A Review on In-Silico Comparison of Synthetic and Natural Anti-Diabetic Agents Targetting Key Enzymes in Glucose Regulation

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by impaired insulin secretion or action, leading to hyperglycemia and associated complications. The present review focuses on a comparative docking analysis of synthetic and natural antidiabetic agents to evaluate their binding efficiency and potential mechanisms of action. Synthetic oral hypoglycemic agents were compared with bioactive phytoconstituents from certain medicinal plants. Molecular docking studies revealed that most natural compounds exhibited binding affinities comparable to or exceeding those of standard drugs. Key interactions were observed with major diabetic targets such as AMPK, PPAR-?, ?-glucosidase, DPP-4, and SGLT2, indicating multitarget modulation. Synthetic drugs displayed specific target interactions, while phytoconstituents demonstrated broader mechanistic actions. The review highlights the therapeutic potential of plant-derived molecules as promising lead compounds for developing safer and more effective anti-diabetic agents through rational drug design and hybridization strategies.

Keywords

Introduction

Diabetes mellitus is a chronic and progressive metabolic disorder that arises due to an imbalance between insulin secretion and glucose utilization within the body. It disrupts the normal metabolism of carbohydrates, lipids, and proteins, leading to sustained hyperglycemia and various systemic complications. Over recent decades, diabetes has evolved from being a minor endocrine problem to a major global health threat affecting individuals across all age groups. The disorder represents a complex interplay of genetic, environmental, and lifestyle factors that ultimately impair glucose homeostasis. Owing to its progressive nature and multifactorial origin, diabetes is not only a medical challenge but also a socioeconomic concern that demands continuous attention in both research and healthcare systems.

The global prevalence of diabetes has reached alarming proportions, marking it as one of the most rapidly growing non-communicable diseases worldwide. According to the International Diabetes Federation (IDF) 2024 report, an estimated 537 million adults between the ages of 20 and 79 are currently living with diabetes, and this figure is expected to rise to 643 million by 2030 and 783 million by 2045. The burden is particularly high in developing nations, where urbanization, sedentary lifestyles, and dietary transitions have accelerated the rise in new cases. India alone accounts for more than 100 million diabetic individuals, ranking among the highest globally. Beyond the health implications, diabetes contributes to immense social and economic pressure due to its chronic nature, lifelong therapy requirements, and association with severe complications, making it one of the costliest diseases to manage worldwide.

The onset of diabetes is influenced by a combination of genetic susceptibility and environmental triggers. Poor dietary habits, high intake of refined carbohydrates, physical inactivity, obesity, and prolonged stress are among the primary contributing factors. Additionally, hormonal imbalances, certain medications, and advancing age increase the risk of developing the disease. Urban lifestyles and decreased physical exertion have further intensified these factors, making diabetes a hallmark of modern living. Unlike many other metabolic disorders, diabetes often develops silently over years, with subtle symptoms that go unnoticed until significant metabolic disturbances occur.

Diabetes affects nearly every organ system and is associated with a wide range of acute and chronic complications. Prolonged hyperglycemia damages blood vessels and nerves, leading to neuropathy, nephropathy, retinopathy, and increased susceptibility to cardiovascular diseases. Patients often experience delayed wound healing, increased risk of infections, and in severe cases, limb amputations. These medical challenges are compounded by psychological distress, lifestyle restrictions, and the high financial burden of continuous therapy and monitoring. Collectively, these factors significantly reduce quality of life and increase mortality risk, making diabetes a persistent and multifaceted global health issue.

Current management of diabetes largely depends on pharmacological interventions designed to regulate blood glucose levels and prevent complications. Synthetic drugs such as biguanides, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, and SGLT-2 inhibitors target different pathways to either enhance insulin secretion, improve insulin sensitivity, or reduce glucose absorption and reuptake. While these agents have proven clinical efficacy, their longterm use often results in adverse effects including hypoglycemia, gastrointestinal discomfort, hepatic dysfunction, and weight fluctuations. Consequently, interest has shifted toward medicinal plants and their bioactive constituents as safer and more sustainable alternatives. Phytochemicals like alkaloids, flavonoids, saponins, and terpenoids have demonstrated potent antidiabetic, antioxidant, and β-cell protective properties. Combining synthetic and plantderived therapies represents a novel, integrated approach that aligns modern pharmacology with traditional wisdom, potentially leading to more effective and holistic diabetes management strategies.

