Glipizide inhibits the glycation of alpha-crystallin: A combined in vitro and in silico approach in retinopathy management.

In human eye, structural proteins, known as crystallins, play a crucial role in maintaining the eye's refractive index. These crystallins constitute majority of the total soluble proteins found in the eye lens. Among them, α-crystallins (α-CR) is one of the major components. Under hyperglycaemic conditions, crystallins become susceptible to glycation that ultimately leads to advanced glycation endproducts (AGEs) formation. Glipizide is a well-known oral medication used in controlling levels of blood sugar, this drug stimulates the insulin release from pancreas. However, this drug has not been thoroughly investigated for its impact on α-CR glycation. In this study, we explored glipizide's protective role against glucose-induced α-CR glycation. Remarkably, glipizide effectively inhibited the formation of early glycation products, ultimately reducing AGEs formation. Additionally, glipizide provides protection against modifications of free lysine residues and lowered the carbonyl content. To gain deeper insights into mechanism of inhibition, we turn to binding studies and bioinformatics. Glipizide formed stable complex with α-CR with values of Gibbs energy ranging from -5.848 to -6.695 kcal/mol. Molecular docking revealed the binding energy as -6.5 kcal/mol and lysine residues emerged as a prominent among the key interacting residues. Notably, glipizide appears to mask lysine residues, thereby contributing to the inhibition of α-CR glycation. Furthermore, analysis of molecular simulation data reinforces the stability of this complex. Consequently, the stable α-CR-glipizide complex may prevent glucose from binding to α-CR. Overall, glipizide holds promise as a preventive measure against glycation of eye lens proteins, potentially benefiting in diabetic retinopathy.