrocycles were more disk- and spherelike, which may contribute to their superior binding to flat sites, while rigidification of nonmacrocycles lead to rodlike ligands that bind well to groove-shaped binding sites. These insights should contribute to altering perceptions of what targets are considered "druggable" and provide support for drug design in beyond rule of 5 space.
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Cites
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Impact of a five-dimensional framework on R&D productivity at AstraZeneca
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“Metrics such as the multiparametric scoring function AB-MPS have been developed to provide guidelines for development of compounds in beyond rule-of-5 space (a lower AB-MPS score indicates a higher likelihood of absorption) [112], and recent analyses of these compounds have provided new descriptors to predict absorpti…”
MethodHow 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
Self-citation
Metadata
- Authors
- Doak, B. C., Zheng, J., Dobritzsch, D., & Kihlberg, J.
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2015-10-30
- Volume
- 59
- Issue
- 6
- Pages
- 2312-2327
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2234248612
- Cited by
- 335
- References
- 17
- FWCI
- 27.28
- Type
- journal article
- Language
- en
- Open access
- closed
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