Molecular docking, molecular dynamics simulation, and ADME profiling of novel benzoxazolone-based OGT inhibitors.

This study presents a computational exploration of a new series of benzoxazolone-amino acid conjugates appended with amino acids as potential inhibitors of O-GlcNAc transferase (OGT), an enzyme of growing therapeutic interest that currently has only one well-established inhibitor, OSMI-4. To address the scarcity of effective and selective OGT inhibitors, the research evaluates both acid (b-series) and ester (a-series) forms of the ligands, aiming to balance binding affinity with favourable pharmacokinetic properties. Acid counterparts generally demonstrated superior binding affinities, while ester analogues were introduced as prodrug candidates to enhance lipophilicity, membrane permeability, and bioavailability. Molecular docking and molecular dynamics (MD) simulations revealed the stability and interaction dynamics of the ligand-protein complexes. Compounds such as 1b, 8b, 9b, and 12b exhibited consistent hydrogen bonding and salt-bridge interactions, maintaining low root-mean-square deviation (RMSD) and fluctuation (RMSF) values-indicators of stable binding and minimal conformational shifts. In contrast, ester counterparts such as 9a and 12a displayed higher flexibility and fewer interactions, supporting their potential role as deliverable prodrugs rather than optimal binding agents. Pharmacokinetic profiling via SwissADME confirmed the drug-likeness of selected compounds, indicating favourable solubility, gastrointestinal absorption, and peripheral tissue targeting without blood-brain barrier penetration. All analogues complied with Lipinski's Rule of Five, affirming their potential as drug candidates. Furthermore, the study identifies key interaction hotspots within the OGT binding pocket and establishes a clear structure-activity relationship (SAR), laying the groundwork for pharmacophore modelling and rational drug design. Overall, this study gives significant insights into the dual optimization of efficacy and bioavailability through esterification strategies and offers a promising foundation for the development of next-generation OGT inhibitors based on benzoxazolone scaffolds.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00422-5.