AI & data driven development of chemical probes for high value Plasmodium targets

Selective binders or inhibitors, also known as small molecule probes, developed against proteins are important tools for increasing our understanding of biology. In particular, the association of malaria parasite proteins to selective small molecule probes will help to uncover the role of unexplored proteins in the different stages of parasites life cycle and reveal their potential as drug targets.

Specific small molecule probes will allow us to determine the parasite rate of kill associated to inhibition, the potential for resistance, the life stage specificity, and the opportunities for selectivity against the closest human orthologue. Collectively these results can be used to reveal novel aspects of malaria biology and triage the best novel targets for new drug discovery programs for malaria.

The project will integrate medicinal chemistry with state-of-the-art computational approaches developed at Dundee to discover and develop small molecule probes that target malaria. The Sophos Discovery Platform has been developed at Dundee to facilitate small molecule computational drug design. This combines Sophos Data for machine learning (ML) and DMPK property prediction, Sophos QM for quantum mechanics-based protein-ligand binding prediction and Sophos Create for molecular design using AI generative approaches and reinforcement learning. The Sophos platform will be used in combination with commercial software where required.

We will apply this AI & data driven design approach to high priority targets for the malaria community associated to unoptimized binders to generate high value specific small molecule probes. Our lab has developed protein expression, biochemical and biophysical assay and identified weak binders for several parasite proteins including lysyl-tRNA synthetase, seryl-tRNA synthetase, GCN5 and acetyl-CoA synthetase.

We will select a diverse set of binders and protein pairs to exemplify our approach. We expect that the combination of cutting-edge computational and chemical synthesis methodologies will considerably speed the delivery of specific probes for several of these parasite proteins. These probes will be made available to collaborators to interrogate malaria parasites biological process.