Small molecule docking to the coral IR homology model
Encouraged by the clear conservation of the functional insulin binding pockets between human IR and coral IR, we investigated the potential of targeting the coral IR through pharmacology using existing human IR ligands. To this end, we systematically docked small molecule ligands to the coral receptor analogous to the human controls described in the accompanying paper (Vizgaudis et al, 2021). We created a table of ligands (Table 2 ) that directly interact with IR. After having found out where those ligands bind in human IR, we here investigated if they also bind to those locations in coral IR. Table 2 shows overall very similar results for docking of the ligands to the coral homology model, as compared to the human results. However, overall the predicted affinities tend to be slightly smaller for the coral-ligand complexes than the human-ligand complexes. This is in line with the observation of the insulin-IR interfaces and may indicate that while not allstabilizing interactions in human will extend to the coral system, a large extent of them do. This is illustrated for the CP ligands inFigure 8 . There is almost complete conservation of the amino acids in contact with the CP inhibitors described in the accompanying paper (Vizgaudis et al, 2021). The only exception is Glu1074 which is a glycine (Gly1030) in human. Figure 9 shows the top ranked poses for the three TLK inhibitors and DDN. Although the entire protein was included in the grid box for docking, all four inhibitors docked to the main ligand binding pocket in between the two lobes of the kinase domain described in the accompanying paper, characteristic for orthosteric tyrosine kinase inhibitors.