Conformation-Driven Dual-Stage Thermal Antiglycation by Pseudo C₂-Symmetric bis-Arylaldimine Scaffold

Chronic hyperglycemia brings forth a cascade of complications in diabetes through reactive dicarbonyls that drive mid-stage Amadori-glycoxidation and end-crosslinking glycation. This study imparts specifically on dual-stage inhibition of bovine serum albumin (BSA) glycation using a conformation-driven interactions at the molecular level. A combination of multi-spectroscopic, physico-biochemical, and computational studies display significant antiglycation activity (IC₅₀ 17.9 µM) in both BSA/fructose and BSA/methyl glyoxal (MGO) models by pseudo-C₂-symmetric vanillin bis-aldimine (VBA-1) as a privileged Schiff base scaffold. Conformational analysis accompanying with docking and molecular dynamic simulation suggests a probable transoid-cisoid equilibrium through which a unique rotameric s-trans conformation facilitates selective binding at IIA subdomain of BSA. This subsequently prevents glycation by modulating micro-environment and minimizing aggregation. Temperature-assisted glycation and time-resolved fluorescence demonstrate a dynamic mode of binding with favorable entropy. The study further explores to identify key residues, polar contacts, micro-environment, excited state analyses, and misfolding mechanisms. These findings emphasize bis-arylaldinine (BA) scaffold as a promising lead for therapeutic intervention in glycation-induced diabetic complications.