International Journal of Research and Development in Pharmacy & Life Sciences
Open Access

Diabetes

A category of illnesses known as diabetes are characterized by elevated blood glucose levels. When a person has diabetes, their body is either unable to use its own insulin efficiently or does not create enough insulin. Blood glucose levels rise, which results in a condition that, if left untreated, can have major health consequences and even be fatal [1]. A person with diabetes has twice as high a risk of dying as a person of same age who does not have the disease. A metabolic condition known as Diabetes Mellitus (DM) is characterized by hyperglycemia, glycosuria, hyperlipidemia, a negative nitrogen balance and occasionally ketoacemia. a common pathogenic [2]. Vascular problems include lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, retinopathy, neuropathy and peripheral vascular insufficiency are caused by changes in the capillary basement membrane, an increase in vessel wall matrix and cellular proliferation [3].

Diabetes mellitus is a clinical condition with a wide range of etiologies. Idiopathic and secondary diabetes mellitus are the two primary subtypes.

• Type 1 diabetic insulin depenedent
• Type 2 diabetes, also known as Non-Insulin Dependent Diabetes Mellitus (NIDDM) [4].

Type 2 diabetes mellitus is a serious worldwide public health concern since it is a common and escalating disorder. The international diabetes federation estimates that 387 million individuals worldwide have been diagnosed with diabetes. Diabetes was diagnosed in 29.1 million adults in the United States in 2012, or 9.3% of the population, according to the Centers for Disease Control and Prevention (CDCP US). Additionally, 86 million people had pre-diabetes that year and 15%-30% of them went on to acquire full-blown diabetes [5]. Generally speaking, 1.4 million newly diagnosed cases are recorded in the US each year. One in three Americans will have diabetes in 2050, according to projections, if this trend keeps up. Patients with diabetes are more likely to experience it [6].

A catalytic enzyme called glucosidase breaks down complicated carbohydrates into easily absorbed sugars. Hypoglycemia medications slow down the rate of simple carbohydrate digestion and absorption in the intestine by inhibiting glucosidase [7]. Acarbose, miglitol, voglibose and anavan are a few of the α-glucosidase inhibitors that are therapeutically utilized for type 2 diabetes. Aside from that, glucosidase inhibitors are beneficial biotools used in the treatment of diseases including hyperlipoproteinemia, obesity and cancer. In addition, glucosidase inhibitors have been seen to aid in the prevention of HIV [8].

Coumarin

Coumarin are a class of organic compounds found in plants. They have a distinctive ring structure and are known for their aroma and flavor. Coumarin possess various biological activities, including antimicrobial, antioxidant, anti-inflammatory and anticancer properties [9]. They are used in the perfume and food industries and some derivatives are used as pharmaceutical drugs. However, certain coumarin can be toxic in high doses [10]. Overall, coumarin have diverse applications and are the subject of ongoing research. Coumarin have been investigated for their potential as antidiabetic agents due to their diverse pharmacological properties. Several studies have shown that certain coumarin derivatives exhibit promising antidiabetic activity [11]. Here are some key points regarding coumarin as antidiabetic agents:

Coumarins have been found to possess glucose-lowering effects by various mechanisms. They can enhance glucose uptake by cells, increase insulin sensitivity, stimulate insulin secretion, and inhibit certain enzymes involved in glucose metabolism. Insulin mimetic activity: Some coumarin have been shown to mimic the action of insulin, promoting glucose uptake and utilization by cells [12]. This insulin mimetic activity can help regulate blood glucose levels in individuals with diabetes. Protection of pancreatic beta cells: Pancreatic beta cells play a crucial role in insulin production. Coumarin have been reported to protect these beta cells from damage, enhance their survival, and promote insulin secretion [13].

Coumarin can modulate various enzymes involved in glucose metabolism, such as glucokinase, glucose 6-phosphatase and glycogen synthase. By regulating these enzymes, coumarins can help maintain normal glucose levels in the body. It's important to note that while coumarin show potential as antidiabetic agents, further research is still needed to establish their efficacy, safety and optimal usage. Additionally, the use of coumarins for diabetes management should be done under the guidance of healthcare professionals. Overall, coumarin hold promise as a class of compounds for the development of novel antidiabetic agents, and ongoing studies continue to explore their potential in this field [14].