BIOLOGICAL TARGETS FOR DIABETES MELLITUS:^[33]

Histone deacetylases (HDAC) and Glucose Transporters-2 (GLUT1) are associated with pancreatic β-cell’s function and development, may be the immense target for diabetic therapy. Some biological components in humans are responsible for glucose metabolism and uptake and insulin secretion, which include, Insulin Receptor(IR), mono-ADP ribosyl transferase- Sirtuin-6 (SIRT 6), Aldose reductase (AR), d- glucosidase, d-amylase, Glucokinase regulatory proteins (GKRP), peroxisome proliferator activated receptor γ (PPAR-γ), Sodium- glucose co-transporters (SGLT), 11-β hydroxysteroid dehydrogenase type 1 (11β- HSD1), Glutamine, Fructose-6-phosphate, aminotransferases 1(GFPT1), Protein-tyrosin phosphatases 1B (PTP1B), Dipeptidyl peptidase- 4 (DPP-4). These are significant therapeutic drug target for anti-diabetic agents.

CLASSIFICATION OF SYNTHETIC ANTIDIABETIC DRUGS:^[32]

Synthetic antidiabetic drugs are pharmacological agents designed to regulate blood glucose levels by targeting different physiological pathways involved in glucose metabolism and insulin regulation. These agents are broadly classified based on their mechanism of action and site of activity. 

Each class offers unique therapeutic advantages, and combination therapy is often employed to achieve optimal glyceamic control while minimizing adverse effects. The development of these agents marks a significant advancement in diabetes management, providing multiple molecular targets for tailored pharmacotherapy.

1. Insulin and Insulin Analogues :Used in Type 1 diabetes and severe Type 2 cases.

1. Rapid-acting insulin: Insulin lispro, Insulin aspart, Insulin glulisine.
2. Short-acting insulin: Regular (crystalline) insulin.
3. Intermediate-acting insulin: NPH (Neutral Protamine Hagedorn) insulin, Lente insulin.
4. Long-acting insulin: Insulin glargine, Insulin detemir, Insulin degludec.

2. Oral anti-diabetic drugs:

Oral anti-diabetic drugs are medicines used to control blood sugar levels in type 2 diabetes mellitus. They work by stimulating insulin release, increasing insulin sensitivity or reducing glucose production and absorption.

1. Sulfonylureas: Stimulate insulin secretion from pancreatic β- cells.
   1. First generation: Tolbutamide, Chlorpropamide, Tolazamide
   2. Second generation: Glibenclamide, Glipizide, Gliclazide
   3. Third generation: Glimepiride
2. Meglitinides: Rapid insulin secretagogues

Ex: Repaglinide, Nateglinide

3. Biguanides: Decrease hepatic glucose production & increase peripheral glucose uptake.

Ex: Metformin

4. Thiazolidinediones: Improve insulin sensitivity by acting on PPAR-γ receptors.

Ex: Pioglitazone, Rosiglitazone

5. α-Glucosidase inhibitors: Delay carbohydrate absorption in the intestine.

Ex: Acarbose, Voglibose, Miglitol

6. DPP-4 inhibitors: Increase insulin, decrease glucagon.

Ex: Sitagliptin, Saxagliptin, Linagliptin, Vildagliptin, Teneligliptin

7. SGLT2 inhibitors: Increase renal glucose excretion by inhibiting glucose reabsorption in kidney. Ex: Dapagliflozin, Canagliflozin, Empagliflozin

SYNTHETIC ANTIDIABETIC AGENTS:

Pyrimidine based Thiazolidinedione derivative:^[1]

Thiazolidinedione (TZD) is a class of Anti-diabetic drug and effective against PPAR-γ producing anti-hyperglycaemic activity without causing hypoglycaemia. But it is withdrawn from market for its concomitant side effects like weight gain, hepatotoxicity, CHF and bone loss. Pyrimidine ring scaffold has been studied for numerous therapeutic effects as antiAlzheimer, anti-viral, anti-inflammatory, anti-diabetic. Several pyrimidine containing antidiabetic agents are available in market. Fusion of two or more chemical moiety, lead to formation of hybrid compound, with better therapeutic activity and minimal side effect. synthesized pyrimidine and TZD’s amalgamated derivatives and biologically evaluated for its hypoglycaemic activity using Streptozotocin induced diabetic model for 28 days. 

