Impact of structural biologists and the Protein Data Bank on small-molecule drug discovery and development

Abstract

The Protein Data Bank (PDB) is an international core data resource central to fundamental biology, biomedicine, bioenergy, and biotechnology/bioengineering. Now celebrating its 50th anniversary, the PDB houses >175,000 experimentally determined atomic structures of proteins, nucleic acids, and their complexes with one another and small molecules and drugs. The importance of three-dimensional (3D) biostructure information for research and education obtains from the intimate link between molecular form and function evident throughout biology. Among the most prolific consumers of PDB data are biomedical researchers, who rely on the open access resource as the authoritative source of well-validated, expertly curated biostructures. This review recounts how the PDB grew from just seven protein structures to contain more than 49,000 structures of human proteins that have proven critical for understanding their roles in human health and disease. It then describes how these structures are used in academe and industry to validate drug targets, assess target druggability, characterize how tool compounds and other small-molecules bind to drug targets, guide medicinal chemistry optimization of binding affinity and selectivity, and overcome challenges during preclinical drug development. Three case studies drawn from oncology exemplify how structural biologists and open access to PDB structures impacted recent regulatory approvals of antineoplastic drugs.

Keywords: FAIR principles; PDB50; Protein Data Bank; RCB Protein Data Bank; drug discovery and development; drug target validation; open-access biodata resource; protein structure; structural biology; structure-guided drug discovery.

Figure 1

Availability of the Protein Data Bank archive helps transform 3D structure data to knowledge, benefiting basic and applied research and education.

Figure 2

Bosutinib binding to Src and Abl.A, chemical structure of bosutinib. B, cocrystal structures of bosutinib (red) bound to the catalytic domains of Src (Left, green; PDB ID: 4mxo (106) and Abl) (Right, blue; PDB ID: 3ue4 (107)) non-receptor tyrosine kinases.

Figure 3

Hinge-binding inhibitors targeting two cyclin-dependent kinases.Left, CDK6 (green) bound to abemaciclib (red) (PDB ID: 5L2s (91)). Right, active site of CDK6 (PDB ID: 5L2s (91)) showing bound abemaciclib (red; PDB ID: 5l2s (91)), overlaid with palbociclib (green; PDB ID: 5L2i (91)) and ribociclib (yellow; PDB ID: 5L2t. (91)).

Figure 4

A, allosteric inhibitor enasidenib (red) targeting homodimeric IDH2 (yellow and blue monomers; PDB ID: 5i96 (96)).B, superposition of apo (green PDB ID: 5i95 (96)) and inhibited (yellow and blue monomers; PDB ID: 5i96 (96)) forms of IDH1 computed by overlaying the central domains (boxed in red). Arrows indicate the locations of the two active sites. The view in (B) is rotated ∼45° about the vertical relative to (A).