Chemistry

Coumarin is an aromatic organic compound with the chemical formula C₉H₆O₂. It is a lactone and can be derived from the natural product coumarin [15]. Coumarin has a pleasant sweet aroma and is often used in the fragrance and flavoring industries. It is found in many plants, including tonka beans, cassia cinnamon, and woodruff, which explains its use in various culinary applications [16].

It's important to differentiate between coumarin, a naturally occurring and synthetic compound used in the fragrance and flavoring industries, and coumarin, which may be a misspelling or a term with a different context. If you were referring to a specific compound or have additional questions about coumarin, feel free to ask for more information.

The chemical structure of coumarin consists of a benzene ring fused with an alpha-pyrone ring. The lactone ring is responsible for its aromatic nature and characteristic odor [17]. Coumarin is found in various plants as a natural product. However, it's important to note that synthetic coumarin is often used in the fragrance and flavor industries due to its cost effective production [18]. Coumarin's sweet smell is reminiscent of freshly cut hay or vanilla. It is widely used in perfumes, colognes, and other scented products. In the flavoring industry, coumarin is employed to add a vanilla-like taste to various foods and beverages [19]. Historically, coumarin has been used in traditional medicine due to its anticoagulant properties. However, it is no longer used for this purpose because of its potential side effects and the availability of more effective and safer anticoagulant medications [20]. While coumarin is generally recognized as safe for use in small quantities as a flavoring agent, it can be harmful in high doses. Ingesting large amounts of coumarin may lead to liver toxicity and other health issues. As a result, regulatory authorities limit the use of coumarin in food products [21]. Chemists have synthesized numerous coumarin derivatives with various substitutions on the aromatic ring. Some of these derivatives have demonstrated interesting biological activities and are of interest in pharmaceutical research.

Docking

The use of molecular docking studies has been one of the most important and essential techniques for discovering new drugs. It allows for the prediction of the molecular interactions that bind and maintain the bond between a protein and a ligand. A brief overview of molecular docking, along with the methodologies that are now available, their development and applications in drug discovery, have been provided in this chapter. Also presented are the relevant fundamental theories, such as sampling methods and scoring functions. The comparison of various molecular docking strategies, particularly those that take receptor backbone flexibility into account, has also been discussed. The final section of the document includes a solved practical exercise and a thorough overview of the protocol to follow, considering the importance of applying such tools and techniques [22].

Docking of derivative of coumarin

The protein structure of selected targets (spike protein and protease) was downloaded and verified from Protein Data Bank (PDB) database. The receptor (target) optimization and preparation were done using Argus lab [23]. The lead molecules both synthetic and natural were drawn using chemdraw ultra and converted to 3D and PDB format using chem bio 3D ultra. Docking of the drugs carried out by Argus lab and visualization of docked molecules was done equipping Biovia visualizer and so 2D and 3D poses were generated.

Method

Protein preparation: The protein structure of Dipeptidyl Peptidase IV (DPPIV) Inhibitors (2RGU) were obtained from RCSB Protein Data Bank, both were derived by X-Ray diffraction method and have the resolution of 2.60 Å appropriately. The proteins were then further processed by eliminating all water molecules and other residues, and the empty spaces were replaced with hydrogen. This was followed by protein optimization.

Ligand preparation: The structures of derived molecules of s were drawn using chem draw professional 16.0 and converted from 2D to 3D by chembio 3D 12.0. The MMFF (Merck Molecular Force Field) procedure, which enables the ligands to achieve the lowest feasible free energy for improved binding, was used to further enhance these structures.

Docking: Using Argus lab version 4.0.1, the synthesized ligands were molecularly docked with the chosen proteins. According to the docking data, we can see the docking score G (free energy) and the amino acids that contributed to the formation of the hydrogen bond between the ligand and the target protein. We illuminate the synthesized ligand's binding effectiveness and affinity using these metrics.

