Thermal Stability of S-Nitrosothiols: Impact of Alkyl Chain Length and Branching on Thermal Stability and Molecular Docking with Thromboxane (A2) Receptor Binding

S-Nitrosothiols (RSNOs) are essential biomolecules involved in various physiological processes, due to their ability to thermally decompose and release nitric oxide (NO). This study investigates the relationship between the variation of the chemical structure of RSNOs and its thermal stability, as well as their binding with the thromboxane A2 (TP) receptor. A series of RSNOs with varying alkyl chain lengths and branching were synthesized and characterized. Thermal stability was evaluated using stepwise isothermal TGA under oxygen and nitrogen atmosphere. Results reveals a direct correlation between chain length and decomposition temperature with longer, straight alkyl chains exhibit higher thermal stability, while branching decreases stability. Isotope labelling studies confirmed the S?N bond cleavage as the initial step in decomposition. Molecular docking studies explored the binding interactions of RSNOs with the TP receptor. Results showed that the natural tripeptide GSNO exhibited a higher binding affinity, (? 8.76???0.03 kcal mol?1) attributed to its ionizable di-carboxylic acid and amine groups which form ionic and hydrogen bonds in the active site of TP receptor. Conversely, the dipeptide, SNAP(D)-Gly-O-n-Bu (? 7.69???0.05 kcal mol?1), and amino-acid, SNAP(D) (? 5.79???0.07 kcal mol?1) showed reduced affinities due to fewer polar interactions with amino acid residues at the binding site and limited hydrophobic stabilization. Remarkably, no significant correlation was observed between thermal stability and binding affinity (R2?=?0.32), indicating a distinct molecular determinants for these properties. These results highlights the needs for a balanced design approach to optimize RSNOs for both stability and receptor interaction.