NVP-BKM120 BKM120 came to different conclusions as to whether residue T854 or T790 was involved.

and Hou NVP-BKM120 BKM120 et al. although interestingly the two studies NVP-BKM120 BKM120 signaling pathway Here, calculations indicate that both T854 and T790 residues make significant water mediated ligand interactions. Stamos et al. noted the T790 bridging water in the erlotinib EGFR crystal structure, but suggested it was not significant citing data reported by Rewcastle et al. in which only a minor effect on affinity was seen for related ligands where the H bond acceptor was substituted for carbon. However, examination of the original activities show 5000 fold loss between compounds that differ only by a nitrogen at the T790 acceptor position which suggests the water is in fact important. And, a recent docking study by Cavasotto et al.
notes that inclusion of this bridging water was necessary to correctly reproduce the binding pose of the EGFR inhibitor AG1478. In conjunction with their proposed steric clash mechanism, Kobayashi et al. also hypothesized that disruption of water mediated binding would be a factor in resistance. For the water mediated interactions at Q791, the H bonds primarily involve Apixaban the backbone carbonyl oxygen thus any alteration of sidechains at this site would be expected to be less detrimental, particularly since there is little direct van der Waals contact or favorable Coulombic interactions with the ligand at Q791. However, the simulation results strongly suggest that a mutation at position T854 would disrupt the quadrifurcated network and, in a manner analogous to T790, disrupt water mediated ligand binding.
This hypothesis is consistent with results recently reported by Bean et al. in which a novel T854A resistance mutation was identified from a patient with reduced affinity for erlotinib. A combination of mutations involving T790 and T854, if biologically viable, would likely lead to further disruption of the H bond network involving inhibitors and an increase in unfavorable fold resistance. While our current studies cannot rule out the recent hypothesis by Yun et al. that T790M resistance is caused primarily by increased affinity for ATP, based on the present simulations, it is reasonable to propose that disruption of water mediated H bond networks involving the inhibitors is a contributing factor.
Additionally, given the fact that our calculations yield quantitative energetic agreement with experiment, yet involve only inhibitors and EGFR, strongly suggests that differences in affinity for ATP are not the sole cause of experimentally observed drug resistance. Additional studies are needed to more fully address this issue. An examination of the network shown in Figure 12 indicates the possibility of designing alternative H bonding involving residues T854, T790, and Q791. EGFR inhibitors based on a 4,6 dianilinopyrimidine scaffold have been reported which are proposed to make direct H bonds with both M793 and T790. However, as expected, the T790M mutant showed resistance against a representative compound in the series presumably due to the loss of a direct H bond between the pyrimidine N3 and the OH at position 790. Wissner et al. has reported an inhibitor in which the bridging nitrogen atom was replaced by a cyano group and proposed to displace the site 1 water. However, the cyano compound was also proposed to make a direct H bond with T854 thus the recently reported T854A mutatio

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