Ligand-protein complex poses optimization: Using the biovia visualizer, the interaction between ligands and proteins was seen in both 2D and 3D models. The 3D pose reveals the location and spatial arrangement of the ligand molecule and binding site, while the 2D diagram of ligand interaction depicts the many forces operating on the ligand molecule, such as hydrogen bonds, van der Waals forces, steric hinderence, etc.

Docking score of derivative of coumarin (Tables 1 and 2).

Molecule	Structure	Docking score	Hydrogen bond	Amino acid
CU1		-9.13879	2.887353 2.899936	358 ARG 669 ARG 206 GLU 357 PHE 630 SER 659 TRP 547 TYR 631 TYR 662 TYR 666 TYR 656 VAL 711 VAL
CU2		-9.8735	2.925626 1.996125	564 ALA 562 ASN 545 ASP 543 LEU 567 LEU 563 TRP 672 TRP 48 TYR 752 TYR 575 VAL
CU3		-11.4578	2.901342 2.691797 2.732471 2.624061	669 ARG 710 ASN 632 GLY 740 HIS 357 PHE 630 SER 629 TRP 659TRP 547 TYR 631 TYR 662 TYR 666 TYR 670 TYR 656 VAL 711 VAL
CU4		-9.60024	2.566374 2.899341 2.914592	564 ALA 562 ASN 545 ASP 628 GLY 632 GLY 748 HIS 543 LEU 567 LEU 563 TRP 627 TRP 629 TRP 48 TYR 547 TYR 752 TYR 546 VAL 575 VAL
CU5		-9.94455	2.900040 2.471755 2.895327 2.637442	205 GLU 206 GLU 549 GLY 357 PHE 550 PRO 659 TRP 547 TYR 631 TYR 662 TYR 666 TYR 656 VAL
CU6		-10.0602	2.778843 2.899966 2.481094	125 ARG 715 GLN 205 GLN 206 GLN 357 PHE 630 SER 659 TRP 547 TYR 631 TYR 634 TYR 662 TYR 666 TYR 656 VAL 711 VAL
CU7		-10.7288	2.193550 2,825780	1360 GLY 1085 PHE 1358 SER 1387 TRP 1357 TRP 1275 TYR 1359 TYR 1390 TYR 1394 TYR 1384 VAL
CU8		-10.8752	N/A	453 ARG 560 ARG 501 ASP 476 GLY 477 LEU 504 LEU 561 LEU 512 LYS 509 MET 559 PHE 510 PRO
CU9		-9.13879	2.696973 2.915285 2.756683 2.893610 2.825194	669 ARG 206 GLU 630 SER 659 TRP 504 LEU 561 LEU 547 TYR 631 TYR 662 TYR 666 TYR 656 VAL
CU10		-9.7656	2.899638 2.967203	631 TYR 634 TYR 662 TYR 666 TYR 656 VAL 711 VAL
CU11		-10.4578	2.754970 2.682085 2.890761 2.787164 2.404071	206 GLU 630 SER 667 THR 659 TRP 547 TYR 631 TYR 662 TYR 666 TYR 656 VAL 711 VAL
CU12		-9.60024	2.897973 2.815685 2.855683 2.653600 2.325144	669 ARG 206 GLU 630 SER 659 TRP 547 TYR 631 TYR 662 TYR 666 TYR 656 VAL
CU13		-9.94455	2.721251 2.766984 2.688007 2.456440 2.865302	707 ALA 713 PHE 239 SER 706 THR 734 TRP 238 TYR 241 TYR 967 SER 1434 THR 1462 TRP 966 TYR 969 TYR
CU14		-10.0602	2.8999984 2.268819	710 ASN 740 HIS 598 LEU 550 PRO 630 SER 659 TRP 547 TYR 631 TYR 662 TYR 666 TYR 656 VAL 711 VAL
CU15		-10.7288	2.999911 2.403775 2.208515	125 ARG 669 ARG 710 ASN 205 GLU 357 PHE 630 SER 659 TRP 631 TYR 662 TYR 666 TYR 670 TYR 656 VAL 711 VAL

Table 1: Docking score of coumarin derivative of 5ZCC in Argus lab.

