Prof. Rod Hubbard

Rod Hubbard has been developing and using methods for analysis and exploitation of protein structure for over 40 years. His early work at York and Harvard in the 1980s was in developing some of the first methods in molecular graphics and modelling methods for proteins.  During the 1990s he helped build the Structural Biology Lab at the University of York and determined the structure of many proteins of therapeutic importance.  This was combined with studies of protein-ligand interactions and some of the first work in finding small fragments that bind to protein targets.  In 1997, he was a founding SAB member of the structure-based pharmaceutical company that became Vernalis. Since 2001, he has divided his time between Vernalis (establishing and applying structure and fragment-based methods for drug discovery) and York (developing and applying fragment-based methods to probe biological function).  More details on his York website.

Using fragments to answer questions in exploratory drug discovery
It is nearly 30 years since a team at Abbott first demonstrated fragment-based drug discovery and there will be many examples at this conference which illustrate how careful medicinal chemistry optimisation of fragment hits can lead to potent lead compounds.

In this presentation I will focus on another major application of fragments – aiding the initial stages of the drug discovery process. Many of the potential therapeutic targets being identified in modern drug discovery are novel with various challenges and questions – such as is there a “ligandable” but functionally relevant site for small molecules to bind?, which sites on the protein and mechanism of action is to be targeted?, is it possible to achieve selectivity? Various modalities of fragment screening can be used to ask these questions and, if successful, provide understanding of the chemical biology of the system as well as possible start points for evolving hit compounds potent enough to establish the platform for a drug discovery project.

Using examples from projects at Vernalis, I will start with a story that illustrates the main features of fragment-based discovery, before discussing exploratory work on various protein targets where different fragment screening approaches attempt to answer these questions.