Virtual screening and molecular docking of red Acalypha wilkesiana leaf extract-derived compounds as SGLT2 inhibitors for Type 2 diabetes therapy

• Authors: Ujupaul Margret Ikezu , Chinyere Benardette Ikpa , Francis Chizoruo Ibe
• Languages of publication: EN

Abstracts

EN

Diabetes mellitus is a hullmark of metabolic disorder, a life – threatening condition that affect millions of individuals globally. Ethno-medicinal and scientific reports abound on the use of Acalypha wilkesiana leaf extract in managing diabetic patients. This study employed gas chromatography-mass spectrometry (GC-MS) and computational approach to investigate the phytochemical profile and potential bioactive properties of A. wilkesiana leaf. GC-MS analysis revealed distinct variations in phytochemical composition ranging from monoterpenes, sesquiterpenes, alkaloids etc,hence identify and validate hit compounds from the crude leaf extract with the potential to inhibit SGLT-2 receptor. Molecular docking results showed that the binding affinity of the hit molecule indazol-4-one, 3,6,6-trimethyl-1-phthalazin-1-yl-1,5,6,7-tetrahydro- (-10.7 kcal/mol) was very close to the control drug Sotagliflozin (–11.4 kcal /mol) at this target. ADMET analysis predicted that the properties of these compounds were within acceptable limits with the hit molecule showing better druglikeness than the conventional drug used as control. These results indicate that A. wilkesiana holds promise as a therapeutic agent for the management of diabetes, warranting further investigation into its therapeutic potential.

Keywords

EN

3-6-6-trimethyl-1-phthalazin-1-yl-1-5-6-7-tetrahydro-; Acalypha wilkesiana; Diabetes; Indazol-4-one; Sodium-glucose cotransporter 2 (SGLT2) Receptor; Sotagliflozin

Discipline

• CHEMISTRY: CHEMISTRY

• Publisher: Scientific Publishing House „DARWIN”
• Journal: World News of Natural Sciences
• Year: 2025
• Volume: 58
• Pages: 209-225

