Currently, few ligands are known to displace these structural waters, the presence
of which decreases druggability of some bromodomains [1]. However, computational analysis of the structured water network suggests that differential stability of
structured waters could be exploited for developing selective inhibitors [31].
For example, structured waters were computationally shown to be more weakly
held within the first bromodomains of BRD4 and BRDT relative to the second
bromodomain within the same proteins and highly homologous bromodomains
within BRD2 and BRD3. In support of this difference in stability, Divakaran et al.
showed a 1,4,5 trisubstituted imidazole, V, could indeed displace structured waters
Fig. 3 (a) Small-molecule inhibitors 6 [27], PFI-3 [28], 5 [29], and V [30] that perturb the
structural waters in the Kac binding site. (b) Crystal structure of inhibitor V with BRD4 BD1
showing the key binding interactions and displacement of two structured waters. Adapted with
permission from Divakaran et al. [30]. Copyright (2018) American Chemical Society
294
W. C. K. Pomerantz et al.
of which decreases druggability of some bromodomains [1]. However, computational analysis of the structured water network suggests that differential stability of
structured waters could be exploited for developing selective inhibitors [31].
For example, structured waters were computationally shown to be more weakly
held within the first bromodomains of BRD4 and BRDT relative to the second
bromodomain within the same proteins and highly homologous bromodomains
within BRD2 and BRD3. In support of this difference in stability, Divakaran et al.
showed a 1,4,5 trisubstituted imidazole, V, could indeed displace structured waters
Fig. 3 (a) Small-molecule inhibitors 6 [27], PFI-3 [28], 5 [29], and V [30] that perturb the
structural waters in the Kac binding site. (b) Crystal structure of inhibitor V with BRD4 BD1
showing the key binding interactions and displacement of two structured waters. Adapted with
permission from Divakaran et al. [30]. Copyright (2018) American Chemical Society
294
W. C. K. Pomerantz et al.