Molecular Docking and ADMET Profiling of Rutin and Luteolin-7-O-glucoside as Promising DPP-IV Inhibitors

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from insulin resistance and impaired insulin secretion. Among the therapeutic targets explored for glycemic control, dipeptidyl peptidase-IV (DPP-IV) has gained considerable attention due to its role in the rapid degradation of incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (1,2). Inhibition of DPP-IV prolongs incretin activity, enhances insulin secretion, suppresses glucagon release, and improves postprandial glucose homeostasis, making DPP-IV inhibitors an established strategy in T2DM management. Several synthetic DPP-IV inhibitors are currently available; however, their long-term use has been associated with adverse effects, including gastrointestinal disturbances, infections, and potential cardiovascular risks (3–5). These limitations have encouraged the search for safer and more effective alternatives, particularly from natural sources. Flavonoids, a diverse class of plant-derived polyphenolic compounds, have demonstrated antidiabetic potential through multiple mechanisms, including antioxidant, anti-inflammatory, and enzyme inhibitory activities (6–10). Rutin and luteolin-7-O-glucoside are naturally occurring flavonoid glycosides widely distributed in medicinal plants and dietary sources (11,12). Both compounds possess multiple hydroxyl groups and aromatic rings that favor strong interactions with biological targets. Previous studies have suggested their potential to modulate glucose metabolism and inhibit carbohydrate-hydrolyzing enzymes; however, their specific interaction patterns with DPP-IV and their pharmacokinetic suitability remain inadequately explored. In this context, the present study employs molecular docking and comprehensive ADMET profiling to investigate the binding affinity, interaction mechanisms, and drug-likeness properties of rutin and luteolin-7-O-glucoside as potential DPP-IV inhibitors. This in silico evaluation aims to provide mechanistic insights and preliminary evidence supporting their development as natural antidiabetic lead compounds.

Figure 1. Active cavity of DPP-IV with Native ligand

ADMET Analysis

The ADMET evaluation revealed clear differences between the native ligand and the two flavonoid derivatives, rutin and luteolin-7-O-glucoside. As shown in Table 1, rutin exhibited the highest molecular weight (610.15 Da) and TPSA (269.43 Ų), while luteolin-7-O-glucoside showed a moderate molecular weight of 448.10 Da with a TPSA of 190.28 Ų, compared to the native ligand (323.22 Da; TPSA 98.82 Ų). Both derivatives displayed low lipophilicity, with logP values of 0.986 for rutin and 0.812 for luteolin-7-O-glucoside, indicating hydrophilic behavior that may limit membrane permeability but enhance aqueous solubility.

Drug-likeness analysis (Table 2) showed that the native ligand achieved a higher QED score (0.543) than rutin (0.140) and luteolin-7-O-glucoside (0.261). Both derivatives violated one Lipinski criterion and failed the GSK and Golden Triangle rules, largely due to their high polarity and hydrogen-bonding capacity. However, their NP scores were markedly higher (2.015 for rutin and 1.972 for luteolin-7-O-glucoside), supporting their classification as bioactive natural product-like compounds.

Absorption predictions (Table 3) indicated poor Caco-2 permeability for rutin (–6.55) and luteolin-7-O-glucoside (–6.39) compared to the native ligand (–5.39). Despite this, both compounds demonstrated favorable human intestinal absorption probabilities (HIA: 0.64 for rutin and 0.47 for luteolin-7-O-glucoside). At higher dose fractions, rutin achieved near-complete absorption (F50% = 0.9999), while luteolin-7-O-glucoside showed similarly high values (F50% = 0.9987). Both compounds were predicted to act as P-gp substrates but not inhibitors, suggesting limited transporter-mediated interactions.

Distribution and metabolism results (Table 4) revealed high plasma protein binding for rutin (85.01%) and luteolin-7-O-glucoside (79.35%), compared to the native ligand (8.03%). Both derivatives exhibited negligible BBB permeability (3.59×10⁻⁵ and 0.0019, respectively), indicating minimal CNS exposure. CYP450 interaction analysis showed weak inhibition and substrate probabilities across major isoforms, including CYP3A4 and CYP2D6, suggesting a low risk of metabolic drug–drug interactions.

Excretion and toxicity assessment (Table 5) demonstrated moderate plasma clearance values for rutin (1.61) and luteolin-7-O-glucoside (3.40), with longer half-lives (4.62 h and 3.97 h, respectively) than the native ligand (1.48 h). Both compounds showed low predicted hepatotoxicity (DILI: 0.94–0.95), Ames toxicity, and carcinogenicity probabilities, confirming a favorable safety profile. Environmental toxicity parameters (Table 6) further indicated low bioaccumulation factors (BCF ≈ 0.52) and acceptable aquatic toxicity values.