Molecule	Structure	Docking score	Hydrogen bond	Amino acid
CU3		-11.4578	2.901342 2.691797 2.732471 2.624061	669 ARG 710 ASN 632 GLY 740 HIS 357 PHE 630 SER 629 TRP 659 TRP 547 TYR 631 TYR 662 TYR 666 TYR 670 TYR 656 VAL 711 VAL
SITAGLIPTIN		-8.35498	2.997917 2.254146	358 ARG 549 GLY 357 PHE 550 PRO 209 SER 630 SER 659 TRP 547 TYR 631 TYR 662 TYR 666 TYR 670 TYR 656 VAL

Table 2: Comparison of docking result with standard molecule.

Docking pose

The docking pose results shows in Figures 1 and 2.

Figure 1: Docking pose of best molecule C3.

Figure 2: Docking pose of sitagliptin (standard drug).

In the Putative Binding site of the DPP 4 Receptor (PDB code 2RGU), which exposes a sizable region limited by a membranebinding domain that acts as an entry conduit for substrate to the active site, the acquired results showed that all analysed ligands had comparable positions and orientations. Additionally, every small molecule's affinity may be thought of as a special instrument in the field of medication development. The affinity of organic compounds and the free energy of binding are correlated. This connection can help in predicting and interpreting how organic chemicals will function on a particular target protein. Additionally, it was demonstrated that receptor shape influences how a medication behaves. Researchers have a chance to find novel acting compounds that might be employed as new therapy choices for diabetes according to the current investigation.

1. Konidala SK, Kotra V, Danduga RC, Kola PK (2020) Coumarin-chalcone hybrids targeting insulin receptor: Design, synthesis, anti-diabetic activity and molecular docking. Bioorg Chem 104: 104207.

   [Crossref] [Google Scholar] [PubMed]

2. Singh AK, Patel PK, Choudhary K, Joshi J, Yadav D, et al. (2020) Quercetin and coumarin inhibit dipeptidyl peptidase-IV and exhibits antioxidant properties: In silico, in vitro, ex vivo. Biomolecules 10: 207.

   [Crossref] [Google Scholar] [PubMed]

3. Reddy DS, Kongot M, Singh V, Maurya N, Patel R, et al. (2019) Coumarin tethered cyclic imides as efficacious glucose uptake agents and investigation of hit candidate to probe its binding mechanism with human serum albumin. Bioorg Chem 92: 103212.

   [Crossref] [Google Scholar]

4. Lee EJ, Kang MK, Kim YH, Kim DY, Oh H, et al. (2020) Coumarin ameliorates impaired bone turnover by inhibiting the formation of advanced glycation end products in diabetic osteoblasts and osteoclasts. Biomolecules 10: 1052.

   [Crossref] [Google Scholar] [PubMed]

5. Mahnashi MH, Alqahtani YS, Alqarni AO, Alyami BA, Jan MS, et al. (2021) Crude extract and isolated bioactive compounds from Notholirion thomsonianum (Royale) Stapf as multitargets antidiabetic agents: In-vitro and molecular docking approaches. BMC Complement Med Ther 21: 1-3.

   [Crossref] [Google Scholar] [PubMed]

6. Basappa VC, Kameshwar VH, Kumara K, Achutha DK, Krishnappagowda LN, et al. (2020) Design and synthesis of coumarin triazole hybrids: Biocompatible anti-diabetic agents, in silico molecular docking and ADME screening. Heliyon 6: e05290.

   [Crossref] [Google Scholar] [PubMed]

7. Pan Y, Liu T, Wang X, Sun J (2022) Research progress of coumarins and their derivatives in the treatment of diabetes. J Enzyme Inhib Med Chem 37: 616-628.

   [Crossref] [Google Scholar] [PubMed]

8. Mishra G, Sachan N, Chawla P (2015) Synthesis and evaluation of thiazolidinedione-coumarin adducts as antidiabetic, anti-inflammatory and antioxidant agents. Lett Org Chem 12: 429-455.

   [Google Scholar]

9. Mo Z, Li L, Yu H, Wu Y, Li H (2019) Coumarins ameliorate diabetogenic action of dexamethasone via Akt activation and AMPK signaling in skeletal muscle. J Pharmacol Sci 139: 151-157.

