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BET Bromodomain Targeting by NSAIDs: Structural, Biophysical, and Computational Insights
Ashok Sridhar1, Nivetha Kandhasami1, Shruti Mathur1
1Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, India.
Abstract:
The bromodomain and extra-terminal (BET) family of proteins, which regulate chromatin function, is an established potential drug target for treating major diseases such as cancer and inflammatory conditions. There is significant research focused on developing new BET inhibitors with innovative molecular structures to target and modulate the epigenetic mechanisms underlying major diseases, including cancer. Herein, we present the crystal structures of the second bromodomain (BD2) of hBRD2 in complex with the FDA-approved drugs, mefenamic acid (ID8) and nimesulide (NIM), and that of the first bromodomain (BD1) of hBRD4 in complex with nimesulide (NIM). Quantitative binding assays by surface plasmon resonance (SPR) confirmed the substantial binding of these drug molecules to the hBRD2 and hBRD4 bromodomains. Using these crystal structures, a series of ID8 and NIM derivatives with improved affinity relative to the parent compounds was designed and evaluated using SeeSAR (BioSolveIT GmbH). Moreover, molecular dynamics simulations were performed on the selected derivatives of ID8 and NIM against these bromodomains and confirmed the stability of these derivatives' binding throughout the simulations. We propose that the derivatives of the aforementioned parent molecules may be potential inhibitors of the function of hBRD2 and hBRD4.
Insights
FDA-approved drugs mefenamic acid and nimesulide bind to bromodomain and extra-terminal (BET) proteins, key targets for cancer and inflammation. Derivatives showed improved binding, suggesting potential as novel BET inhibitors.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- The bromodomain and extra-terminal (BET) protein family regulates chromatin function and is a significant drug target for cancer and inflammatory diseases.
- Developing novel BET inhibitors with innovative molecular structures is crucial for targeting epigenetic mechanisms.
Purpose of the Study:
- To present crystal structures of hBRD2 and hBRD4 bromodomains complexed with FDA-approved drugs.
- To design and evaluate novel BET inhibitors based on existing drug scaffolds.
Main Methods:
- X-ray crystallography to determine protein-ligand complex structures.
- Surface plasmon resonance (SPR) for quantitative binding affinity assays.
- Computational methods including SeeSAR and molecular dynamics simulations for derivative design and stability analysis.
Main Results:
- Crystal structures of hBRD2 BD2 with mefenamic acid (ID8) and nimesulide (NIM).
- Crystal structure of hBRD4 BD1 with nimesulide (NIM).
- SPR confirmed substantial binding of ID8 and NIM to hBRD2 and hBRD4 bromodomains.
- Designed ID8 and NIM derivatives exhibited improved binding affinity.
- Molecular dynamics simulations confirmed the stability of derivative binding.
Conclusions:
- Mefenamic acid and nimesulide bind to hBRD2 and hBRD4 bromodomains.
- Designed derivatives of mefenamic acid and nimesulide show potential as effective inhibitors of hBRD2 and hBRD4.
- These findings contribute to the development of novel epigenetic therapies for cancer and inflammatory conditions.
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