Rational Design of (Oxadiazol-2-yl) Thiazolidin-4-one Derivatives for Parkinson’s Disease: Insights from MD Simulations and Quantum Studies

INTRODUCTION: Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Sirtuin 3 (SIRT3), a mitochondrial NAD⁺-dependent deacetylase, has emerged as a promising therapeutic target due to its vital role in mitochondrial homeostasis and resistance to oxidative stress. However, existing SIRT3 modulators suffer from poor selectivity, suboptimal CNS penetration, and limited binding affinity. This study aimed to design and evaluate novel oxadiazole-thiazolidin-4-one hybrid compounds as potential SIRT3 modulators with improved neuroprotective profiles. METHODS: A comprehensive computational workflow was carried out using the Schrödinger Suite 2025-1, including ADMET profiling, molecular docking, molecular dynamics (MD) simulations, Thermal MM/GBSA binding free energy estimation, and protein dynamics analyses (DCCM, PCA, FEL). Additionally, Density Functional Theory (DFT) and Fukui function analyses were conducted to elucidate electronic properties and reactive sites relevant to bioactivity. RESULTS: The designed hybrids exhibited higher SIRT3 binding affinities than known modulators, with binding free energies ranging from -8.9 to -4.88 kcal/mol compared to resveratrol (-7.14 kcal/mol). Among them, TZOX04 [3-(5-benzyl-1,3,4-oxadiazol-2-yl)-2-(2,3,4-trihydroxyphenyl)thiazolidin-4- one] demonstrated the strongest binding energy (-8.94 kcal/mol), favorable drug-likeness, and optimal CNS permeability (logBB = 0.42). DISCUSSION: Molecular dynamics confirmed the stability of the SIRT3-TZOX04 complex over 100 ns, while DFT and Fukui analyses identified key electron-rich regions contributing to reactivity and interaction potential. The oxadiazole-thiazolidinone hybridization approach provided a significant improvement in binding and pharmacokinetic behaviour over existing modulators. CONCLUSION: This work represents the first systematic investigation of oxadiazole-thiazolidin-4-one hybrids as SIRT3 modulators. TZOX04 emerged as a promising lead compound with enhanced binding affinity, stability, and pharmacokinetic characteristics for PD therapy. These findings warrant future synthetic and biochemical validation to confirm therapeutic efficacy.