Protein crystallography and drug discovery: recollections of knowledge exchange between academia and industry

Abstract

The development of structure-guided drug discovery is a story of knowledge exchange where new ideas originate from all parts of the research ecosystem. Dorothy Crowfoot Hodgkin obtained insulin from Boots Pure Drug Company in the 1930s and insulin crystallization was optimized in the company Novo in the 1950s, allowing the structure to be determined at Oxford University. The structure of renin was developed in academia, on this occasion in London, in response to a need to develop antihypertensives in pharma. The idea of a dimeric aspartic protease came from an international academic team and was discovered in HIV; it eventually led to new HIV antivirals being developed in industry. Structure-guided fragment-based discovery was developed in large pharma and biotechs, but has been exploited in academia for the development of new inhibitors targeting protein-protein interactions and also antimicrobials to combat mycobacterial infections such as tuberculosis. These observations provide a strong argument against the so-called 'linear model', where ideas flow only in one direction from academic institutions to industry. Structure-guided drug discovery is a story of applications of protein crystallography and knowledge exhange between academia and industry that has led to new drug approvals for cancer and other common medical conditions by the Food and Drug Administration in the USA, as well as hope for the treatment of rare genetic diseases and infectious diseases that are a particular challenge in the developing world.

Keywords: cancer; disease; fragment-based structure-guided drug discovery; protein crystallography; protein structure.

Figure 1

Rhombohedral insulin crystals used in the treatment of diabetes and in the determination of the structure of insulin.

Figure 2

The insulin hexamer defined by X-ray analysis by Adams et al. (1969 ▸). The hexamer has 32 symmetry and is viewed along the threefold axis, on which two zincs are found. 2-Zinc-insulin hexamers are found in insulin-storage granules in beta cells of the islets of Langerhans and are used in crystalline forms of insulin used to treat diabetes.

Figure 3

Designing renin inhibitors in the 1980s based on models of renin (Blundell et al., 1983 ▸). This was achieved using interactive graphics, maintaining the hydrogen bonds and filling the specificity pockets.

Figure 4

Schematic to illustrate the concept of drug discovery by exploring biological space encompassing genome information to identify new targets, followed by exploration of chemical space using screening libraries based on knowledge of the target protein structure. The target protein in the illustration is HIV-1 proteinase (PDB entry 3phv) and the drug is HIV-1 proteinase inhibitor (PDB entry 9hvp). The figure is reproduced with permission from Thomas et al. (2017 ▸).

Figure 5

Fragment-based drug discovery: fragment screening, validation and chemical optimization through iterative growth and/or linking.

Figure 6

Targeting the interaction between the tumour suppressor BRCA2 and the recombination enzyme RAD51. Protein engineering was used to create a monomeric form of RAD51 by humanizing a thermostable archaeal orthologue, RadA, known as MAYM RadA, and using this protein for fragment screening. View through the Phe pocket of crystal structures of validated fragments. Weighted 2mF _o − DF _c electron-density maps of the partially refined structures are calculated before inclusion of ligands. This figure was created by Dr Marko Hyvönen using material published in Scott et al. (2013 ▸).

Figure 7

Fragment binding (a) and retention of the initial conformation and interactions during fragment linking (b) to EthR. Ligands are in stick representation and the EthR ligand-binding channel surface is shown in blue. All atoms follow the CPK colouring scheme. Hydrogen bonds are represented by dashed lines. Reproduced with permission from Surade et al. (2014 ▸).