In Silico Molecular Docking, Validation, ADMET, and Drug Likeness Prediction of Phytochemicals Against Multiple Therapeutic Targets of Diabetes Mellitus In Silico Evaluation of Antidiabetic Phytochemicals
Iranian Journal of Pharmaceutical Sciences,
Vol. 21 No. 1 (2025),
21 January 2025
,
Page 357-381
https://doi.org/10.22037/ijps.v21i1.47074
Abstract
Diabetes mellitus (DM) is among the most prevalent chronic metabolic disorders worldwide. According to the World Health Organization (WHO) and the International Diabetes Federation (IDF), the incidence of diabetes is rising sharply in both India and Western countries. In silico approaches, including molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, drug-likeness prediction, and virtual screening, offer valuable insights for identifying effective ligands from phytochemicals that may serve as potential antidiabetic agents. This study focused on the evaluation of 277 phytochemicals derived from 20 plants reported to have antidiabetic properties, targeting six key receptors involved in the development of diabetes mellitus. Molecular docking was conducted at the active sites of these receptors, and Discovery Studio V24 was employed to map the interactions of the amino acid residues in both two- and three-dimensional representations with the phytochemical ligands. The docking study was validated by superimposing the re-docked complex onto the native co-crystallized ligand. Additionally, the Ramachandran plot was utilized to confirm the secondary structural integrity of the protein models. The in-silico analysis revealed that phytochemicals such as Quercetin, isomonospermoside, isocoreopsin, lukianol, ellagic acid, isosteviol, glutinone, monospermoside, and cadabicine exhibited significant binding affinities with the target proteins. Furthermore, these compounds demonstrated favorable oral bioavailability, drug-like properties, and ADMET profiles compared to standard antidiabetic drugs. Medicinal plants such as Butea monosperma (Palash), Coccinia grandis (Telakucha), Carissa carandas (Koromcha), Euphorbia neriifolia (Indian Spurge Tree), and Capparis decidua (Karil), which contain these bioactive phytochemicals, hold promise for the development of novel antidiabetic therapies within conventional medicine. These findings suggest that natural compounds with these core structures could serve as valuable lead compounds for diabetes treatment, contingent upon further validation through comprehensive in vitro and in vivo studies.
- Diabetes mellitus;
- In-silico
- Molecular docking
- ADMET
- Phytochemicals
- Drug likeness
How to Cite
References
Silva JA, Souza ECF, Echazú Böschemeier AG, Costa CCM, Bezerra HS, Feitosa EELC. Diagnosis of diabetes mellitus and living with a chronic condition: participatory study. BMC Public Health. 2018;18:699.
American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2010;33(Suppl 1):S62–S69.
IDF Diabetes Atlas 2021. International Diabetes Federation. Available from: https://diabetesatlas.org/atlas/tenth-edition/. Accessed 2024 Nov 13.
Magliano DJ, Boyko EJ, International Diabetes Federation 10th edition scientific committee. What is diabetes? In: IDF Diabetes Atlas [Internet]. 10th ed. International Diabetes Federation; 2021.
Kaushik P, Lal Khokra S, Rana AC, Kaushik D. Pharmacophore modeling and molecular docking studies on Pinus roxburghii as a target for diabetes mellitus. Adv Bioinformatics. 2014;2014:1-8.
Inzucchi SE, Tunceli K, Qiu Y, Rajpathak S, Brodovicz KG, Engel SS, et al. Progression to insulin therapy among patients with type 2 diabetes treated with sitagliptin or sulphonylurea plus metformin dual therapy. Diabetes Obes Metab. 2015;17(10):956-64.
Rizvi SI, Mishra N. Traditional Indian medicines used for the management of diabetes mellitus. J Diabetes Res. 2013;2013:e712092.
Salmaso V, Moro S. Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: an overview. Front Pharmacol. 2018;9:923.
Macalino SJY, Gosu V, Hong S, Choi S. Role of computer-aided drug design in modern drug discovery. Arch Pharm Res. 2015;38(9):1686-1701.
Tanrikulu Y, Krüger B, Proschak E. The holistic integration of virtual screening in drug discovery. Drug Discov Today. 2013;18(7-8):358-64.
Saleem M, Farooq A, Ahmad S, Shafiq N, Riaz N, Jabbar A, et al. Chemical constituents of Citrus sinensis var. Shukri from Pakistan. J Asian Nat Prod Res. 2010;12(8):702-706.
Jayaprakasha GK, Jagan Mohan Rao L, Sakariah KK. Chemical composition of the flower oil of Cinnamomum zeylanicum Blume. J Agric Food Chem. 2000;48(9):4294-4295.
