Professor Roderick E Hubbard

01904 328267

Structure-based drug discovery


My research interests are in using information about protein structures to design new medicines.  I divide my time between academic research within YSBL at York and applied research at the pharmaceutical company, Vernalis.

At Vernalis, we use the methods of structure-based drug discovery to discover new compounds which can be taken forward in clinical trials to treat various diseases and conditions, including cancer. 

At York we develop and apply these methods to explore the details of mechanism that underpin aspects of the kinetics and thermodynamics of binding of ligands to proteins. 

Current research includes:

  • Development of molecular modelling methods
    • The program rDock
    • Prediction of binding of small ligands to proteins
  • Fragment based discovery
    • New ideas in fragment library design
    • Application to carbohydrate processing proteins


Over the past thirty years, the York group has determined the structures of a large number of therapeutically important proteins. Examples include early protein engineering on modified insulins and humanised antibodies as well as important drug targets such as kinases, proteases and the estrogen receptor. These structures have increased our understanding of the mechanism of action and biological function of the proteins. In addition, the structures provide ideas on how to change the activity of the proteins. These ideas have developed into a range of structure-based methods that identify and help design new compounds that can bind to the proteins and change the way the proteins behave – useful either as starting points for drugs or as molecules to probe the biological function of the protein. The methods used include protein crystallography, high field NMR spectroscopy, surface plasmon resonance (SPR), fragment-based screening, computational docking, virtual screening and molecular modelling and design. The development and application of these methods is the major focus of our current research. The methods are also being applied to protein structures being determined in the Structural Biology Laboratory that are potential therapeutic targets in malaria, TB or bacterial infection.

Fragment-based discovery

Stucture of fragments bound to an active site

It is extremely difficult to design or discover a small molecule compound that binds strongly and selectively to a particular protein target. Just small changes in a compound can have big effects on binding making it very unlikely you can find effective molecules by random synthesis. Fragment-based methods work by identifying very small fragments that bind weakly to different parts of an active site. Determination of the crystal structures of these fragments bound to the protein can then be used to design composite molecules that will bind strongly. We have established an 800 member fragment library and use NMR and other biophysical methods to identify which fragments bind. The crystal structures of the fragments bound to the protein (as in the figure) are then used to discover or design larger compounds which bind to the protein with greater affinity. Projects in the laboratory include the further design and development of the fragment library, analysis of fragment binding modes across multiple proteins and investigating whether fragment based methods can help design compounds that bind to specific multiple protein targets.


Virtual screening

In virtual screening, relatively simple computational chemistry calculations are used to assess each compound from a large database of accessible molecules for its ability to bind to the active site. This rather crude screening identifies a subset of the compounds for further analysis or filtering. York is a partner in the development of the rDock program. Projects in the laboratory include investigating and optimising new features in the software to deal with solvent presence and position, investigation of new features to dock against a family of protein structures.

Schematic showing the virtual screening process.
Schematic showing the virtual screening process. Molecular docking calculations select which compounds from a large library can fit into the binding site of the protein to produce an initial list of virtual hits. Detailed molecular calculations are then used to decide which are the best hit compounds which are then selected for assay

Brief Career Summary

Apart from brief sabbaticals at Harvard, Rod Hubbard’s academic career has been at the University of York. During the 1980s he was a pioneer in the development of molecular graphics and modeling systems for studying protein structure (HYDRA and QUANTA) that still remain in use today. In the 1990s, he helped to build (and directed) the Structural Biology Laboratory at York as a major centre, with over 80 scientists studying the structure and function of proteins. For the past fifteen years, his personal research interests have focused on understanding the relationship between structure, mechanism and function in various protein systems (including proteases, nuclear receptors and kinases) and experimental and theoretical studies of protein-ligand interactions. Since 2001, he has spent some of his time at the company Vernalis, where he helped establish and apply structure-based drug discovery methods. He is a consultant to a number of pharmaceutical and technology companies, sits on a number of Research Council committees and boards and is chair of various external advisory groups for large scale academic projects.