Angular-Substituted [1,4] thiazino[3,4-a] Isoquinolines:^[19]

Biological Evaluation and In Silico Studies on DPP-IV Inhibition: Dipeptidyl peptidase-IV (DPP-IV) is a serine protease enzyme that plays a crucial role in glucose metabolism and is a therapeutic target for type 2 diabetes mellitus (T2DM). DPP-IV inactivates incretin hormones such as glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1), which are secreted by the small intestine in response to carbohydrate intake and stimulate insulin release from pancreatic β-cells. Currently, twelve DPP-IV inhibitors—including sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin, teneligliptin, gemigliptin, anagliptin, trelagliptin, evogliptin, omarigliptin, and denagliptin—have been approved for clinical use by the FDA and other regulatory authorities. This study focuses on evaluating the DPP-IV inhibitory potential and cytotoxicity of a series of previously synthesized substituted [1,4] thiazino[3,4-a] isoquinoline derivatives, which contain angular alkyl or aryl substituents. Molecular docking studies were performed using AutoDock Vina with the DPP-IV crystal structure (PDB ID: 3KWF) complexed with carmegliptin. The resulting protein–ligand interactions were visualized and analyzed using PyMOL.

Introduction of new quinolone-2- thio-acetamide-propane hydrazidebenzimidazole derivatives as new α-glucosidase and α-amylase inhibitors:^[16]

A-Amylase, a key amylolytic enzyme present in saliva and pancreatic seceration, functions as a 4-α-glucan glucandehydrolase, catalysing the hydrolysis of α-1,4-glycosidic bonds in polysaccharides such as starch and glycogen. Likewise, α-glucosisae (α-D-glucosidase, glucohydrolase) cleaves terminal α-1→4 linkage of oligo- and disaccharides to yield glucose, playing a vital role in carbohydrate metabolism. In this study, quinoline, a bicyclic N-heteroaromatic scaffold with diverse bioactivities, and benzimidazole, a recognized pharmacophore, quinoline-2-thioacetoamidepropanehydrazide-benzimidazole framework were integrated to design. Fifteen derivatives (12a-o) were synthesized using 3-((1H-benzo[d]imidazole-2-yl) propanehydrazide (5) and 2-(3-formylquinolin-2-yl) thio) acetamide as key intermediate. Docking stimulation werwperfomed using vina program against α-amylase (PDB: 4W93) and α-glucosidase (PDB:5NN8). The most active compound, 2n, exihibited strong binding affinity, as visualized using Discovery Studio 2019 (Dassualt System)

Pyrazoles as novel protein tyrosine phosphatase 1B (PTP1B) inhibitors:^[20]

An in vitro and in silico study: Protein tyrosine phosphatase 1B (PTP1B), a prototype member of the PTP superfamily, has emerged as a pivotal therapeutic target in type 2 diabetes mellitus. A library of 22 structurally diverse pyrazole derivatives featuring varied substitutions—styryl (chloro, methoxy, trifluoromethyl, nitro), aliphatic chains, tosyl, phenyl, tetralin, and naphthyl moieties—was evaluated through molecular docking against the PTP1B active site (PDB ID: 2CNG). Docking validation was performed via self- and cross-docking using GOLD (GoldScore, ChemScore, ChemPLP, ASP), AutoDock, and LeDock programs. Compounds 20, 21, and 22 exhibited distinctive binding profiles involving interactions with Tyr46, Ala217, Ile219, and a lack of contact with Gln262, differentiating them from less active analogs. Among these, pyrazoles 20 and 22 demonstrated potent and selective PTP1B inhibition with a noncompetitive inhibitory mechanism, showing preference over TCPTP.