Farias APP, Monteiro ODS, Da Silva JKR, Figueiredo PLB, Rodrigues AAC, Monteiro IN, et al. Chemical composition and biological activities of two chemotype-oils from Cinnamomum verum J. Presl growing in North Brazil. J Food Sci Technol. 2020;57(9):3176-3183.
Sharma V, Rao LJM. An overview on chemical composition, bioactivity and processing of leaves of Cinnamomum tamala. Crit Rev Food Sci Nutr. 2014;54(4):433-448.
Rameshkumar KB, George V, Shiburaj S. Chemical constituents and antibacterial activity of the leaf oil of Cinnamomum chemungianum Mohan et Henry. J Essent Oil Res. 2007;19(1):98-100.
Vijayakumar K, Prasanna B, Rengarajan RL, Rathinam A, Velayuthaprabhu S, Vijaya Anand A. Antidiabetic and hypolipidemic effects of Cinnamon cassia bark extracts: an in vitro, in vivo, and in silico approach. Arch Physiol Biochem. 2023;129(3):338-348.
Fathima HM, Thangavelu L, Roy A. Antidiabetic activity of Cassia fistula (alpha amylase – inhibitory effect). J Adv Pharm Educ Res. 2018;8(1):12-15.
Raj JY, Peter MPJ, Joy V. Chemical compounds investigation of Cassia auriculata seeds: a potential folklore medicinal plant. Asian J Plant Sci Res. 2012;2(2):187-192.
Ram M, Ram Krishna Rao M, Anisha G, Prabhu K, Shil S, Nagarajan V. Preliminary phytochemical and gas chromatography-mass spectrometry study of one medicinal plant Carissa carandas. Drug Invent Today. 2019;12(8):1629-1630.
Dutt HC, Singh S, Avula B, Khan IA, Bedi YS. Pharmacological review of Caralluma R.Br. with special reference to appetite suppression and anti-obesity. J Med Food. 2012;15(2):108-119.
Danish M, Singh P, Mishra G, Srivastava S, Jha KK, Khosa RL. Cassia fistula Linn. (Amulthus) – An important medicinal plant: a review of its traditional uses, phytochemistry and pharmacological properties. J Nat Prod Plant Resour. 2011;1(1):101-118.
Tiwari P, Jena S, Sahu P. Butea monosperma: Phytochemistry and pharmacology. 3. 2019:19-26.
Iftikhar A, Aslam B, Iftikhar M, Majeed W, Batool M, Zahoor B, et al. Effect of Caesalpinia bonduc polyphenol extract on alloxan-induced diabetic rats in attenuating hyperglycemia by upregulating insulin secretion and inhibiting JNK signaling pathway. Oxid Med Cell Longev. 2020;2020:1-14.
Anjum S, Asif M, Zia K, Jahan B, Ashraf M, Hussain S, et al. Biological and phytochemical studies on Capparis decidua (Forssk) Edgew from Cholistan desert. Nat Prod Res. 2020;34(16):2315-2318.
Salehi A, Kumar VA, Sharopov F, Ramírez-Alarcón K, Ruiz-Ortega A, Ayatollahi SA, et al. Antidiabetic potential of medicinal plants and their active components. Biomolecules. 2019;9(10):551.
Mohan Maruga Raja MK, Jainab N. In vitro cytotoxic, antioxidant and GC-MS study of leaf extracts of Clerodendrum phlomidis. Int J Pharm Sci Res. 2017;8:4433.
Hiradeve SM, Rangari VD. Elephantopus scaber Linn.: A review on its ethnomedical, phytochemical and pharmacological profile. J Appl Biomed. 2014;12:49-61.
Rastogi S, Pandey MM, Rawat AKS. An ethnomedicinal, phytochemical and pharmacological profile of Desmodium gangeticum (L.) DC. and Desmodium adscendens (Sw.) DC. J Ethnopharmacol. 2011;136:283-296.
Sharma V, Gautam DNS, Radu AF, Behl T, Bungau SG, Vesa CM. Reviewing the traditional/modern uses, phytochemistry, essential oils/extracts and pharmacology of Embelia ribes Burm. Antioxidants. 2022;11:1359.
Chaudhary P, Singh D, Swapnil P, Meena M, Janmeda P. Euphorbia neriifolia (Indian Spurge Tree): A plant of multiple biological and pharmacological activities. Sustainability. 2023;15:1225.
Vo Van L, Pham EC, Nguyen CV, Duong NTN, Vi Le Thi T, Truong TN. In vitro and in vivo antidiabetic activity, isolation of flavonoids, and in silico molecular docking of stem extract of Merremia tridentata (L.). Biomed Pharmacother. 2022;146:112611.
