Aldose reductase (AR) is an enzyme involved in the polyol pathway that catalyzes the reduction of glucose to sorbitol, leading to oxidative and osmotic stress within cells and contributing to many diseases, including diabetic nephropathy (DN), a leading cause of end-stage renal disease. Citrullus colocynthis is recognized as a feasible source of bioactive compounds for the management of various diseases; however, it remains underexplored for therapeutic compounds that can inhibit AR to mitigate DN. This study investigated the antidiabetic nephropathy properties of Citrullus colocynthis methanol extract (CCME) by targeting AR inhibition using in-silico and in-vitro methods. CCME was obtained by soaking 100 g of oven-dried pulverized fruit in 1000 mL of methanol for 72 hours. In vitro AR inhibition was performed using a standard method, with glibenclamide as the reference antidiabetic drug. Pharmacophore screening, molecular docking, MM-GBSA, molecular interaction analysis, and ADMET screening were performed on the Gas Chromatography-Mass Spectroscopy (GC-MS) identified constituent of CCME, and a 100 ns molecular dynamics simulation (MDS) was performed to examine the stability and conformational behaviors of the lead compound in comparison with Epalrestat. The AR percentage inhibition of CCME increased with concentration, and the IC 50 for CCME was lower (85.29 ± 17.9 µg/ml) compared to Glibenclamide (149.5 ± 21.15 µg/ml), suggesting a comparable inhibitory activity. GC-MS analysis revealed a total of 87 bioactive compounds, and the in-silico analysis of these compounds identified 2-decoxy-5-(1,2-dihydroxyethyl)oxolane-3,4-diol as the lead compound, considering several results. CCME holds promising candidates requiring further investigation as an alternative natural AR inhibition for DN.
Ibrahim et al. (Sun,) studied this question.