The enzyme dihydroorotate dehydrogenase (DHODH) is one the hottest malaria drug targets under investigation today. The University of Texas Southwestern’s project to discover and develop targeted inhibitors with the ability to hit this target and stop the parasite in its tracks was awarded MMV’s 2010 Project of the Year in recognition of its impressive progress to rapidly bring these inhibitors towards clinical testing. Dr Ian Bathurst speaks about the project.
1. There are a number of partners involved in this project, how did they each contribute?
Meg was the lead torch-bearer and was the one to apply to work with MMV on the project. Her group provided enzymology support for the team and she was also able to determine the co-crystal structure of DHODH bound to several different classes of DHODH inhibitors. This was a really crucial advance for the project as instead of performing the medicinal chemistry optimization blindly we had the structure to act as our guide. Other members of the team had a significant role to play: Prof. Pradip Rathod was involved from the outset providing chemistry and parasite biology expertise; Prof. Sue Charman provided pharmacokinetic and physicochemical expertise; Jose Miguel Coteron-Lopez from GSK helped with some of the chemistry; while Genzyme collaborated on developing models to assess the propensity to raise resistance against the compounds. We also had input from Dr Carl Craft, former Chief Scientific Officer at MMV who helped to ensure the select compounds were drugable – that is to say, well tolerated and effective from a treatment perspective. Both Dave Matthews and David Floyd also provided key advice to help optimize the compounds to make them more drug-like. Last, but certainly not least, we are very grateful to the National Institutes of Health (NIH), who provided much of the funding for the project.
2. With so many contributors, how did you go about coordinating the project?
The way I approach it is as a facilitator – my role is to ensure everyone has the resources to do their job. Part of that is to hold regular conference calls and project team meetings. This helps coordinate efforts and make sure that all the team members are aware of the latest results. Sharing new information as it arises is also key: If I hear of a scientist doing relevant work I inform the team. For example, if an experimental model is needed to meet a specific project objective, I find out who has it and try to access it to share with members of the team.