Identifying promising inhibitors against epilepsy using virtual screening

Andy Smith†, Selma Sapmaz†

†Cresset, New Cambridge House, Bassingbourn Road, Litlington, Cambridgeshire, SG8 0SS, UK

Selene Therapeutics is pioneering a new therapeutic strategy against refractory epilepsy by developing small molecule inhibitors of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme that participates in several key cellular homeostatic processes.

Cresset Discovery is supporting Selene in the identification of central nervous system (CNS) penetrant DHODH inhibitor compounds using virtual screening. Virtual screening is a highly valuable computational method that enables the sampling of available chemical space from reliable suppliers, and is far more cost effective than wet high throughput screening (HTS).

Our work focused on the development of consistent ligand and structure-based models. This used known actives from the literature biased towards those which are predicted to be CNS penetrant. These models were used to identify key features of the ligands and hence protein regions which are key for activity, leading to the identification of two distinct binding modes - one of which relied on key water mediated interactions. 

Following presentation of these results to Selene, we concluded that it was preferable to build two distinct protein ligand templates as references for the virtual screening process (Figure 1).

Virtual screening was performed using Blaze™, which evaluated a library of 23 million commercially available compounds. The top results from this screen were filtered using appropriate drug-likeness filters, by removal of unwanted chemistries and predicted CNS penetration. Ligands passing these filters were then docked and ranked using the Lead Finder™ virtual screening scoring function and Cresset’s Electrostatic Complementarity™ score. The Cresset modelers then used their insight and experience in medicinal chemistry to propose a final selection of hits, which will be progressed to wet-lab screening.

Figure 1. The two protein ligand systems for use as template for virtual screening.