Contributors

author

Ujupaul Margret Ikezu

• Department of Chemistry, Imo State University, Owerri, Nigeria

author

Chinyere Benardette Ikpa

• Department of Chemistry, Imo State University, Owerri, Nigeria

author

Francis Chizoruo Ibe

• Department of Chemistry, Imo State University, Owerri, Nigeria

References

• [1] Ozougwu, J.C., Obimba, K.C., Belonwu, C.D., and Unakalamba, C.B. (2013). The pathogenesis and pathophysiology of type 1 and type 2 diabetes mellitus, J. Physiol. Pathophysiol. 4: 46–57. doi: 10.5897/JPAP2013.0001
• [2] Antar, S,A., Ashour,N,A., Sharaky, M., Khattab, M., Ashour, N,A., Zaid, R.T., Roh, J.E., Elkamhawy, A., and Al-Karmalawy, A.A., (2023). Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments. Biomedicine & Pharmacotherapy, Volume 168, 115734
• [3] Behzad, M., Saber, A., Somayeh, S., Mohsen, A., and  Fatemeh, B., (2018). The most useful medicinal herbs to treat diabetes. Vietnamese Journal for Medical Biotechnology and Medicine Incorporating Advances in Regenerative Medicine, Vol 5, No 8, 2538-2551
• [4] Wimmer, R.A., Leopoldi, A., Aichinger, M. et al. Human blood vessel organoids as a model of diabetic vasculopathy. Nature 565, 505–510 (2019). https://doi.org/10.1038/s41586-018-0858-8
• [5] Bloomgarden, Z., (2022). Novel approaches to the treatment of type 1 diabetes. J Diabetes 14: 724-726
• [6] Olokoba, A.B., Obateru, O.A., and Olokoba, L.B. (2012). Type 2 Diabetes Mellitus: A Review of Current Trends. Oman Med. J. 27: 269-273. doi: 10.5001/omj.2012.68
• [7] Sengoku, T., Ishizaki, T., Goto, Y., Iwao, T., Ohtera, S., Sakai, M., Kato, G., Nakayama, T., and Takahashi, Y., (2022). Prevalence of type 2 diabetes by age, sex and geographical area among two million public assistance recipients in Japan: a cross-sectional study using a nationally representative claims database. J Epidemiol Community Health 76(4): 391-397
• [8] Gale, E.A.M. Declassifying diabetes. Diabetologia 49, 1989–1995 (2006). https://doi.org/10.1007/s00125-006-0348-7
• [9] Sukanta, R., Arya, G., Ankit, M., Varnita ,K., Sourav, D., Subas, C.D., Anibandeep, B., and Bapi, G., (2024). Terpenoids as potential phytoconstituent in the treatment of diabetes; from preclinical advanvement. Phytomedicine 129; 155638, DOI: 10.1016/j.phymed.2024.155638
• [10] Yedjou, C.G., Grigsby, J., Mbemi, A., Daryllynn N., Mildort, B., Latinwo, L., and Tchounwou, P.B. (2023). The Management of Diabetes Mellitus Using Medicinal Plants and Vitamins. Int J Mol Sci, 24(10): 9085. doi: 10.3390/ijms24109085
• [11] Muhammad, F., (2020). Diabetes: A Silent Killer in Nigeria, Jundishapur Journal of Chronic Disease Care, vol 9, (4); e105702. https://doi.org/10.5812/jjcd.105702
• [12] Kakkar, R., (2016). Rising burden of diabetes-public health challenges and way out. Nepal J. Epidemiol. 6: 557–559. doi: 10.3126/nje.v6i2.15160
• [13] Chukwuma, C.I., Matsabisa, M.G., AuwalIbrahim, M., Ochuko, L., Erukainure, L., Chabalala M.H., and ShahidulIslam, M.D. (2019). Medicinal plants with concomitant anti-diabetic and anti-hypertensive effects as potential sources of dual acting therapies against diabetes and hypertension, Journal of Ethnopharmacology Volume 235, 329-360
• [14] Florez, J.C. Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: Where are the insulin resistance genes? Diabetologia 51, 1100-1110 (2008). https://doi.org/10.1007/s00125-008-1025-9
• [15] Liu, Z., Ma , X., Ilyas , I., Zheng, X., Luo, S., Little, S.P., Kamato, D., Sahebkar, A., Wu, W., Weng , J., and Xu, S., (2021). Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. Theranostics, 11 (2021), pp. 4502-4515
• [16] Vallon, V., (2015). The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu. Rev. Med. 66: 255-270, 10.1146/annurev-med-051013-110046
• [17] Zhang, Y., Liu, X., Zhang, H., and Wang, X., (2022). Efficacy and safety of empagliflozin on nonalcoholic fatty liver disease: a systematic review and meta-analysis. Front. Endocrinol. 13, Article 836455, 10.3389/fendo.2022.836455