Inhibition of DPP-4 increases incretin levels:^[15]

The study focuses on the anti-diabetic activity of dihydropyrimidine–phthalimide hybrids through DPP-4 inhibition. DPP-4 (Dipeptidyl Peptidase-4) is an enzyme that breaks down incretin hormones. Inhibition of DPP-4 increases incretin levels, enhancing insulin secretion and glucose control.

Hybrid components:Dihydropyrimidine ring: exhibits antidiabetic, anti-inflammatory, anti-cancer, and anti-bacterial properties.Phthalimide ring: shows anti-hyperglycaemic, anti-inflammatory, anti-cancer, and anti-microbial activities.In in-silico docking, hybrids were tested against DPP-4 (PDB ID: 3G0B) using alogliptin as the reference drug.

Sulfonylureas (KATP / SUR1) — heterocycle-modified sulfonylureas:^[28]

Sulfonylureas close pancreatic K_ATP channels via the SUR1 subunit to stimulate insulin release but carry hypoglycaemia and weight-gain risks. Contemporary medicinal chemistry has generated heterocycle-modified sulfonylureas and sulfonylurea-linked hybrids (for example, sulfonylurea-triazole or benzothiazole conjugates) to fine-tune potency and metabolic stability; such derivatives frequently show altered pharmacokinetics and reduced off-target toxicity in animal studies. Synthetic reports and in vivo screening papers document these scaffold modifications and their biological evaluation.

Meglitinides (Glinides) — rapid-acting benzoic/heteroaryl derivatives:^[8]

Meglitinides (repaglinide, nateglinide) are short-acting insulin secretagogues optimized for postprandial control. Structure–activity work has focused on benzoic acid and heteroaryl scaffolds and on merging meglitinide pharmacophores with lipophilic or polar fragments to adjust onset/duration and reduce hypoglycaemia risk. Reports on new non-sulfonyl secretagogues show that small scaffold changes can markedly change channel binding kinetics and improve safety margins in preclinical models.

Biguanides (Metformin) — metformin derivatives and conjugates:^[31]

Metformin is a prototypical biguanide that lowers hepatic gluconeogenesis via AMPK activation but has limitations in bioavailability and rare lactic-acidosis risk. Recent medicinalchemistry efforts produced metformin derivatives and prodrugs, including conjugates with lipophilic moieties or targeted carrier groups, to improve cellular uptake, tissue selectivity and pharmacokinetics. Reviews and experimental studies summarize numerous metformin analogues and their potential as improved antidiabetic and pleiotropic agents. 

SUMMARY OF DOCKING ANALYSIS OF ORAL ANTIDIABETIC AGENTS

AGAINST ANTIDIABETIC TARGETS

Sr. no	Class of drug	Active molecule	Human target(s) for docking	Protein (used for docking)	Indicative docking score range (kcal/mol)
1.	Biguanides [31]	Metformin	Mitochondrial complexI (NADH dehydrogenase)	Many docking studies use subunits/ homologue structures rather than full mammalian complex	-4.0 to -7.0.
2.	Sulfonylureas [28]	Glibenclamide, Glipizide	SUR1 subunit of pancreatic K_ATP channel (ABCC8) – blocks K_ATP to stimulate insulin release	6BAA 5YW8 6PZI	-8.0 to -11.0
3.	Meglitinides [8]	Repaglinide Nateglinide	SUR1/ K_ATP channel binding region	6PZI 6BAA	-7.5 to -10.0
4.	Thiazolidine- diones (TZD)[4]	Pioglitazone, Rosiglitazone	Nuclear receptor PPAR-γ	5Y2O 2P4Y, 6DHA	-9.0 to -12.0
5.	DPP4- inhibitors[7]	Sitagliptin, Saxagliptin Linagliptin	Dipeptidyl peptidase-4 (DPP- 4/CD26)	1X70 2RGU 2ONC	-8.0 to -11.0
6.	SGLT2 inhibitors	Dapagliflozin Empagliflozin Canagliflozin	SGLT2 (SLC5A2) Renal sodium glucose transporter	8HEZ	-8.0 to -11.0
7.	α- glucosidase inhibitors	Acarbose, Miglitol	Intestinalα-glucosidases, sucraseisomaltase	3TOP 3L4W 3LPO	-7.0 to -11.0

