Antidiabetic Potency of Flavonoids Using a Systematic Computer-Aided Drug Design Platform

Deepankar Rath; Gurudutta Pattnaik; Biswakanth Kar; Gopal Krishna Padhy; Chandrasekhar Patro; Pallishree Bhukta

doi:10.52756/ijerr.2024.v40spl.020

Deepankar Rath School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Odisha-752050, India https://orcid.org/0000-0002-7003-5896
Gurudutta Pattnaik School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Odisha-752050, India https://orcid.org/0000-0002-3532-721X
Biswakanth Kar School of Pharmaceutical Sciences, Siksha ‘O’ Anusandhan University, Odisha-751030, India https://orcid.org/0000-0002-4530-1005
Gopal Krishna Padhy School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Odisha-752050, India https://orcid.org/0000-0002-0997-8879
Chandrasekhar Patro School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Odisha-752050, India https://orcid.org/0000-0003-2886-8664
Pallishree Bhukta School of Pharmacy and Life Sciences, Centurion University of Technology and Management, Odisha-752050, India https://orcid.org/0000-0002-5826-9569

DOI: https://doi.org/10.52756/ijerr.2024.v40spl.020

Keywords: Diabetes mellitus, Flavonoids, Naringin, Molecular docking, Toxicity prediction, Drug-ability profiles

Abstract

Diabetic mellitus (DM) is a chronic metabolic disorder, with type 2 diabetes (T2DM) being the most prevalent type globally. Despite the availability of several target-specific drugs, the prevalence rate has remained uncontrollable, prompting a systematic exploration of plant secondary metabolites or phytochemicals for mainstream use. Among all natural resources, citrus fruits like oranges, lemons, grapefruits and limes are rich sources of flavonoids and get more attention due to their higher antioxidant, anti-inflammatory and immunomodulatory effects. Additionally, researchers have employed various strategies to locate the most bioactive and drug-able flavonoids from these herbal extracts for use in managing diabetes. Therefore, the present study selected nine citrus-fruit-derived flavonoids and tested their antidiabetic potency using four target enzymes: α-amylase, AKT Serine/Threonine Kinase 1 (AKT1), dipeptidyl peptidase-4 (DPP-IV), and glucose transporter 1 (GLU1) through molecular docking studies. In addition, we have predicted the physiochemical profile, toxicity, bioavailability, lead-likeness, drug-likeness, and lethal dose of flavonoids, along with five standard antidiabetic drugs, to select the most potential candidates. We used AutoDock 4.2 for the docking study, BIOVID-Discovery Studio for the protein-ligand interaction study, SwissADME, ProTox 3.0 and Molsot tools to predict the drug-likeness profile. Individual and average docking scores indicated that naringin (-11.2 and -10.40 kcal/mol) was the most potent flavonoid, and glimepiride (-11.1 and -10.1 kcal/mol) against AKT1 had the most potential among the five antidiabetic drugs. Naringin had non-toxic profiles, a positive drug-likeness score, and ideal physicochemical profiles, which suggested that it might be the best candidate for further testing. To sum up, the computer-aided drug design platform is an important part of the current drug discovery module to accelerate phyto-based drug discovery within limited time and resources.

References

Acharya, C.K., Das, B., Madhu, N.R., Sau, S., Manna De, M., & Sarkar, B. (2023). A Comprehensive Pharmacological Appraisal of Indian Traditional Medicinal Plants with Anti-diabetic Potential. Springer Nature Singapore Pte Ltd., Advances in Diabetes Research and Management, pp. 163–193, Online ISBN-978-981-19-0027-3. https://doi.org/10.1007/978-981-19-0027-3_8

Ahangarpour, A., Sayahi, M., & Sayahi, M. (2019). The antidiabetic and antioxidant properties of some phenolic phytochemicals: A review study. Diabetes Metab. Syndr., 13(1), 854-857. https://doi.org/10.1016/j.dsx.2018.11.051

Alam, S., Sarker, M.M.R., Sultana, T.N., Chowdhury, M.N.R., Rashid, M.A., Chaity, N.I., Zhao, C., Xiao, J., Hafez, E.E., Khan, S.A., & Mohamed, I.N. (2022). Antidiabetic phytochemicals from medicinal plants: prospective candidates for new drug discovery and development. Front Endocrinol (Lausanne), 13, 800714. https://doi.org/10.3389/fendo.2022.800714

Al-Ishaq, R.K., Abotaleb, M., Kubatka, P., Kajo, K., & Büsselberg, D. (2019). Flavonoids and Their Anti-Diabetic Effects: Cellular Mechanisms and Effects to Improve Blood Sugar Levels. Biomolecules, 9(9), 430. https://doi.org/10.3390/biom9090430.

