Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 May;25(5):837-850.
doi: 10.1016/j.drudis.2020.02.002. Epub 2020 Feb 14.

Impact of the Protein Data Bank on antineoplastic approvals

John D Westbrook  1 , Rose Soskind  2 , Brian P Hudson  1 , Stephen K Burley  3
Affiliations
Review

Impact of the Protein Data Bank on antineoplastic approvals

John D Westbrook et al. Drug Discov Today. 2020 May.

Abstract

Open access to 3D structure information from the Protein Data Bank (PDB) facilitated discovery and development of >90% of the 79 new antineoplastic agents (54 small molecules, 25 biologics) with known molecular targets approved by the FDA 2010-2018. Analyses of PDB holdings, the scientific literature and related documents for each drug-target combination revealed that the impact of public-domain 3D structure data was broad and substantial, ranging from understanding target biology (∼95% of all targets) to identifying a given target as probably druggable (∼95% of all targets) to structure-guided lead optimization (>70% of all small-molecule drugs). In addition to aggregate impact assessments, illustrative case studies are presented for three protein kinase inhibitors, an allosteric enzyme inhibitor and seven advanced-stage melanoma therapeutics.

PubMed Disclaimer

Conflict of interest statement

Conflicts of interest

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Hinge-binding inhibitors targeting two cyclin-dependent kinases. (a) CDK4 (purple) bound to cyclin-D1 (green) (PDB ID: 2w96). (b) CDK6 (blue) bound to multiple tumor suppressor (red) (PDB ID: 1bi7). (c) CDK6 (blue) bound to abemaciclib (yellow) (PDB ID: 5l2s). (d) Active site of CDK6 (PDB ID: 5l2s) showing bound abemaciclib (yellow; PDB ID: 5l2s), overlaid with palbociclib (red; PDB ID: 5l2i) and ribociclib (green; PDB ID: 5l2t).
Figure 2.
Figure 2.
Allosteric inhibitor enasidenib (yellow) targeting homodimeric IDH2 (green and blue) (PDB ID: 5i96).
Figure 3.
Figure 3.
Hinge-binding inhibitors targeting mutant BRAF. (a) V600E BRAF kinase (blue) bound to vemurafenib (yellow) (PDB ID: 3og7). (b) Active site of V600E BRAF kinase (PDB ID: 3og7) showing vemurafenib (yellow; PDB ID: 3og7) overlaid with dabrafenib (red; PDB ID: 4xv2).
Figure 4.
Figure 4.
Immune checkpoint blockade. (a) PD-1(red) bound to PD-L1 (blue) (PDB ID: 3bik). (b) PD-1 (red) bound to PD-L2 (light blue) (PDB ID: 3bp5). (c) PD-1 (red) recognition by pembrolizumab Fab (green) (PDB ID: 5ggs). (d) PD-1 (red) recognition by nivolumab Fab (green) (PDB ID: 5ggr).
See this image and copyright information in PMC

References

    1. Blundell TL (2017) Protein crystallography and drug discovery: recollections of knowledge exchange between academia and industry. IUCrJ 4, 308–321 - PMC - PubMed
    1. Klebe G, ed. (2013) Drug design: methodology, concepts, and mode-of-action, Berlin: Springer
    1. Burley SK et al. (2018) RCSB Protein Data Bank: sustaining a living digital data resource that enables breakthroughs in scientific research and biomedical education. Protein Sci 27, 316–330 - PMC - PubMed
    1. Brown KK et al. (2018) Approaches to target tractability assessment – a practical perspective. MedChemComm 9, 606–613 - PMC - PubMed
    1. Stoll F et al. (2011) Utility of protein structures in overcoming ADMET-related issues of drug-like compounds. Drug Discov. Today 16, 530–538 - PubMed

Publication types

Substances

LinkOut - more resources