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Molecular Dynamic Simulations of Bromodomain and Extra-Terminal Protein 4 Bonded to Potent Inhibitors
Siao Chen1, Yi He1, Yajiao Geng1
1Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, China.
Abstract:
Bromodomain and extra-terminal domain (BET) subfamily is the most studied subfamily of bromodomain-containing proteins (BCPs) family which can modulate acetylation signal transduction and produce diverse physiological functions. Thus, the BET family can be treated as an alternative strategy for targeting androgen-receptor (AR)-driven cancers. In order to explore the effect of inhibitors binding to BRD4 (the most studied member of BET family), four 150 ns molecular dynamic simulations were performed (free BRD4, Cpd4-BRD4, Cpd9-BRD4 and Cpd19-BRD4). Docking studies showed that Cpd9 and Cpd19 were located at the active pocket, as well as Cpd4. Molecular dynamics (MD) simulations indicated that only Cpd19 binding to BRD4 can induce residue Trp81-Ala89 partly become α-helix during MD simulations. MM-GBSA calculations suggested that Cpd19 had the best binding effect with BRD4 followed by Cpd4 and Cpd9. Computational alanine scanning results indicated that mutations in Phe83 made the greatest effects in Cpd9-BRD4 and Cpd19-BRD4 complexes, showing that Phe83 may play crucial roles in Cpd9 and Cpd19 binding to BRD4. Our results can provide some useful clues for further BCPs family search.
Insights
Bromodomain and extra-terminal domain (BET) inhibitors show potential for treating androgen-receptor-driven cancers. Cpd19 demonstrated the strongest binding to BRD4, with Phe83 being crucial for inhibitor interactions.
Area of Science:
- Structural biology
- Computational chemistry
- Cancer therapeutics
Background:
- Bromodomain and extra-terminal domain (BET) proteins are key regulators of gene transcription.
- The BET family, particularly BRD4, is a validated target for androgen-receptor-driven cancers.
- Understanding inhibitor binding to BRD4 is crucial for developing novel cancer therapies.
Purpose of the Study:
- To investigate the binding interactions of small molecule inhibitors with BRD4.
- To evaluate the effects of inhibitor binding on BRD4 structure and dynamics.
- To identify key residues involved in inhibitor-BRD4 complex formation.
Main Methods:
- Molecular dynamics (MD) simulations of BRD4 with and without inhibitors (Cpd4, Cpd9, Cpd19).
- Molecular docking studies to assess inhibitor positioning within the BRD4 active site.
- MM-GBSA calculations for binding free energy estimation and computational alanine scanning.
Main Results:
- Cpd4, Cpd9, and Cpd19 were successfully docked into the BRD4 active pocket.
- Cpd19 binding induced a partial α-helix formation in the Trp81-Ala89 region.
- Cpd19 exhibited the highest binding affinity, followed by Cpd4 and Cpd9; Phe83 was critical for Cpd9 and Cpd19 binding.
Conclusions:
- Cpd19 is a promising BRD4 inhibitor with significant binding effects.
- The residue Phe83 plays a vital role in the interaction of BRD4 with Cpd9 and Cpd19.
- These findings offer valuable insights for the design of new bromodomain-containing protein inhibitors.
