Theoretical exploration of the binding selectivity of inhibitors to BRD7 and BRD9 with multiple short molecular dynamics simulations

Wang, Lifei; Wang, Yan; Zhao, Juan; Yu, Y X; Kang, Ning; Yang, Zhiyong

doi:10.1039/d2ra02637f

Cited by 9 publications

(8 citation statements)

References 99 publications

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“…BRD7/9 inhibitors have a pharmacophore that mimics an acetylated Lys and forms a hydrogen bond with the highly conserved Asn in the BD binding pocket (BRD7 Asn211 , BRD9 Asn216 . 27,43 More recent crystal structures of BRD9 BD and BRD7 BD indicate that the aromatic systems in BI7273, BI9564, I-BRD9, TP-472, and Bromosporine form π-π interactions with BRD7 Tyr217 or BRD9 Tyr222 In these structures, the hydrophobic pocket in BRD7 (Figure 2, left) is also available in BRD9, indicating that these compounds achieve selectivity through an alternate mechanism than originally proposed (Figures 5A, 5B, and S4). 27,43 Using pregenerated receptor grids, we docked 1-78 and 2-77 into the structures of BRD7 and BRD9 BDs crystallized with BI7273 (Figure 5A, PDB: 6V1E; and Figure 5B, PDB: 5EU1, respectively).…”

Section: Resultsmentioning

confidence: 80%

“…27,43 More recent crystal structures of BRD9 BD and BRD7 BD indicate that the aromatic systems in BI7273, BI9564, I-BRD9, TP-472, and Bromosporine form π-π interactions with BRD7 Tyr217 or BRD9 Tyr222 In these structures, the hydrophobic pocket in BRD7 (Figure 2, left) is also available in BRD9, indicating that these compounds achieve selectivity through an alternate mechanism than originally proposed (Figures 5A, 5B, and S4). 27,43 Using pregenerated receptor grids, we docked 1-78 and 2-77 into the structures of BRD7 and BRD9 BDs crystallized with BI7273 (Figure 5A, PDB: 6V1E; and Figure 5B, PDB: 5EU1, respectively). 2-77 interacts with BRD7 BD to maintain the same key interactions found between BI7273 and BRD7 Asn211 and BRD7 Tyr217 (Figure 5C).…”

Section: Resultsmentioning

confidence: 80%

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Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Ordonez

Maschinot²,

Wang

et al. 2023

Preprint

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Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromo-domain-containing protein 7 (BRD7) has been implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a se-ries of ligands designed to occupy this binding region and identified two BRD7-selective inhibitors, 1-78 and 2-77, that bind with nanomolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands oc-cupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.

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Section: Resultsmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 80%

Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Ordonez

Maschinot²,

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…BRD7/9 inhibitors have a pharmacophore that mimics an acetylated Lys and forms a hydrogen bond with the highly conserved Asn in the BD binding pocket (BRD7 Asn211 and BRD9 Asn216 ). , More recent crystal structures of BRD9 BD and BRD7 BD indicate that the aromatic systems in BI7273, BI9564, I-BRD9, TP-472, and bromosporine form π–π interactions with BRD7 Tyr217 or BRD9 Tyr222 . In these structures, the hydrophobic pocket in BRD7 (Figure , left) is also available in BRD9, indicating that these compounds achieve selectivity through an alternate mechanism than originally proposed (Figure A,B and Figure S5).…”

Section: Resultsmentioning

confidence: 99%

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer

Ordonez-Rubiano,

Maschinot,

Wang

et al. 2023

J. Med. Chem.

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Bromodomain-containing proteins are readers of acetylated lysine and play important roles in cancer. Bromodomain-containing protein 7 (BRD7) is implicated in multiple malignancies; however, there are no selective chemical probes to study its function in disease. Using crystal structures of BRD7 and BRD9 bromodomains (BDs) bound to BRD9-selective ligands, we identified a binding pocket exclusive to BRD7. We synthesized a series of ligands designed to occupy this binding region and identified two inhibitors with increased selectivity toward BRD7, 1-78 and 2-77, which bind with submicromolar affinity to the BRD7 BD. Our binding mode analyses indicate that these ligands occupy a uniquely accessible binding cleft in BRD7 and maintain key interactions with the asparagine and tyrosine residues critical for acetylated lysine binding. Finally, we validated the utility and selectivity of the compounds in cell-based models of prostate cancer.

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“…We speculate that differences in conformational dynamics between BD paralogues might play an important role in determining binding affinities. Indeed, a previous study has shown that differences in binding-loop dynamics between the BDs of BRD7 and BRD9 influences interactions with small molecules (Wang et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Discovery and characterization of cyclic peptides selective for theC-terminal bromodomains of BET family proteins

Franck

Patel

Walport

et al. 2022

Preprint

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DNA encoded cyclic peptide libraries offer unique opportunities to discover high-potency, high-specificity ligands directed against a target protein. We set out to explore the potential for such libraries to provide ligands that can distinguish between bromodomains from the closely related paralogues of the Bromodomain and ExtraTerminal domain (BET) family of epigenetic regulators. Analysis of peptides isolated from a screen against the C-terminal bromodomain of family member BRD2, together with new peptides discovered in previous screens against the corresponding domain from BRD3 and BRD4, reveals peptides with nanomolar and subnanomolar affinities. X-ray crystal structures of several of these bromodomain-peptide complexes reveal diverse structures and binding modes, which nevertheless display several conserved binding features. A subset of the peptides demonstrates significant paralogue-level specificity, though structural analysis does not reveal clear physicochemical explanations for this specificity. Our data demonstrate the power of cyclic peptides to discriminate between highly similar proteins with high potency and hint that differences in conformational dynamics between BET-family bromodomains might modulate binding affinities amongst family members for particular ligands.

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Theoretical exploration of the binding selectivity of inhibitors to BRD7 and BRD9 with multiple short molecular dynamics simulations

Abstract: Bromodomains (BRDs) are structurally conserved epigenetic reader modules observed in numerous chromatin- and transcription-associated proteins that have a capability to identify acetylated lysine residues.

Cited by 9 publications

References 99 publications

Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Rational design and development of selective BRD7 bromodomain inhibitors and their activity in prostate cancer

Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer

Discovery and characterization of cyclic peptides selective for theC-terminal bromodomains of BET family proteins

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