uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
How Beyond Rule of 5 Drugs and Clinical Candidates Bind to Their Targets.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
2016 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 6, 2312-2327 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2016. Vol. 59, no 6, 2312-2327 p.
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-287442DOI: 10.1021/acs.jmedchem.5b01286ISI: 000372946500003PubMedID: 26457449OAI: oai:DiVA.org:uu-287442DiVA: diva2:922736
Available from: 2016-04-25 Created: 2016-04-25 Last updated: 2016-05-18Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Dobritzsch, DoreenKihlberg, Jan
By organisation
Department of Chemistry - BMC
In the same journal
Journal of Medicinal Chemistry
Medicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 184 hits
ReferencesLink to record
Permanent link

Direct link