ALDH1A3 Inhibition by Prosopis farcta Phytochemicals: A Computational Exploration of a Potential Antidiabetic Mechanism.

BACKGROUND: Diabetes mellitus is a chronic condition caused by insufficient insulin secretion or impaired insulin action. Traditionally, pancreatic β-cell loss has been attributed to hyperglycemia-induced apoptosis. However, more recent evidence indicates that β-cells can also undergo dedifferentiation, a process in which they lose their specialized identity and revert to a precursor-like state. ALDH1A3 has been reported as a marker associated with dedifferentiated β-cells in diabetes, making it a potential molecular target for studies of β-cell identity and their redifferentiation. OBJECTIVES: This study aimed to evaluate the potential interactions between phytochemicals in Prosopis farcta root extract and ALDH1A3 using an in silico workflow that included molecular docking, molecular dynamics simulations, and Molecular Mechanics Generalized Born Surface Area (MM-GBSA) analysis. METHODS: This in silico study evaluated phytochemicals reported in the root extract of Prosopis farcta. The three-dimensional structures of the phytochemicals were downloaded from the PubChem database in SDF format. Molecular docking and molecular dynamics simulations were performed using PyRx and GROMACS, respectively. MM-GBSA analysis was performed using gmx_MMPBSA. RESULTS: Docking analysis suggested that several Prosopis farcta phytochemicals could interact with functionally relevant regions of ALDH1A3, including the retinal- and NAD-binding regions. Among the evaluated compounds, luteolin 7-O-glucoside and luteolin 3'-glucoside exhibited favorable docking scores and stable interaction profiles in subsequent MD and MM-GBSA analyses. These findings suggest that these compounds may form energetically favorable interactions with ALDH1A3. CONCLUSIONS: Among the evaluated Prosopis farcta phytochemicals, luteolin 7-O-glucoside and luteolin 3'-glucoside emerged as the most promising computational candidates for further ALDH1A3-focused studies. These findings provide an initial basis for investigating whether interaction with ALDH1A3 may represent a potential mechanism contributing to the reported antidiabetic effects of Prosopis farcta extract and its possible relevance to β-cell dysfunction in diabetes. However, experimental validation is essential to confirm ALDH1A3 inhibition, its effects on β-cell redifferentiation, and antidiabetic potential.