Bhutani R, Pathak DP, Kapoor G, Husain A, Iqbal MA. Novel hybrids of benzothiazole-1,3,4-oxadiazole-4-thiazolidinone: Synthesis, in silico ADME study, molecular docking and in vivo antidiabetic assessment. Bioorg Chem. 2019;83:6-19.
Antony P, Baby B, Aleissaee HM, Vijayan R. A molecular modeling investigation of the therapeutic potential of marine compounds as DPP-4 inhibitors. Mar Drugs. 2022;20:777.
Jain NV, Tambekar OP, Bodhankar SL, Bansode DA. A comparative molecular docking study of phytocompounds in red wine for the management of coronary artery disease and diabetes. J Prev Diagn Treat Strateg Med. 2022;1:255.
Patil M, Patil S, Maheshwari VL, Zawar L, Patil RH. Recent updates on in silico screening of natural products as potential inhibitors of enzymes of biomedical and pharmaceutical importance. In: Maheshwari VL, Patil RH, eds. Natural Products as Enzyme Inhibitors: An Industrial Perspective. Singapore: Springer Nature; 2022:105-123.
Ladokun OA, Abiola A, Okikiola D, Ayodeji F. GC-MS and molecular docking studies of Hunteria umbellata methanolic extract as a potent antidiabetic. Inform Med Unlocked. 2018;13:1-8.
Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem substance and compound databases. Nucleic Acids Res. 2016;44:D1202-13.
Fekadu M, Zeleke D, Abdi B, Guttula A, Eswaramoorthy R, Melaku Y. Synthesis, in silico molecular docking analysis, pharmacokinetic properties and evaluation of antibacterial and antioxidant activities of fluoroquinolines. BMC Chem. 2022;16:1.
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: an open chemical toolbox. J Cheminform. 2011;3:33.
Wang Q, He J, Wu D, Wang J, Yan J, Li H. Interaction of α-cyperone with human serum albumin: Determination of the binding site by using Discovery Studio and via spectroscopic methods. J Lumin. 2015;164:81-5.
Berman HM, Battistuz T, Bhat TN, Bluhm WF, Bourne PE, Burkhardt K, et al. The Protein Data Bank. Acta Crystallogr D Biol Crystallogr. 2002;58:899-907.
Laskowski RA, Furnham N, Thornton JM. The Ramachandran plot and protein structure validation. In: Biomolecular Forms and Functions. India: World Scientific/Indian Institute of Science; 2012:62-75.
Ng R. Drugs: From Discovery to Approval. 3rd ed. New Jersey: John Wiley & Sons; 2015.
Ercan S, Şenses Y. Design and molecular docking studies of new inhibitor candidates for EBNA1 DNA binding site: A computational study. Mol Simul. 2020;46:332-9.
Trott O, Olson AJ. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455-61.
C S, DK S, Ragunathan V, Tiwari P, A S, BD P. Molecular docking, validation, dynamics simulations, and pharmacokinetic prediction of natural compounds against the SARS-CoV-2 main-protease. J Biomol Struct Dyn. 2022;40:585-611.
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717.
Lipinski CA. Lead- and drug-like compounds: The rule-of-five revolution. Drug Discov Today Technol. 2004;1:337-41.
ProTox 3.0: A webserver for the prediction of toxicity of chemicals | Nucleic Acids Res | Oxford Academic. Available at: https://academic.oup.com/nar/article/52/W1/W513/7655780. Accessed 14 August 2024.
Yamashita S, Furubayashi T, Kataoka M, Sakane T, Sezaki H, Tokuda H. Optimized conditions for prediction of intestinal drug permeability using Caco-2 cells. Eur J Pharm Sci. 2000;10:195-204.
Yee S. In vitro permeability across Caco-2 cells (colonic) can predict in vivo (small intestinal) absorption in man—Fact or myth. Pharm Res. 1997;14(6):763–6.
Ajay, Bemis GW, Murcko MA. Designing libraries with CNS activity. J Med Chem. 1999;42(25):4942–51.
Kaur N, Kumar V, Nayak SK, Wadhwa P, Kaur P, Sahu SK. Alpha‐amylase as molecular target for treatment of diabetes mellitus: A comprehensive review. Chem Biol Drug Des. 2021;98(4):539–60.
Timalsina D, Bhusal D, Devkota HP, Pokhrel KP, Sharma KR. α-Amylase inhibitory activity of Catunaregam spinosa (Thunb.) Tirveng.: In vitro and in silico studies. Biomed Res Int. 2021;2021:4133876.
