In Silico Engineering of Proline Amide Derivatives as Potential Inhibitors of Human BET Bromodomains

ABSTRACT

In the pursuit of novel BET protein inhibitors, a series of proline‐derived amides were synthesized via coupling reactions with aryl and alkyl substituents, affording yields ranging from 40% to 73%. The molecular structures were optimized using density functional theory (DFT), followed by an in‐depth computational evaluation. Molecular docking and molecular dynamics simulations were employed to investigate protein–ligand interactions and stability, while ADME and toxicity assessments (Protox) provided insights into drug‐likeness and safety. Among the tested compounds, five complexes demonstrated favorable binding profiles and emerged as potential BET inhibitor candidates, particularly targeting BRD2 , BRD3 , and BRDT . These findings highlight the potential of proline amide derivatives as lead scaffolds for the development of BET ‐targeted therapeutics.