Therapeutic protein degradation by design?
The old problem and the new paradigm Classical small molecule drug paradigms generally involve intervention at a ligand protein binding ...
Last month F2G published a paper in PNAS  describing F901318, the leading representative of a novel class of antifungal drug. Dr Martin Slater, Director of Cresset Discovery Services, is a co-author on the paper. He describes how modeling work carried out by Cresset Discovery Services was critical to predicting the binding mode of the inhibitor and important interacting amino acid residues. F901318 is currently in clinical development for the treatment of invasive aspergillosis.
There is an important medical need for new antifungal agents with novel mechanisms of action to treat the increasing number of patients with life-threatening systemic fungal disease and to overcome the growing problem of resistance to current therapies.
F2G are a UK-based antifungal drug discovery and development company who have identified F901318 as a leading representative of the orotomides, a novel class of antifungal drug. Their identification of dihydroorotate dehydrogenase (DHODH) as the mechanism by which F901318 inhibits and kills Aspergillus fumigatus has been a major breakthrough differentiating F901318 from other systemic antifungal agents.
F2G had a large amount of proprietary cellular activity data developed over time against their antifungal screening platform. After an initial hit finding campaign significant progress had been made using classical medicinal chemistry approaches.
F2G were keen to inform and assist the development process by gaining a molecular level understanding of the target protein ligand system. They approached Cresset Discovery Services for help in elucidating the molecular interaction of the target protein-ligand system.
Cresset’s unique approach of defining the electrostatics around the active chemotype made it possible to identify the precise nature of the various sites on the active molecules. In conjunction with sequence analysis across the wider DHODH family, Cresset scientists were able to match these subtle ligand features to the patterns of residues that were likely to be key.
Subsequent homology and ligand protein interaction modeling of Aspergillus fumigatus DHODH using the XED force field identified a predicted binding mode of the inhibitor and important interacting amino acid residues.
We combined a detailed ligand centric approach using Forge with protein modeling using a prototype of the new Cresset protein tool to arrive at a binding hypothesis consistent with the selectivity profile. The modeling process is fully reported in the paper .
Having made a binding hypothesis, a number of lab experiments were initiated by F2G to check the predictions e.g., using site directed mutagenesis.
Most satisfyingly, the lab results supported our predictions.
F901318 is currently in late Phase 1 clinical trials, offering hope that the antifungal armamentarium can be expanded to include a class of agent with a mechanism of action distinct from currently marketed antifungals.
Cresset’s consulting work with F2G provided valuable insight into the predicted interaction pattern of the main chemical series with the Aspergillus DHODH target protein. As with many research projects, any level of understanding achieved is often a prelude to even deeper questions, and there are many remaining to be answered for this unique system. Cresset continues to work closely with F2G, providing software and services to support them in their ongoing projects.
Dr Martin Slater
Director, Cresset Discovery Services