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Comparison to the (-)-Balanol

The binding mode of (-)-balanol and the new derivatives is basically the same, although there are some distinct differences. The phenol and pyridine share the canonical H-bond to the hinge region residue Val123. Additionally, the phenol can make a second H-bond to the carbonyl of Tyr122. The ben-zophenone in (-)-balanol has two hydroxyl groups on ring C and one hy-droxyl and one carboxylate on ring D. These highly hydrophilic substituents are involved in extensive H-bonds (see above). The derivatives have sub-stituents only on ring D, the hydroxyl group, a fluor substituent in the position of the carboxylate group and an additional methoxy group. The fluor substituent points in a similar direction as the carboxylate (towards Ser53), but is unable to make an H-bond. The hydroxyl substituent has hydrophilic contacts or H-bonds to Glu91 and Lys72 that are similar in all structures. The methoxy group extends deeper into another pocket, towards Phe187, Gln84 and His87, which is not occupied by the (-)-balanol. Asp184 of the conserved DFG motif that initiates the activation loop deserves special attention. It is probably the most flexible residue in the ATP pocket, with the greatest degree of ligand-induced motions: its sidechain points away from the pocket when it coordinates with the manganese atoms in the AMP-PNP structure (PDB-code 1CDK), or the hydroxyl group on the benzophenone ring (C) in the (-)-balanol complex, and also in the presence of ligands such as H-1152P, Y-27632, H89 and H7, but it points into the pocket with ligands such as H8 or HA-1077 and the azepane derivatives. In the latter case it forms an H-bond to the azepane nitrogen, except for the double amide 4, where the H-bond is made to the amide nitrogen of the linker. Thr183 and Leu173 seem also to be flexible, and their sidechain orientation varies. Thus the hydroxyl group of Thr183 makes H-bonds either to a conserved water molecule or to the inhibitor.

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