Design of novel drug candidates inhibiting coxsackie virus B3 (CVB3) using computer-aided methods: QSAR modeling, molecular docking, molecular dynamics, biological efficacy, retrosynthesis and quantum chemical calculations

Background Coxsackie B3 virus (CVB3) poses a significant public health challenge due to the severity of its associated clinical disorders, driving an urgent need for novel therapeutic agents. Building upon previous research that identified potent isoxazole-based antiviral derivatives, two promising candidate compounds (P3 and P4) were previously identified through computational screening. Objective This study aims to propose a viable synthetic pathway for candidate compound P3 via retrosynthetic analysis, validate its binding kinetics through ligand-release channel dynamics, and elucidate the reaction mechanisms governing its synthesis. Methods Retrosynthetic analysis was conducted to establish a synthetic route for compound P3. The potential mechanism of the key 1,3-dipolar cycloaddition reaction was investigated theoretically. To examine the exit pathways and kinetic behavior of the ligands from the receptor active site to the surface, unbinding release simulations were performed using CaverDock software. Results Retrosynthetic design successfully established a plausible synthetic route toward compound P3, with mechanistic predictions confirming that its formation via 1,3-dipolar cycloaddition is thermodynamically controlled. CaverDock channel analysis identified the primary migration tunnels utilized by the ligands, demonstrating that compound P3 exhibits superior unbinding kinetics and release profiles compared to other derivatives. Conclusions These findings corroborate prior QSAR and molecular docking predictions regarding the high efficacy of compound P3. By providing both a synthetic roadmap and vital insights into ligand–receptor interaction dynamics, this work offers a reliable benchmark for the rational design and synthesis of novel CVB3 antiviral therapeutics. However, further experimental validation is required to confirm the in vitro and in vivo efficacy and safety profile of these proposed candidates.