Aryal, D., Joshi, S., Thapa, N.K., Chaudhary, P., Basaula, S., Joshi, U., Bhandari, D., Rogers, H.M., Bhattarai, S., Sharma, K.R., Regmi, B.P., & Parajuli, N. (2024). Dietary phenolic compounds as promising therapeutic agents for diabetes and its complications: A comprehensive review. Food Sci. Nutr., 12(5), 3025-3045. https://doi.org/10.1002/fsn3.3983

Biswas, T., Behera, B. K., & Madhu, N.R. (2023). Technology in the Management of Type 1 and Type 2 Diabetes Mellitus: Recent Status and Future Prospects. 26 pages, Springer Nature Singapore Pte Ltd., Advances in Diabetes Research and Management. pp. 111–136. Online ISBN-978-981-19-0027-3. https://doi.org/10.1007/978-981-19-0027-3_6

Cassar, S., Dunn, C., & Ramos, M.F. (2021). Zebrafish as an Animal Model for Ocular Toxicity Testing: A Review of Ocular Anatomy and Functional Assays. Toxicol. Pathol., 49(3), 438-454. https://doi.org/10.1177/0192623320964748

Chen, X., Li, H., Tian, L., Li, Q., Luo, J., & Zhang, Y. (2020). Analysis of the Physicochemical Properties of Acaricides Based on Lipinski's Rule of Five. J. Comput. Biol., 27(9), 1397-1406. https://doi.org/10.1089/cmb.2019.0323.

Cloete, L. (2022). Diabetes mellitus: an overview of the types, symptoms, complications and 400 managements. Nurs. Stand., 37, 61-66. https://doi.org/10.7748/ns.2021.e11709

Dhakar, S., & Tare, H. (2023). Therapeutic Potential of Polyherbal Tablets: A Comprehensive Assessment of Pharmacological Activity. Int. J. Exp. Res. Rev., 34(Special Vol.), 97-105. https://doi.org/10.52756/ijerr.2023.v34spl.010

Gao, J., & Shen, W. (2021). Xenopus in revealing developmental toxicity and modeling human diseases. Environ Pollut., 268(PtB), 115809. https://doi.org/10.1016/j.envpol.2020.115809.

Grover, M., & Utreja, P. (2014). Recent advances in drug delivery systems for anti-diabetic drugs: a review. Curr. Drug Deliv., 11(4), 444-457. https://doi.org/10.2174/1567201811666140118225021

Gupta, A., Jamal, A., Jamil, D.A., & Al-Aubaidy, H.A. (2023). A systematic review exploring the mechanisms by which citrus bioflavonoid supplementation benefits blood glucose levels and metabolic complications in type 2 diabetes mellitus. Diabetes Metab Syndr., 17(11), 102884. https://doi.org/10.1016/j.dsx.2023.102884.

IDF Diabetes Atlas. (2024). https://diabetesatlas.org/. (Accessed on 4th April 2024).

Jaiswal, S., & Gupta, P. (2023). GLSTM: A novel approach for prediction of real & synthetic PID diabetes data using GANs and LSTM classification model. Int. J. Exp. Res. Rev., 30, 32-45. https://doi.org/10.52756/ijerr.2023.v30.004

Kim, H.M., & Kang, J.S. (2021). Metabolomic Studies for the Evaluation of Toxicity Induced by Environmental Toxicants on Model Organisms. Metabolites, 11(8), 485. https://doi.org/10.3390/metabo11080485.

