Dundee’s drug discovery unit took a target-based approach to drug design
Today, MMV’s Project of the Year 2018 was officially awarded to a discovery team led by Prof. Ian Gilbert, Prof. Kevin Read and Dr Beatriz Baragaña at the Drug Discovery Unit (DDU), University of Dundee, UK at a meeting of MMV’s Expert Scientific Advisory Committee (ESAC) held in Madrid. Working alongside Dr Paul Willis and Delphine Baud at MMV, as well as Sir Simon Campbell, of ESAC, the project team identified an exciting new compound series, active against a novel biological target – Plasmodium falciparum’s enzyme lysyl-tRNA synthetase (PfKRS1).
In the early phases of malaria drug discovery, scientists use validated assays to perform two types of screening – phenotypic or target-based. In phenotypic screening, the aim is simply to identify compound series that kill the parasite, even if the exact mechanism of action is unknown. Over the last decade, MMV has identified the majority of its compounds this way.
A more focused approach, however, is target-based screening, which aims to identify compound series that can inhibit specific biological processes or molecules that are known to be effective treatment targets. This approach, which has proved successful in many therapy areas, brings together complementary methodologies (including structural biology, computational chemistry, molecular biology and biochemistry). It also builds on existing knowledge, where available – such as the structure of a binding site – to inform and expedite drug design.
The initial challenge with the target-based approach, however, is identifying a good drug target. At present, there are relatively few validated targets in the malaria parasite. The discovery and validation of PfKRS1 as a novel biological target is therefore an important and exciting development.
Professor Gilbert said, “This is an exciting project, using information about the structure of the enzyme and computational chemistry to design potential new drugs. Whilst there is still a long way to go and many hurdles to overcome, the team has made great progress over the last year.”
“The Dundee team was awarded MMV Project of the Year 2018 as their work with MMV really represents a step forward from business-as-usual drug discovery,” said Dr Timothy Wells, MMV’s Chief Scientific Officer. “Having a greater understanding of the structure of the drug target has been like shining a bright light on the work to optimise the drug series – it means we can be really precise as we improve the selectivity and potency of the compounds.”
Some of the background to this work has recently been published in the Proceedings of the National Academy of Sciences (doi: 10.1073/pnas.1814685116).