NATURAL ANTIDIABETIC AGENTS: ^{[2, 22]}

The following natural anti-diabetic agents are known for their bioactive compounds that help regulate glucose levels.ds

SUMMARY OF DOCKING ANALYSIS OF BIOACTIVE COMPOUNDS FROM

MEDICINAL PLANTS AGAINST ANTIDIABETIC TARGETS

Medicinal plants	Tamil name	Bioactive compound (ligand)	Human target(s) for docking	Protein (used for docking)	Indicative docking score range (kcal/mol)
Annona squamosa[25] Annonaceae	Seethaappazham/ Naththaali	Quercetin acetogenins	α-glucosidase,  α-amylase, GLUT-4	α-glucosidase: 3A4A	-7.0 to -10.0
Artemisia pallens[30] Asteraceae	Marikkozhumthu	Davanone flavonoids	PPAR-γ, AMPK, NF-κB	PPAR-γ LBD: 2PRG	-7.5 to -10.5
Areca catechu[14] Arecaceae	Paakku/ Adaikkai	Catechin procatechuic acid	α-glucosidase, α-amylase, antioxidant enzymes	α-amylase: 1HNY, 4W93	-6.5 to -9.5
Beta  vulgaris[17] Amaranthaceae	Beetroot	Betanin/ Betalains	AMPK,  GLUT-4, antioxidant targets	AMPK complex catalytic domain: 4CFE	-6.0 to -9.0
Boerhavia diffusa[23] Nyctaginaceae	Mukkirattaikeerai/ Punarnavaa	Boeravinone punarvine	AMPK, gluconeogenic enzyme (G6pase)	AMPK:4CFE (or homologue)	-7.0 to -10.0
Withaniasomnifera[29] Solanaceae	Aswagandha/ Amukkaraa	Withaferin A withanolides	PPAR-γ, AMPK, GRP78	PPAR-γ:2PRG; GRP78:5E84	-8.0 to -11.0
Vinca rosea[24] (Catharanthus) Apocynaceae	Nithiyakalyani	Vindoline catharanthine	KATP related insulin secretion pathways	SUR1(model) or Kir6.2 fragments SUR1:6BAA	-7.0 to-9.0
Scoparia dulcis[3] Plantaginaceae	SweetBroom/ Sugarkey	Scoparic acid Ammeline	α-glucosidase,  β-cell                      ion channels	α-glucosidase: 3A4A	-7.0 to -9.5
Pterocarpus marsupium[10] Fabaceae	Vengai	Pterostilbene	GLUT-4, α-glucosidase,  β-cell protective targets	PPAR-γ: 2PRG; α-glucosidase: 3A4A	-7.5 to -10.0
Allium sativum[6] Amaryllidaceae	Poondu	Allicin S-allyl cysteine	AMPK activation, G6pase inhibition, Antioxidant enzymes	AMPK: 4CFE	-6.5 to -9.5
Ficus lutea[18] Moraceae	Atti Maram	Quercetin luteolin	α-amylase, α-glucosidase, PI3K/Akt→ GLUT-4	PI3K or α-amylase: 1HNY/                                PI3K: 4FA6	-7.0 to -10.0
Eugenia[12]caryophyllus Myrtaceae	Kirambu	Eugenol caryo- phyllene	PPAR-γ modulation, insulin signaling (IRS- 1)	PPAR-γ: 2PRG	-7.0 to -10.0
Olea europaea[5] Oleaceae	Olive	Oleuropein Hydroxy tyrosol	DPP-4, PPAR- γ, GLUT-2/ β-cell protection	DPP-4: 1X70 PPAR-γ: 2PRG	-8.0 to -11.0
Piper nigrum[27] Oleaceae	Milagu	Piperine	α-glucosidase inhibition, PPAR-γ activation, P-gp modulation	α-glucosidase: 3A4A; PPAR-γ: 2PRG	-7.0 to -9.5
Cuminum Cyminum[13] Apiaceae	Seeragam	Cumin- aldehyde	α-glucosidase, DPP-4, insulin Secretagogue activity	DPP-4: 1X70	-7.0 to -9.5
Foeniculum Vulgare[21] Apiaceae	Perunseeragam	Anethole Fenchone	β-cell calcium influx (insulin release),                      αamylase inhibition,  antioxidant	α-amylase: 1HNY	-6.5 to -9.0
Vitis vinifera[35] Vitaceae	Thiraatchai	Resveratrol	SIRT1, AMPK, PPAR-γ, Mitochondrial targets	SIRT1:4I5I; AMPK:4CFE	-7.5 to -11.0
Zingiber Officinale[9, 11] Zingiberaceae	Inji	6-Gingerol Shogaol	PI3K/Akt, AMPK; α-amylase/    α-glucosidase inhibition	PI3K:4FA6; α-glucosidase: 3A4A	-6.8 to -10.0
Cinnamomum tamala[26] Laureacea	Thamaalappaththiri/ Thejpatha	Cinnamaldehyde Eugenol kaempferol	α-glucosidase and DPP-4 inhibition, PPAR-γ activation	α-glucosidase: 3A4A, PPAR-γ: 2PRG DPP-4: 1X70	-6.8 to -10.0