Mata, R., Flores-Bocanegra, L., Ovalle-Magallanes, B., & Figueroa, M. (2023). Natural products from plants targeting key enzymes for the future development of antidiabetic agents. Nat. Prod. Rep., 40(7), 1198-1249. https://doi.org/10.1039/D3NP00007A

Newman, D.J., & Cragg, G.M (2020). Natural Products as Sources of New Drugs over the Nearly Four 455 Decades from 01/1981 to 09/2019. J. Nat. Prod., 83(3), 770-803. https://doi.org/10.1021/acs.jnatprod.9b01285

Padhi, S., Nayak, A.K., Behera, A. (2020). Type II diabetes mellitus: a review on recent drug based therapeutics. Biomed Pharmacother., 131, 110708. https://doi.org/10.1016/j.biopha.2020.110708

Pawar, S., Pawade, K., Nipate, S., Balap, A., Pimple, B., Wagh, V., Kachave, R., & Gaikwad, A. (2023). Preclinical evaluation of the diabetic wound healing activity of phytoconstituents extracted from Ficus racemosa Linn. leaves. Int. J. Exp. Res. Rev., 32, 365-377. https://doi.org/10.52756/ijerr.2023.v32.032

Pramanik, B. (2018). A comparative study on the knowledge, attitude and risk perception regarding complications of type-2 diabetes mellitus between male and female diabetic patients attending diabetic clinics in selected hospital of West Bengal, India. Int. J. Exp. Res. Rev., 15, 16-27. https://doi.org/10.52756/ijerr.2018.v15.004

Rath, D., Kar, B., Pattnaik, G., & Bhukta, P. (2023). Flavonoids and their role in the remedy of diabetes mellitus: A review. Asian Journal of Chemistry, 35(9), 2021–2030. https://doi.org/10.14233/ajchem.2023.28082

Rath, D., Pattnaik, G., & Kar, B. (2021). An Overview on ethnopharmacology of different medicinal plants of Odisha state of India in the management of diabetes mellitus. Asian Journal of Chemistry, 33(11), 2589–2598. https://doi.org/10.14233/ajchem.2021.23389

Roy, R., Chakraborty, A., Jana, K., Sarkar, B., Biswas, P., & Madhu, N.R. (2023). The Broader Aspects of Treating Diabetes with the Application of Nanobiotechnology. Springer Nature Singapore Pte Ltd., Advances in Diabetes Research and Management, pp. 137–162, Online ISBN-978-981-19-0027-3. https://doi.org/10.1007/978-981-19-0027-3_7

Sahoo, A., Fuloria, S., Swain, S.S., Panda, S.K., Sekar, M., Subramaniyan, V., Panda, M., Jena, A.K., Sathasivam, K.V., & Fuloria, N.K. (2021) Potential of marine terpenoids against SARS-COV-2: an in silico drug development approach. Biomedicines, 9(11), 1505. https://doi.org/10.3390/biomedicines9111505

Sahoo, A., Jena, A.K., & Panda, M. (2022a). Experimental and clinical trial investigations of phyto-extracts, phyto-chemicals and phyto-formulations against oral lichen planus: A systematic review. J. Ethnopharmacol., 298, 115591. https://doi.org/10.1016/j.jep.2022.115591.

Sahoo, A., Swain, S.S., Paital, B., & Panda, M. (2022b). Combinatorial approach of vitamin C derivative and anti-HIV drug-darunavir against SARS-CoV-2. Front Biosci. (Landmark Ed), 27(1),10. https://doi.org/10.31083/j.fbl2701010.

Sarkar, S., Sadhu, S., Roy, R., Tarafdar, S., Mukherjee, N., Sil, M., Goswami, A., & Madhu, N.R. (2023). Contemporary Drifts in Diabetes Management. Int. J. App. Pharm., 15(2), 1-9. https://doi.org/10.22159/ijap.2023v15i2.46792

Seidel, V. (2020). Plant-derived chemicals: A source of inspiration for new drugs. Plants (Basel)., 480(9),1562. https://doi.org/10.3390/plants9111562