• [18] Lim, S., Eckel, R.H., and Koh, K.K., (2018). Clinical implications of current cardiovascular outcome trials with sodium glucose cotransporter-2 (SGLT2) inhibitors, Atherosclerosis, 272 : 33-40, 10.1016/j.atherosclerosis.2018.03.013
• [19] Duru, I.A., Enenebeaku, U.E., Ngozi‑Olehi, L.C., Enyoh, C.E., Duru, C.E., Umar, H.I., Kuthi, N.A., Kumar, N., and Dharmarpu, V., (2024) Experimental and Computational Insights into Gangronema latifolium Leaf Compounds as GLP‑1 Receptor Agonists. The Tunisian Chemical Society and Springer Nature Switzerland AG 2024, https://doi.org/10.1007/s42250-024-00951-0
• [20] Sifuna, N. (2022). African Traditional Medicine: Its Potential, Limitations and Challenges. Journal of Healthcare 5(1): 141-150
• [21] Abiola, O.A., (2020). Acalypha wilkesiana: prospect as an agricultural biocide. Journal of Advanced Research and Reviews, 06(01), 166-172. DOI: 10.30574/wjarr.2020.6.1.0102
• [22] 22.Omage, K., and Azeke, M.A., (2014). Medicinal potential of Acalyha wilkesiana leaves. Advances in Research, vol 2(11): 655-665, Article no. AIR.2014.11.009
• [23] Omage, K., Azeke, M, A., and Omage, S.O., (2018). Evaluation of the efficacy of Acalypha wilkesiana leaves in managing cardiovascular disease risk factors in rabbits exposed to salt-loaded diets, Clinical Phytoscience volume 4, Article number: 1
• [24] Seebaluck, R., Gurib-Fakim, A. and Mahomoodally, F., (2015). Medicinal plant from the genus Acalypha (Euphorbiaceae)- a review of their ethnopharmacology and phytochemical, Journal of Ethnopharmacol 159: 137-57, doi: 10.1016/j.jep.2014.10.040PMID: 25446604
• [25] Bitwell, C., Indra, S.S., Luke, C., and Kakoma, M.K., (2023). A review of modern and conventional extraction techniques and their applications for extracting phytochemicals from plants. Sci Afr 19: e01585. https://doi.org/10.1016/j.sciaf.2023.e01585
• [26] Ikezu, U. J. M. and Ikpa,C. B. C. (2024). Computational Insights Into Leaf Compounds Of Pterocarpus Santalinoides Against Fabh Protein Receptor. J. Chem. Soc. Nigeria, vol. 49. No. 5, 716-735. DOI: https://doi.org/10.46602/jcsn.v49i5.1003
• [27] Enenebeaku, U.E., Duru, C.E., Mgbemena, I.C., Ukwandu, N.C., Nwigwe, H.C., Enenebeaku, C.K., and Okotcha, E.N. (2021). Phytochemical evaluation and molecular docking of bioactive compounds from the roots of Dictyandra arborescens (Welw.) against Plasmodium berghei protein targets. Trop J Nat Prod Res 5(2): 370–381
• [28] Ikpa, C.B.C., and Maduka, O.T. (2024). In-silico molecular studies of the phytochemicals in ethanolic extract of Chromolaena odorata against H+/K+-ATPase enzyme for Proton Pump inhibitor. J. Integr. Sci. Technol. 12(5), 801
• [29] Hiraizumi, M., Akashi, T., Murasaki, K., Kishida, H., Kumanomidou, T., Torimoto, N., Nureki, O., and Miyaguchi, I. (2024). Transport and inhibition mechanism of the human SGLT2-MAP17 glucose transporter. Nat Struct Mol Biol 31: 159-169
• [30] Duru, C.E., Duru, I.A., and Bilar, A., (2020). Computational investigation of sugar fermentation inhibition by bergenin at the pyruvate decarboxylate isoenzyme 1 target of Charomyces cervisiae. J Med Plants Stud 8(6): 21-25
• [31] Venditti, A., Serrilli , A.M., Rizza, L., and Frasca, G., (2013). Aromadendrine, anew component of the flavonoid pattern of Olea europaea L. and its anti-inflammatory activity. Nat Prod Res, 27 (4-5): 340-9. Doi: 10.1080/14786419.2012.693924
• [32] Jayachandran, P., Gayathri, R.,Jayaraman, S., Vishnu, P., and Kavitha, S. (2023). Antioxidative Stress Potential of Piperine in the Gastrocnemius Muscle of High Fat Diet and Sucrose Induced Type 2 Diabetic Rats. HIV Nursing 23(3): 81-89
• [33] Behl, T., Gupta, A., Albratty, M., Najmi, A., Meraya, A,M., Alhazmi, H.A., Anwer, K., Saurabh Bhatia, S., and Bungau, S,G., (2022). Alkaloidal Phytoconstituents for Diabetes Management: Exploring the Unrevealed Potential. Molecules 27(18): 5851. doi: 10.3390/molecules27185851
• [34] Duan, Y., Yang, X., Zeng, X., Wang, W., Deng, Y., and Cao, D. (2024). Enhancing molecular property prediction through task-oriented transfer learning: integrating universal structural insights and domain-specific knowledge. Journal of Medicinal Chemistry 67(11): 9575-9586

• Document Type: article