Kamble RP, Ghosh P, Kulkarni AA. Identification of α-amylase inhibitory compounds from leaves of Careya arborea Roxb. and in silico docking studies. South Afr J Bot. 2022;151:493–503.
Azam SS, Uddin R, Wadood A. Structure and dynamics of alpha-glucosidase through molecular dynamics simulation studies. J Mol Liq. 2012;174:58–62.
Terra WR, Ferreira C. Biochemistry of digestion. In: Comprehensive Molecular Insect Science. Elsevier; 2005. p. 171–224.
Taj S, Ashfaq UA, Aslam S, Ahmad M, Bhatti SH. Alpha-glucosidase activity of novel pyrazolobenzothiazine 5,5-dioxide derivatives for the treatment of diabetes mellitus: Invitro combined with molecular docking approach. Biologia. 2019;74(11):1523–30.
Duez H, Cariou B, Staels B. DPP-4 inhibitors in the treatment of type 2 diabetes. Biochem Pharmacol. 2012;83(7):823–32.
Ansari P, Choudhury ST, Seidel V, Rahman AB, Aziz MA, Richi AE, et al. Therapeutic potential of Quercetin in the management of type-2 diabetes mellitus. Life (Basel). 2022;12(8):1146.
Junaedi EC, Megantara S, Mustarichie R. Determination of potential compounds of stevia leaves (Stevia rebaudiana Bertoni) against DPP4 as candidates for antidiabetic drugs. 2020.
Vyas B, Silakari O, Singh Bahia M, Singh B. Glutamine: Fructose-6-phosphate amidotransferase (GFAT): Homology modelling and designing of new inhibitors using pharmacophore and docking based hierarchical virtual screening protocol. SAR QSAR Environ Res. 2013;24(9):733–52.
Bhuyan P, Sarma S, Ganguly M, Hazarika J, Mahanta R. Glutamine: Fructose-6-phosphate aminotransferase (GFAT) inhibitory activity of the anthocyanins present in black rice bran: A probable mechanism for the antidiabetic effect. J Mol Struct. 2020;1222:128957.
Kumar A, Chauhan S. Pancreatic lipase inhibitors: The road voyaged and successes. Life Sci. 2021;271:119115.
Swilam N, Nawwar MAM, Radwan RA, Mostafa ES. Antidiabetic activity and in silico molecular docking of polyphenols from Ammannia baccifera L. subsp. aegyptiaca (Willd.) Koehne waste: Structure elucidation of undescribed acylated flavonol diglucoside. Plants. 2022;11(3):452.
Wang Q, Imam MU, Yida Z, Wang F. Peroxisome proliferator-activated receptor gamma (PPARγ) as a target for concurrent management of diabetes and obesity-related cancer. Curr Pharm Des. 2017;23(26):3672–7.
Sharma P, Joshi T, Joshi T, Chandra S, Tamta S. In silico screening of potential antidiabetic phytochemicals from Phyllanthus emblica against therapeutic targets of type 2 diabetes. J Ethnopharmacol. 2020;248:112268.
Srinivasan P, Vijayakumar S, Kothandaraman S, Palani M. Antidiabetic activity of Quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches. J Pharm Anal. 2018;8(2):109–18.
Srinivasan P, Vijayakumar S, Kothandaraman S, Palani M. Antidiabetic activity of Quercetin extracted from Phyllanthus emblica L. fruit: In silico and in vivo approaches. J. Pharm. Anal. (2018) 8:109–118.
Rasheed Z, Akhtar N, Khan A, Khan KA, Haqqi TM. Butrin, isobutrin, and butein from medicinal plant Butea monosperma selectively inhibit nuclear factor-kappaB in activated human mast cells: suppression of tumor necrosis factor-alpha, interleukin (IL)-6, and IL-8. J. Pharmacol. Exp. Ther. (2010) 333:354–363.
Ahmad S, Alouffi S, Khan S, Khan M, Akasha R, Ashraf JM, Farhan M, Shahab U, Khan MY. Physicochemical characterization of in vitro LDL glycation and its inhibition by ellagic acid (EA): an in vivo approach to inhibit diabetes in experimental animals. Biomed. Res. Int. (2022) 2022:5583298.
Nordentoft I, Jeppesen PB, Hong J, Abudula R, Hermansen K. Isosteviol increases insulin sensitivity and changes gene expression of key insulin regulatory genes and transcription factors in islets of the diabetic KKAy mouse. Diabetes Obes. Metab. (2008) 10:939–949.
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