Protective Efficacy of Nafronyl in Diabetic Retinopathy Through Targeted Inhibition of Key Enzymes.

Diabetic retinopathy is governed by abnormal apoptosis, increased capillary pressure, and other linked pathology that needs an efficient treatment by multitargeted approaches. Thus, the current study aimed to explore the potential of inhibition of targeted enzymes (DPP4, ACE-2, and aldose reductase) and free radical scavenging capabilities of selected compounds (nafronyl or naftidrofuryl) through in silico and in vivo investigations. Significant binding energies were observed in complexes of aldolase reductase, angiotensin type 1 receptor, and DPP4 against the nafronyl and sitagliptin more than -7.5 kcal/mol. Further validation of free energy was confirmed by calculations of molecular mechanics Poisson-Boltzmann surface area (MMPBSA), and configurational stabilities examined by PCA (principal component analysis). Additionally, drug-likeness was examined by the Swiss ADME web tool, which showed significant findings. Consequently, in vivo experimentations showed significant inflammation and alterations in retinal layers of inner plexiform (inner limiting membrane, nerve fibers, and ganglionic cells), inner nuclear layer (bipolar cells and horizontal cells), and photoreceptors cells. Whereas the treatments (nafronyl and sitagliptin) caused significant improvements in the histoarchitecture of the retina. Additionally, the HOMA indices (IR-insulin resistance, sensitivity, and beta cells functioning) and levels of free radicals were significantly altered in the diabetic control group in comparison to intact control. Nafronyl administration showed significant ameliorations in HOMA indices as well as antioxidant levels. Based on the results, it can be concluded that nafronyl efficiently interacts with target enzymes, which may result in potent inhibition and ameliorations in retinal histology as well as glucose homeostasis and antioxidants.