Molecular docking/dynamics simulations, MEP analysis, and pharmacokinetics prediction of some withangulatin A derivatives as allosteric glutaminase C inhibitors in breast cancer

The current study aims to understand the binding mechanism and intermolecular interactions of the novel Withangulatin A derivatives towards the allosteric site of Glutaminase C (GAC) using in silico analysis. The molecular docking and dynamics simulation results revealed that compounds L5, L8, L13, and L18 show high affinity toward the allosteric pocket of the GAC (PDB:3UO9), as confirmed by the high negative score values and hydrogen bonds. We found that these compounds interact with the most important residues and suggest a similar binding mechanism to the native compound (BPTES) and the clinical trial drug (CB-839). The combination of molecular electrostatic potential (MEP) analysis and molecular docking/dynamics studies confirms that the favorable reactive sites of these compounds establish many hydrogen bonds with active site residues of the target. Finally, pharmacokinetics prediction showed that L8 and L13 present the best ADMET profile among the selected compounds, and they share similar properties with the clinical compound CB-839. The obtained results in this investigation demonstrate that these two Withangulatin A derivatives might be used for further development as new allosteric GAC inhibitors for treating TNBC. [Display omitted]