Overall, the inclusion of quantitative ADMET results demonstrates that although rutin and luteolin-7-O-glucoside exhibit limited oral drug-likeness due to high polarity, they possess favorable safety, metabolic, and excretion profiles. These characteristics support their potential as lead compounds, particularly when combined with formulation or structural optimization strategies to improve bioavailability.

Table 1. Physicochemical properties of selected derivatives

Table 2. Drug-likeness properties of designed derivatives

Table 3. Absorption parameter of selected compounds

Table 4. Distribution and metabolism parameter of selected molecules

Table 5. Excretion and Toxicity parameters of selected compounds

Table 6. Environmental toxicity profile of designed molecules

Table 7. ADMET radar of most potent compounds and native ligand

Molecular Docking

Molecular docking was performed to elucidate the binding behavior of rutin and luteolin-7-O-glucoside within the active site of DPP-IV (PDB ID: 6B1E). The native ligand exhibited a docking score of −7.0 kcal/mol and formed key interactions with the catalytic residue GLU205 through conventional hydrogen bonding, along with a hydrophobic π-alkyl interaction with PHE357. These interactions are consistent with reported DPP-IV binding modes, where GLU205 plays a critical role in substrate recognition and inhibition. Luteolin-7-O-glucoside demonstrated a stronger binding affinity than the native ligand, with a docking score of −8.9 kcal/mol, indicating enhanced stability of the ligand–protein complex. This compound formed multiple hydrogen bonds with essential active-site residues, including GLU205, GLU206, SER630, HIS740, ARG125, SER209, TYR547, and TYR585. Notably, the interaction with GLU205 at a shorter bond distance (1.97 Å) suggests a stronger hydrogen bond compared to the native ligand. Additionally, π–π stacking interactions with PHE357 further stabilized the complex, highlighting the importance of aromatic interactions in DPP-IV inhibition. The extensive hydrogen-bonding network provided by the hydroxyl groups of luteolin-7-O-glucoside likely contributes to its improved docking score and binding efficiency. Rutin exhibited the highest binding affinity among the tested compounds, with a docking score of −9.9 kcal/mol, reflecting a highly stable interaction with the DPP-IV active site. Rutin formed numerous conventional hydrogen bonds with key residues such as ASP545, TRP629, VAL546, TYR456, GLN553, ARG560, and ASN562, with several bond distances below 2.5 Å, indicating strong intermolecular interactions. In addition to hydrogen bonding, rutin displayed carbon–hydrogen bonding with GLY628, π-cation and π-donor hydrogen bond interactions with LYS554, and hydrophobic π-alkyl interactions, collectively enhancing binding stability. The involvement of residues surrounding the S1 and S2 subsites of DPP-IV suggests that rutin may effectively block substrate access to the catalytic region. Overall, the docking results indicate that both rutin and luteolin-7-O-glucoside bind more strongly to DPP-IV than the native ligand, with rutin showing the most favorable interaction profile. The superior docking scores and extensive interaction networks of these flavonoid glycosides can be attributed to their multiple hydroxyl groups and aromatic rings, which facilitate hydrogen bonding, electrostatic, and hydrophobic interactions. These findings support the potential of rutin and luteolin-7-O-glucoside as promising natural DPP-IV inhibitors and warrant further validation through molecular dynamics simulations and in vitro enzyme inhibition studies.

Table 8. Binding interactions of selected compounds with DPP-IV ( PDB ID  6B1E)

Table 9. 2D and 3D binding interactions of most potent compounds with DPP-IV

In conclusion this study systematically evaluated rutin and luteolin-7-O-glucoside as potential DPP-IV inhibitors through an integrated molecular docking and ADMET profiling approach Molecular docking results demonstrated that both flavonoid glycosides exhibited stronger binding affinities toward DPP-IV compared to the native ligand, with rutin showing the most favorable docking score and luteolin-7-O-glucoside. The enhanced binding was attributed to extensive hydrogen-bonding networks, π–π stacking, and electrostatic interactions with key residues within the S1 and S2 subsites of the enzyme, suggesting effective blockage of substrate access to the catalytic region. ADMET analysis revealed that although both compounds possess high polarity and limited oral drug-likeness according to classical rules, they displayed acceptable intestinal absorption probabilities, minimal blood–brain barrier penetration, weak CYP450 interactions, and low predicted toxicity. Their favorable safety, metabolic stability, and excretion profiles support their suitability as lead molecules. Overall, the combined docking and ADMET findings highlight rutin and luteolin-7-O-glucoside as promising natural scaffolds for DPP-IV inhibition. Further optimization strategies, including formulation approaches, molecular modifications, molecular dynamics simulations, and in vitro enzyme inhibition studies, are warranted to improve bioavailability and confirm their antidiabetic potential.

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