   [Crossref] [Google Scholar] [PubMed]

10. Qi LW, Liu EH, Chu C, Peng YB, Cai HX, et al. (2010) Anti-diabetic agents from natural products-an update from 2004 to 2009. Curr Top Med Chem 10: 434-457.

    [Crossref] [Google Scholar] [PubMed]

11. Randelovic S, Bipat R (2021) A review of coumarins and coumarin-related compounds for their potential antidiabetic effect. Clin Med Insights Endocrinol Diabetes 14: 11795514211042023.

    [Crossref] [Google Scholar] [PubMed]

12. Maurya AK, Mulpuru V, Mishra N (2020) Discovery of novel coumarin analogs against the a-glucosidase protein target of Diabetes mellitus: Pharmacophore-based QSAR, docking, and molecular dynamics simulation studies. ACS Omega 5: 32234-32249.

    [Crossref] [Google Scholar] [PubMed]

13. Lee SO, Choi SZ, Lee JH, Chung SH, Park SH, et al. (2004) Antidiabetic coumarin and cyclitol compounds from Peucedanum japonicum. Arch Pharm Res 27: 1207–1210.

    [Crossref] [Google Scholar] [PubMed]

14. Durgapal SD, Soman SS (2019) Evaluation of novel coumarin-proline sulfonamide hybrids as anticancer and antidiabetic agents. Synth Commun 49: 2869-2883.

    [Crossref] [Google Scholar]

15. Mi J, Peng Y, Zhang H, Wang X, Huo Y, et al. (2018) A new benzofuran derivative glycoside and a new coumarin glycoside from roots of Heracleum dissectum Ledeb. Med Chem Res 27: 470-475.

    [Crossref] [Google Scholar]

16. Sharifi-Rad J, Cruz-Martins N, Lopez-Jornet P, Lopez EP, Harun N, et al. (2021) Natural coumarins: Exploring the pharmacological complexity and underlying molecular mechanisms. Oxid Med Cell Longev 2021: 6492346.

    [Crossref] [Google Scholar] [PubMed]

17. Adib M, Peytam F, Rahmanian-Jazi M, Mohammadi-Khanaposhtani M, Mahernia S, et al. (2018) Design, synthesis and in vitro a-glucosidase inhibition of novel coumarin-pyridines as potent antidiabetic agents. New J Chem 42: 17268-17278.

    [Crossref] [Google Scholar]

18. Thant TM, Aminah NS, Kristanti AN, Ramadhan R, Phuwapraisirisan P, et al. (2021) A new pyrano coumarin from Clausena excavata roots displaying dual inhibition against a-glucosidase and free radical. Nat Prod Res 35: 556-561.

    [Crossref] [Google Scholar]

19. Kenchappa R, Bodke YD, Chandrashekar A, Sindhe MA, Peethambar SK (2017) Synthesis of coumarin derivatives containing pyrazole and indenone rings as potent antioxidant and antihyperglycemic agents. Arab J Chem 10: S3895-3906.

    [Crossref] [Google Scholar]

20. Li H, Yao Y, Li L (2017) Coumarins as potential antidiabetic agents. J Pharm Pharmacol 69: 1253-1264.

    [Crossref] [Google Scholar] [PubMed]

21. Husain AA, Husain AS, Gawhale ND, Khan SL, Murlidhar DV, et al. (2022) An Overview of Natural and Synthetic Coumarin Derivatives as Potential Antidiabetic Agents. J Pharm Negat Results 21: 739-744.

    [Crossref] [Google Scholar]

22. Sravanthi TV, Sajitha Lulu S, Vino S, Jayasri MA, Mohanapriya A, et al. (2017) Synthesis, docking, and evaluation of novel thiazoles for potent antidiabetic activity. Med Chem Res 26: 1306-1315.

    [Crossref] [Google Scholar]

23. Sepehri N, Mohammadi-Khanaposhtani M, Asemanipoor N, Hosseini S, Biglar M, et al. (2020) Synthesis, characterization, molecular docking, and biological activities of coumarin-1, 2, 3-triazole-acetamide hybrid derivatives. Arch Pharm 353: 2000109.

    [Crossref] [Google Scholar] [PubMed]