To rationalize the affinity and selectivity profiles, we analyzed poses from previous docking studies to a DYRK1a-derived homology model of DYRK2, which showed that compound 6i may adopt a binding mode that is significantly different from the experimentally established indirubin-kinase binding mode.
Put it in timekeeping mode(the mode that shows the time).
Although there are some differences in the details of the binding geometries, all show binding modes that suggest overlap with the site of myosin binding to actin and are likely to interfere with the position of tropomyosin in the inhibited form of the thin filament.
Further, they show new binding modes that may also apply to natural protein substrates of PKAc, which have not been revealed by previous crystallographic studies.
In addition, the analysis of individual residue contribution and protein ligand binding mode show that the three functional groups on R1, R2, and R3 of the compound 3a can mimic the spatial orientation of the side chains of Phe19, Trp23, and Leu26 of p53, respectively.
The binding mode analysis showed that Asn47 of CBX2 formed a hydrogen bond with the OH group of C-terminal cap of UNC3866, inducing the conformational changes of diethyllysine of UNC3866 that is obviously different from that in CBX7.
Docking study performed for 8a with ATP binding site of EGFR-TK showed the similar binding mode to that of AZD9291.
Compounds that adopted binding mode T2 show the R 2-pyridyl subunit forming a hydrogen bonding interaction with the side chain of Ser330, and the thiazolidinone carbonyl group forming a hydrogen bonding interaction with the side chain of Asn376.
They also show similarities in the binding mode with that of the natural caspase inhibitor XIAP (X-linked inhibitor of apoptosis).
Assuming that our measurements on two sets of distinct di- and tri-peptides reflect the stoichiometries in general, our new data add to our previous multiple binding mode model by showing that tri-peptides are transported using three protons, whereas di-peptides are transported using four or possibly even five protons per cycle.
