Design of novel isoxazole derivatives as tubulin inhibitors using computer-aided techniques: QSAR modeling, ADMETox, molecular docking, molecular dynamics, biological efficacy, and retrosynthesis.

In the current work, computational methods were used to investigate new isoxazole derivatives that could be used as tubulin inhibitors. The study aims to develop a reliable quantitative structure-activity relationship (QSAR) model, following the criteria set by Golbraikh, Tropsha, and Roy. As a result, seven candidate compounds were developed, all having higher activity than the well-established anticancer agent Cisplatin (Cisp). According to the ADMETox test, the candidates , , and can be toxic. As a result, we have chosen to focus our study on compounds , , and . Molecular docking analysis revealed that drug candidate exhibits the highest stability within the oxidized quinone reductase 2 (PDB ID: 4zvm), target receptor (ΔG() = ΔG(Pr3) = -10.4 < ΔG() = -10.0 < ΔG(Cisp) = -7.3 kcal/mol). This finding aligns with the activity predictions made by the QSAR model. Furthermore, molecular dynamics simulations of the Pr2-4zvm complex over 100 ns confirm the ligand's robust stability within the receptor's active site, supporting the results obtained from molecular docking and the QSAR model predictions. The CaverDock software was utilized to identify the tunnels likely to be followed by ligands moving from the active site to the receptor surface. This analysis also helped in determining the biological efficacy of the target compounds. The results indicated that the compound is more effective than the others. Finally, the computer-assisted retrosynthesis process of two high confidence sequences was used to synthesize drug candidates.