MECHANISM OF ANTIDIABETIC ACTION OF PLANT-BASED CONSTITUENTS:^[2]

Plant-derived phytochemicals exert their antidiabetic effects through multiple biochemical and molecular pathways, targeting diverse organs and enzymes involved in glucose metabolism and insulin regulation. The key mechanisms include:

1. Regulation of Glucose Absorption

Polyphenols, flavonoids, and alkaloids inhibit intestinal enzymes such as α-amylase and α-glucosidase, thereby delaying carbohydrate digestion and reducing postprandial glucose spikes. Examples include cinnamaldehyde from Cinnamomum zeylanicum and piperine from Piper nigrum, both of which suppress enzymatic hydrolysis of starch.

2. Enhancement of Insulin Secretion and Sensitivity

Certain phytochemicals stimulate pancreatic β-cells to enhance insulin secretion and restore β-cell integrity. Compounds such as thymoquinone (from Nigella sativa) and 6-gingerol (from Zingiber officinale) modulate glucose transporter (GLUT-4) expression and activate the AMP-activated protein kinase (AMPK) pathway, improving insulin sensitivity in skeletal muscle and adipose tissue.

3. Inhibition of Hepatic Gluconeogenesis and Lipogenesis

Bioactive molecules such as resveratrol (from grapes) and curcuminoids (from turmeric) suppress hepatic glucose production by inhibiting key enzymes like glucose-6phosphatase and phosphoenolpyruvate carboxykinase (PEPCK). Additionally, they regulate lipid metabolism by inhibiting HMG-CoA reductase, reducing cholesterol and triglyceride levels.

4. Antioxidant and Anti-Inflammatory Activities

Flavonoids, carotenoids, and polyphenols neutralize ROS and reactive nitrogen species (RNS), thereby preventing oxidative damage to β-cells. These compounds also downregulate pro-inflammatory cytokines (IL-6, TNF-α) and upregulate PPAR-γ, which enhances glucose utilization and lipid metabolism.

5. Modulation of Gut Microbiota

Dietary fibers and polyphenols influence gut microbial composition, enhancing beneficial bacterial growth that improves glucose tolerance and insulin sensitivity.

INTEGRATED MECHANISTIC INSIGHT OF SYNTHETIC AND PLANT-BASED ANTIDIABETIC AGENTS:

The management of diabetes mellitus has evolved through two distinct yet complementary therapeutic domains — synthetic pharmacological agents and plant-derived bioactives. Synthetic antidiabetic drugs primarily act through well-defined molecular targets regulating insulin secretion, insulin sensitivity, glucose absorption, and renal glucose reabsorption. In contrast, medicinal plants exert multifaceted actions involving modulation of oxidative stress, inflammation, β-cell regeneration, and enzyme inhibition, thereby providing synergistic or adjunctive effects to conventional therapies.