Shamsudin, N.F., Ahmed, Q.U., Mahmood, S., Shah, S.A.A., Sarian, M.N., Khattak, M.M.A.K., Khatib, A., Sabere, A.S.M., Yusoff, Y.M., & Latip, J. (2022). Flavonoids as antidiabetic and anti-inflammatory agents: a review on structural activity relationship-based studies and meta-analysis. Int. J. Mol. Sci., 23(20), 12605. https://doi.org/10.3390/ijms232012605

Sur, T., Das, A., Bashar, S., Tarafdar, S., Sarkar, B., & Madhu, N.R. (2023). Biochemical Assay for Measuring Diabetes Mellitus. Springer Nature Singapore Pte Ltd., Advances in Diabetes Research and Management, pp. 1–20, Online ISBN-978-981-19-0027-3, https://doi.org/10.1007/978-981-19-0027-3_1

Swain, S.S., & Hussain, T. (2022a). Combined Bioinformatics and Combinatorial Chemistry Tools to Locate Drug-Able Anti-TB Phytochemicals: A cost-effective platform for natural product-based drug discovery. Chem. Biodivers., 19(11), e202200267. https://doi.org/10.1002/cbdv.202200267.

Swain, S.S., Hussain, T., & Pati, S. (2021). Drug-lead Anti-tuberculosis phytochemicals: A systematic review. Curr. Top Med. Chem., 21(20), 1832-1868. https://doi.org/10.2174/1568026621666210705170510

Swain, S.S., Paidesetty, S.K., Dehury, B., Sahoo, J., Vedithi, S.C., Mahapatra, N., Hussain, T., & Padhy, R.N. (2018). Molecular docking and simulation study for synthesis of alternative dapsone derivative as a newer antileprosy drug in multidrug therapy. J. Cell Biochem., 119(12), 9838-9852. https://doi.org/10.1002/jcb.27304

Swain, S.S., Rout, S.S., Sahoo, A., Oyedemi, S.O., & Hussain, T. (2022c). Antituberculosis, antioxidant and cytotoxicity profiles of quercetin: a systematic and cost-effective in silico and in vitro approach. Nat. Prod. Res., 36(18), 4763-4767. https://doi.org/10.1080/14786419.2021.2008387

Swain, S.S., Singh, S.R., Sahoo, A., Hussain, T., & Pati, S. (2022a). Anti-HIV-drug and phyto-flavonoid combination against SARS-CoV-2: a molecular docking-simulation base assessment. J. Biomol. Struct. Dyn., 40(14), 6463-6476. https://doi.org/10.1080/07391102.2021.1885495

Swain, S.S., Singh, S.R., Sahoo, A., Panda, P.K., Hussain, T., & Pati, S. (2022b). Integrated bioinformatics-cheminformatics approach toward locating pseudo-potential antiviral marine alkaloids against SARS-CoV-2-Mpro. Proteins, 90(9), 1617-1633. https://doi.org/10.1002/prot.26341.

The Lancet (2023). Diabetes: a defining disease of the 21st century. Lancet 401(10394), 2087.504. https://doi.org/10.1016/S0140-6736(23)01296-5

Tyagi, K., Kumar, D., & Gupta, R. (2024). Application of Genetic Algorithms for Medical Diagnosis of Diabetes Mellitus. International Journal of Experimental Research and Review, 37(Special Vo), 1-10. https://doi.org/10.52756/ijerr.2024.v37spl.001

Vikhe, S., Aladi, P., & Vikhe, R. (2024). Antidiabetic and antihyperlipidemic effects of crude fractions from Chlorophytum borivilianum root methanolic extract on streptozotocin induced diabetic rats and phytochemical investigation by LCMS analysis. International Journal of Experimental Research and Review, 38, 26-36. https://doi.org/10.52756/ijerr.2024.v38.003

Visvanathan, R., & Williamson, G. (2023). Citrus polyphenols and risk of type 2 diabetes: Evidence from mechanistic studies. Crit. Rev. Food Sci. Nutr., 63(14), 2178-2202. https://doi.org/10.1080/10408398.2021.1971945.

WHO (2024). Diabetes: https://www.who.int/health-topics/diabetes#tab=tab_1. (Accessed on 2nd April 2024).