In Silico Rational Design of Novel 1,3,4-Oxadiazole Thioether Derivatives for the Discovery of Xanthomonas oryzae...

A series of newly designed 1,3,4-oxadiazole derivatives demonstrated highly effective inhibitors against Xanthomonas oryzae pv. oryzae (Xoo) and exhibited significant antiviral and anti-biofilm properties. To further explore the structure-activity relationships of these compounds and develop novel molecules with higher activity, this study systematically analyzed the relationship between the structure and activity of a series of 1,3,4-oxadiazole compounds using computational methods including 3D-QSAR, molecular docking, and molecular dynamics simulations. Based on a dataset containing 39 compounds, two reliable 3D-QSAR statistical models were established: CoMFA (q² = 0.729, SEE = 0.075, r² = 0.960, F = 103.183) and CoMSIA/ADH (q² = 0.805, SEE = 0.059, r² = 0.978, F = 157.574). A 3D contour plot analysis revealed key structural factors influencing molecular activity. Molecular docking studies explored the interaction mode between the small molecule and the target protein 3E5U, identifying important residues such as ARG300. Based on model predictions and results comparison, we designed eight new molecules with inhibitory activity superior to the template compound. Molecular dynamics simulations further confirmed the stability of the binding between new molecules and protein complex. Pharmacokinetic evaluation indicated that these new molecules have promising clinical application prospects.