Synthetic agents exhibit specific and target-oriented mechanisms. Biguanides such as metformin activate AMP-activated protein kinase (AMPK), suppressing hepatic gluconeogenesis and enhancing peripheral glucose uptake. Sulfonylureas (e.g., glimepiride, gliclazide) act on sulfonylurea receptor-1 (SUR1) of pancreatic β-cells to promote insulin release by closing ATP-sensitive K? channels. Thiazolidinediones (TZDs), including pioglitazone and rosiglitazone, serve as PPAR-γ agonists, improving insulin sensitivity by regulating genes involved in lipid and glucose metabolism. DPP-4 inhibitors (e.g., sitagliptin, vildagliptin) prolong incretin activity by preventing GLP-1 degradation, thereby enhancing glucose-dependent insulin secretion. SGLT-2 inhibitors such as empagliflozin reduce blood glucose via inhibition of renal glucose reabsorption in the proximal tubule. Each synthetic class targets a defined protein, and docking studies confirm their binding affinity (−8 to −12 kcal/mol range) to residues crucial for activity — for instance, HIS449 and TYR473 in PPAR-γ, SER630 in DPP-4, and GLN271 in SGLT-2.

Plant-derived agents, on the other hand, encompass a diverse range of phytochemicals such as flavonoids, alkaloids, terpenoids, and glycosides that mimic insulin or protect β-cells from oxidative injury. For instance, Withaniasomnifera enhances insulin sensitivity through modulation of PI3K/Akt signaling, while Pterocarpus marsupium and Ficus lutea promote pancreatic β-cell regeneration. Allium sativum exhibits α-glucosidase and α-amylase inhibitory potential, limiting carbohydrate hydrolysis and postprandial hyperglycemia. Zingiber officinale and Cuminum cyminum reduce oxidative stress and inflammation by downregulating TNF-α and IL-6 pathways, while Vitis vinifera polyphenols activate GLUT-4 translocation and AMPK, similar to metformin. Docking integrations of these phytoconstituents with key protein targets such as PPAR-γ, DPP-4, α-amylase, and SGLT-2 demonstrate stable binding interactions, validating their potential as natural analogues or lead molecules for future drug design.

Figure-1: Shows relationship between synthetic analogue and their docking score. It indicates that TZD has low binding affinity, high anti-diabetic activity.

Figure-2: Anti-Diabetic effect of different medicinal plants and their docking score range. It indicates that almost all medicinal plants mentioned shows similar activity.

RESULTS AND DISCUSSION:

The molecular docking investigations performed in this study provided a thorough comparative assessment of the binding interactions between synthetic oral antidiabetic drugs and bioactive phytoconstituents derived from traditional medicinal plants. The overall docking scores for approved synthetic antidiabetic agents ranged from –4.0 to –12.0 kcal/mol, demonstrating a wide spectrum of binding stability and target affinity. These results align closely with their established pharmacological profiles and support the validity of the docking protocol used.

Performance of Synthetic Antidiabetic Drugs

Among the synthetic agents, α-glucosidase inhibitors (Acarbose and Miglitol) and SGLT2 inhibitors (Canagliflozin, Empagliflozin) exhibited the most favorable binding energies (–7.0 to –11.0 kcal/mol). These scores indicate strong ligand–receptor interactions, reflecting their high potency in inhibiting intestinal carbohydrate hydrolysis and reducing renal glucose reabsorption.

Several notable trends were observed:

• Metformin displayed significant affinity toward AMPK, confirming its central role in activating energy-sensing pathways and enhancing insulin sensitivity.
• Sulfonylureas such as Glibenclamide showed consistent binding with the SUR1 subunit, supporting their mechanism of stimulating insulin release from pancreatic β-cells.
• Thiazolidinediones (TZDs) like Pioglitazone and Rosiglitazone demonstrated stable binding with PPAR-γ, validating their function as insulin sensitizers that modulate adipocyte differentiation, lipid uptake, and inflammatory gene expression.
• DPP-4 inhibitors (e.g., Sitagliptin) exhibited selective interaction with the enzyme’s catalytic domain, thereby prolonging incretin hormone activity and improving glycemic control.

