BET Bromodomain Targeting by NSAIDs: Structural, Biophysical, and Computational Insights

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.