Fig. 7: YakA as a druggable target in A. fumigatus.

A An Alphafold2 model of the YakA protein docked to a library of small molecules using blind docking. Druggable pockets P1–P3 are shown as surface renders. The biggest pocket, P1, binds the largest number of fragments (778/1000), and is at the active site of the kinase. The druggability score from PockDrug for P1 is 0.81. Two smaller pockets, P2 and P3, are found on the C-lobe of the YakA. Druggability scores for P2 and P3 are 0.73 and 0.64 respectively. Pocket P1 is shown in further detail in complex with the 1-ECBC molecule. Charged residues in the pocket are indicated. The ∆G of 1-ECBC at the top scoring binding position is −7.7 kcal/mol. B Microscopic evaluation of YakA-GFP upon iron limitation and addition of 1-ECBC. Hyphae were followed for 1 h upon 1-ECBC addition. ECBC prevents localisation of YakA to the septal pore, but does not induce removal once it is in place. Scale bar = 10 µm. C Checkerboard assay (n = 3) for 1-ECBC and voriconazole to assess synergism of these drugs to inhibit growth of A. fumigatus MFIG001. The FICI (top-left) was calculated and shown synergism (<0.5).