Orotomides, a new class of DHODH targeting anti-fungal drugs

F2G specializes in finding new anti-infectives, especially systemic antifungal therapeutics. Cresset Discovery worked with F2G over a number of years on Olorofim, which has recently entered Phase II clinical development. Olorofim represents a new class of antifungal agents known as the Orotomides which selectively inhibit the fungal mitochondrial enzyme DHODH.

Cresset scientists worked on F2G’s SAR for cellular and in-vitro data to provide some rationalization for the activity/selectivity against close and distant DHODH enzymes. Ligand and protein molecular modeling on F2G’S active series provided a compelling rationale for the ‘likely’ binding interactions involved in Aspergillus strains, which were consistent with the experimental site directed mutagenesis.

Cresset Discovery's collaboration with F2G extended across multiple projects and over a number of years, culminating in involvement in a PNAS publication in 2016 ¹.

Left: Homology model of A. fumigatus DHODH with the estimated binding mode of Olorofim. The A. fumigatus DHODH was modeled based on the human structure (PDB ID code 1D3G). Right: Brequinar bound to human DHODH (PDB ID code 1D3G).

1. PNAS, 2016 113 (45) 12809-12814 (F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase)