Browsing by Subject "halogen bond"

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    Computational Analysis on a Novel Set of 1,4,5 tri-Substituted Imidazole Based Bromodomain Inhibitors with Human BRD4
    (2020-05) Jones, Peter
    Bromodomain-Containing Protein 4 (BRD4) is a human transcriptional regulator and member of the N-Terminal Bromodomain and Extra Terminal Domain (BET) family of proteins. BRD4 binds to acetylated chromatin, preserving epigenetic modifications in the chromatin structure and activating the positive transcription elongation factor (p-TEFb) complex. This complex phosphorylates RNA polymerase II and promotes transcription of the immediate downstream genomic element. BRD4 shows promise as a target for anticancer therapies, with most research focusing on a class of drugs known as BET inhibitors. These drugs bind to the active site of BET family proteins, preventing BRD4 specifically from associating with chromatin. However, there is a lack of atomistic understanding regarding the binding of these drugs to BET family members. Many factors which influence the binding affinity of a series of 1,4,5 tri-substituted imidazole-based bromodomain inhibitors bound to the active site of BRD4 have yet to be characterized. Further, the effects of these inhibitors on the structural waters intrinsic to BRD4 remains unclear. Experimental work has suggested that the IC50 of this series of BET inhibitors could be explained in terms of a few specific interactions in the binding site. In this analysis, Free Energy Perturbations (FEP) are used to probe the relative free energy of binding for this set of differentially substituted BET inhibitors. Our working hypothesis is that the chlorine, bromine, and iodine substitutions participate in a halogen bond with the backbone oxygen of Met105 in BRD4, stabilizing the drug in the active site. Further, we propose that substitutions which cannot form this halogen bond, such as fluorine and other non-halogen substitutions, would have a higher free energy of binding. FEP analysis revealed that the chlorinated, brominated, and iodinated substitutions displayed a lower free energy of binding than the other substitutions, with evidence of a halogen bond between the drug and the backbone oxygen of Met105. It was also observed that this set of BET inhibitors displaces several highly coordinated solvent molecules in the active site of BRD4. By contrast, a simulation of BRD4 complexed with JQ1, another known BET inhibitor, does not displace these waters. These results support our hypothesis that a halogen bond is formed between the large halogen substitutions and the protein, increasing the binding affinity for substitutions that can participate in this type of interaction. This halogen bond can be exploited for improving this set inhibitors and designing novel compounds which bind more favorably to BRD4.