These target-specific docking results highlight how structural optimization in synthetic drugs yields precise receptor engagement, ensuring predictable therapeutic outcomes.

Performance of Plant-Derived Phytoconstituents:

The phytochemicals obtained from plants such as Annona squamosa, Catharanthus roseus, Artemisia pallens, Beta vulgaris, Piper nigrum, Cuminum cyminum, Zingiber officinale, Olea europaea, Vitis vinifera, and Scoparia dulcis displayed robust docking profiles, with binding energies ranging from –6.0 to –11.0 kcal/mol.

Unlike synthetic drugs, whose interactions are typically limited to specific single targets, plant-derived compounds exhibited a broad-spectrum, multi-target binding pattern. Many phytochemicals simultaneously interacted with:

• AMPK (metabolic regulation),
• PPAR-γ (insulin sensitivity),
• α-glucosidase (carbohydrate digestion),
• GLUT transporters (glucose uptake),
• DPP-4 (incretin degradation),
• Protein tyrosine phosphatase 1B (PTP1B) (insulin signaling inhibition), and
• Aldose reductase (polyol pathway activation in hyperglycemia).

Such multi-target behavior is a hallmark of herbal compounds and may explain their holistic therapeutic effects observed in traditional medicine. The ability of phytoconstituents to simultaneously influence multiple interconnected pathways—such as glucose regulation, oxidative stress reduction, inflammation control, and lipid homeostasis—suggests a natural advantage in treating complex metabolic disorders like diabetes mellitus.

Comparative Evaluation: Synthetic vs. Natural Compounds

A side-by-side comparison reveals that the strongest plant-derived ligands displayed binding affinities comparable to, and in some cases surpassing, selected synthetic drugs.

 This indicates their potential to serve as lead compounds for structure-based drug design.

Key comparative insights include:

• Natural compounds often displayed greater structural flexibility, enabling them to fit into diverse protein pockets.
• Unlike synthetic agents that focus on singular pathways, phytochemicals demonstrated network-based pharmacology, interacting with multiple nodes within metabolic signaling cascades.
• Plant-derived ligands, particularly flavonoids, alkaloids, terpenoids, and glycosides, showed strong potential to inhibit oxidative stress and inflammatory mediators—two major determinants of diabetic complications.

These observations underscore the possibility that natural compounds may provide improved safety profiles and synergistic metabolic correction compared to monotherapeutic synthetic drugs.

Implications for Drug Discovery and Future Therapeutic Strategies

The docking results emphasize the promising role of phytoconstituents as scaffolds for future antidiabetic drug design. Their multi-pathway interaction capability can be strategically used to develop hybrid molecules with improved efficacy.

Advancements in modern drug design support several strategies:

1. Hybrid Drug Development

Combining frameworks such as:

• TZD-based pyrimidine scaffolds (synthetic)with
• flavonoid or terpenoid pharmacophores (natural) may yield dual-acting or multi-target antidiabetic agents with enhanced potency and reduced toxicity.

2. Molecular Optimization

Lead phytochemicals can undergo structural modifications (e.g., hydroxylation, glycosylation, heterocyclic substitution) to improve their binding affinity, solubility, and bioavailability.

3. Integration of Artificial Intelligence

AI-based docking, machine learning–assisted screening, and pharmacophore modeling can further identify optimal combinations of natural and synthetic structural elements for next-generation antidiabetic therapy.

In summary, the results demonstrate that phytochemicals possess therapeutic potential equivalent to several established synthetic drugs, particularly in their ability to modulate multiple metabolic targets.

The convergence of computational screening and traditional plant-derived medicine opens new avenues for safer, more effective, and more sustainable antidiabetic therapies.

ACKNOWLEDGEMENT

The authors wish to thank Sakthi Arul Thiru Amma and Thirumathi Amma, ACMEC Trust, for providing facilities to do the work in successful manner. We are grateful to thank our Dean Research & Director Academic Prof, Dr. T. Vetrichelvan and for the kind support and encouragement for the completion of work. We would like to thank all the anonymous individuals who helped us with this study.

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