## 3 Results and Discussion  
### In silico Analysis  
A set of 86 phenolic compounds (Table S1), comprising phenolic acids, flavanols, flavones, flavanonols, and flavanones, which was derived from an extensive literature re view, was generated [30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40]. The mentioned phenolic compounds contain the characteristic phytochemicals of the studied herb species. In continuation, the molecular targets selection for docking studies was based on the results of the open web server TargetNet ([[http://targetnet.scbdd.com](http://targetnet.scbdd.com)]([http://targetnet.scbdd.com](http://targetnet.scbdd.com)) (accessed on 1 July 2022). An ensemble target prediction was performed in this study, including a combination of fingerprint types (such as FP2, FP4, Daylight, MACCS, ECFP2, ECFP4, and ECFP6) [41]. The results for all combinatiplons indicated aldose reductase (AR) as the most promising target. This finding is supported by the area under the receiver operating characteristic curve (AUC) values, which exhibited an acceptable values (greater than 0.5), highlighting the model probability of selecting active over inactive compounds [41]. Therefore, molecular docking simulations were performed for all phytochemicals in an effort to predict their potential inhibitory affinity against AR enzyme. Aldose reductase (AR) is the principal enzyme of polyol pathway, which is related to hyperglycemia conditions and plays a critical role in the development of diabetic complications including cataract, retinopathy, nephropathy, and neuropathy [46; 47]. As a result, AR represents an attractive therapeutic target for the prevention of and reduction in the effects of diabetic complications. Many studies have been performed targeting the discovery of novel molecules as potential AR inhibitors [48; 49; 50]. The already known synthetic AR inhibitors, such as sorbini and tolrestat, suffer from drawbacks due to their poor permeation and safety concerns [46]. Therefore, compounds of natural origin have received considerable attention as an alternative. Specifically, among the phytochemicals, for instance, quercetin and other flavonoids or their derivatives, exhibit significant inhibitory activity [51; 52]. The derived docking pose evaluation was based not only on docking scores, but also on the visual inspection focusing on the presence of interactions with crucial amino acids identified by the recrystallized ligand of AR (Figure 1). Particularly in the case of the AR enzyme, the criteria for visual inspection include hydrogen bond formation with the amino acids Tyr48, His110, and Trp111. The formation of halogen bonds with Val47 and Thr113, and the existence of pi-pi interactions with Trp111 are all characterized as crucial for binding (Figure 1). Therefore, the molecular docking results analysis indicated cafaric acid, naringenin, quercetin, and rosmarinic acid (Figure 2), which are compounds bearing completely different chemical scaffolds from known synthetic AR inhibitors, as the most promising candidates. Notably, quercetin has already been reported as a strong AR inhibitor [46; 52], confirming our docking results and methodology. Figure 1: The binding mode of the cocrystallized ligand ((2-[(4-bromophenylyl)carbamoyl]-5-chlorophenoxyylacetic acid-W8X) at the active site of AR (PDB ID: 4 LAU). Halogen bonds, hydrogen bonds, and pi-pi interactions are depicted in purple, yellow, and blue dashed lines, respectively. The carbonyl groups of caftaric acid (docking score (ds) = \(-\)8.05 kcal\(\cdot\)mol\({}^{-1}\)) form hydrogen bonds with the crucial amino acids Tyr48, His110, and Trp111. Additionally, the phenolic ring of caftaric acid interacts via a pi-pi stacking with the aromatic ring of the crucial amino acid Trp111. The docked pose of naringenin indicated an interaction motif, including the formation of hydrogen bonds with His110 and Thr113 and a pi-pi stacking with Trp111, as the cocrystallized ligand.