Binding Affinity and Mode of Binding of Related Balanol Derivatives

The other inhibitors 4, 5, and 8, with amide, ether, and vinyl linkers between the azepane and benzophenone moieties, were cocrystallized with PKA; the structures are superimposed with the ester 1 in Fig. 10. The crystal structures confirm that the bound conformations are unperturbed by the modifications. The conformation of the linker for which the torsional angle is an-

Fig. 10 Intermolecular bonding contacts in the complex between PKA and the balanol derivative. (Breitenlechner et al. 2004)

tiperiplanar in all molecules is trans with respect to azepane and benzophe-none. This conformation is required because it orients the azepane and the benzophenone towards their binding pockets. Therefore, molecules which are preorganized in aqueous solution in the trans conformations should have higher binding affinities [which is in agreement with the biochemical data (Table 3)]. And indeed, ester 1 and amide 4 show tight binding (IC50=5 nM or 4 nM, respectively), similar to (-)-balanol.

In the complex between the double amide 4 and PKA, there is a rearrangement of the sidechains of Asp184, Thr183 and Lys72 compared to the complex of the ester with PKA. The sidechain of Asp184 is rotated towards the amide linker and makes an H-bond to the amide nitrogen in addition to the H-bond to the azepane nitrogen; Lys72 forms an additional H-bond to the inhibitor hydroxyl group of the benzophenone, and Thr183 H-bonds to

Table 3 Properties of balanol derivatives


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