Thermodynamic Optimisation and Structural Engineering of Lipoic Acid Derivatives for Enhanced Pain Relief and Diabetic Neuropathy Modulation

Background: Diabetic neuropathy is a difficult condition, and current treatments like lipoic acid work poorly because they do not bind well to their target receptors. Methods: We used thermodynamics-guided design to optimise lipoic acid for TrkA and p75NTR, improving pain relief and neuroprotection. LA-6SH8Ph was engineered for stronger hydrogen bonding and hydrophobic interactions and delivered via liposomes for >85% bioavailability. Results: LA-6SH8Ph binds TrkA 25 times stronger than native lipoic acid and stabilises interactions via enthalpy and entropy. In dorsal root ganglion cultures, it reduces Nav1.7 expression and neuronal hyperexcitability, while liposomal delivery enhances bioavailability and lowers oxidative stress. Off-target effects and toxicity are minimal. Conclusion: Thermodynamic optimisation produced LA-6SH8Ph with stronger receptor binding and better efficacy in diabetic neuropathy. Combining structure-based design, thermodynamic profiling and advanced delivery makes it a promising candidate for further testing in diabetic neuropathy and other nerve growth factor-related disorders.