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.