A target-based approach to drug design
MMV’s Project of the Year 2018 has been 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, working alongside Dr Paul Willis and Delphine Baud at MMV, as well as Sir Simon Campbell, of ESAC (MMV's Expert Scientific Advisory Commitee). 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.
Left to right: Prof. Kevin Read, Dr Beatriz Baragaña and Prof. Ian Gilbert
→ Go to the news story announcing the award.
→ Go to an interview with five members of the project team for more information on the target-based approach to drug design.