Screening of Potential Compounds in Tomato ( Solanum lycopersicum ) as Candidates for Anti Diabetes Mellitus Complications

Sekararum Narwasthu; Muhamad Fahmi; Nia Kurnianingsih; Titin Andri Wihastuti; Fatchiyah Fatchiyah

doi:10.22146/ijc.93505

Screening of Potential Compounds in Tomato (Solanum lycopersicum) as Candidates for Anti Diabetes Mellitus Complications

https://doi.org/10.22146/ijc.93505

Sekararum Narwasthu⁽¹⁾, Muhamad Fahmi⁽²⁾, Nia Kurnianingsih⁽³⁾, Titin Andri Wihastuti⁽⁴⁾, Fatchiyah Fatchiyah^(5*)

(1) Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Brawijaya, Jl. Veteran 10-11, Malang 65145, Indonesia; Research Center of Smart Molecule of Natural Genetics Resources, Universitas Brawijaya, Jl. Veteran 10-11, Malang 65145, Indonesia
(2) Research Department, Research Institute for Humanity and Nature, 457-4 Motoyama, Kamigamo, Kita-ku, Kyoto 6038047, Japan
(3) Department of Physiology, Faculty of Medicine, Universitas Brawijaya, Jl. Veteran 10-11, Malang 65145, Indonesia
(4) Department of Biomedical, Medical Faculty, Brawijaya University, Malang, Indonesia
(5) Department of Biology, Faculty of Mathematics and Natural Sciences, Universitas Brawijaya, Jl. Veteran 10-11, Malang 65145, Indonesia; Research Center of Smart Molecule of Natural Genetics Resources, Universitas Brawijaya, Jl. Veteran 10-11, Malang 65145, Indonesia
(*) Corresponding Author

Abstract

This study aimed to identify the potential of natural compounds in tomatoes for diabetic complications intervention using amino acid profile, HP-TLC, antioxidant assay, enzymatic inhibitor assay, and in silico approach. Fresh air-dried tomatoes were analyzed for several screening assays including amino acid determination, HP-TLC, antioxidant activity using FRAP, α-amylase, and α-glucosidase enzyme inhibition. Virtual screening, molecular docking and molecular dynamics were performed using Molinspiration, pKcSM, AutoDock Vina, Discovery Studio, PyMOL, and Yasara software. Tomato bioactive compounds showed promising drug-likeness, antioxidant and α-amylase/glucosidase inhibitory activities, and potential for AGE-RAGE interaction. Out of 19 compounds from whole tomatoes complying with Lipinski’s rule of five, genistein, apigenin, and naringenin exhibited high oral absorption potential. Tomato contains genistein compound based on HP-TLC and the compound has high antioxidant and antidiabetic activities. Genistein has a stronger binding affinity with RAGE compared to AGE, indicating its potential as a competitive inhibitor. Additionally, genistein displayed stable ligand movements and higher binding energy values in MD simulations compared to the control. These findings suggest the potential of tomato bioactive compounds for further development as antidiabetic agents targeting AGE-RAGE interaction. In conclusion, genistein in tomatoes is indicated as a candidate for anti-complications of diabetes mellitus.

Keywords

AGEs; diabetes; genistein; RAGE; tomatoes

Full Text:

Full Text PDF Full Text PDF-Suppl. Data

References

[1] Bestari, I.L., 2020, Characteristics of patients with type 2 diabetes mellitus at Surabaya haji general hospital, Indones. J. Public Health, 15 (3), 286–294.

[2] Magliano, D.J., Boyko, E.J., and IDF Diabetes Atlas 10^th Edition Scientific Committee, 2021, IDF Diabetes Atlas, International Diabetes Federation, Brussels, Belgium.

[3] Ratnasari, I., Ngadiarti, I., and Fauziyah, L., 2022, Application of diabetes self-management education and support in outpatients with type II DM, Media Gizi Indonesia, 17 (1), 43–50.

[4] Sunday, H.G., Sadia, A.H., and Ojo, O.G., 2022, Mechanisms of diabetes mellitus progression: A review, J. Diabetic Nephropathy Diabetes Manage., 1 (1), 1–5.

[5] Wu, Y., Fu, R., Lei, C., Deng, Y., Lou, W., Wang, L., Zheng, Y., Deng, X., Yang, S., Wang, M., Zhai, Z., Zhu, Y., Xiang, D., Hu, J., Dai, Z., and Gao, J., 2021, Estimates of type 2 diabetes mellitus burden attributable to particulate matter pollution and its 30-year change patterns: A systematic analysis of data from the global burden of disease study 2019, Front. Endocrinol., 12, 689079.

[6] Bongarzone, S., Savickas, V., Luzi, F., and Gee, A.D., 2017, Targeting the receptor for advanced glycation endproducts (RAGE): A medicinal chemistry perspective, J. Med. Chem., 60 (17), 7213–7232.

[7] Perrone, A., Giovino, A., Benny, J., and Martinelli, F., 2020, Advanced glycation end products (AGEs): Biochemistry, signaling, analytical methods, and epigenetic effects, Oxid. Med. Cell. Longevity, 2020, 3818196.

[8] Xu, K., Zhang, L., Yu, N., Ren, Z., Wang, T., Zhang, Y., Zhao, X., and Yu, T., 2023, Effects of advanced glycation end products (AGEs) on the differentiation potential of primary stem cells: A systematic review, Stem Cell Res. Ther., 14 (1), 74.

[9] Prasad, C., Davis, K.E., Imrhan, V., Juma, S., and Vijayagopal, P., 2019, Advanced glycation end products and risks for chronic diseases: Intervening through lifestyle modification, Am. J. Lifestyle. Med., 13 (4), 384–404.

[10] Oshitari, T., 2023, Advanced glycation end-products and diabetic neuropathy of the retina, Int. J. Mol. Sci., 24 (3), 2927.

[11] Wong, C.Y., Leong, K.H., He, X., Zheng, F., Sun, J., Wang, Z., Heh, C.H., and Kong, K.W., 2022, Phytochemicals of six selected herbal plants and their inhibitory activities towards free radicals and glycation, Food Biosci., 46, 101557.

[12] Kumar, M., Tomar, M., Bhuyan, D.J., Punia, S., Grasso, S., Sá, A.G.A., Carciofi, B.A.M., Arrutia, F., Changan, S., Radha, R., Singh, S., Dhumal, S., Senapathy, M., Satankar, V., Anitha, T., Sharma, A., Pandiselvam, R., Amarowicz, R., and Mekhemar, M., 2021, Tomato (Solanum lycopersicum L.) seed: A review on bioactives and biomedical activities, Biomed. Pharmacother., 142, 112018.

[13] Rowaiye, A.B., Oli, A.N., Onuh, O.A., Emeter, N.W., Bur, D., Obideyi, O.A., Dayisi, O.C., Akpa, J.N., Birah, L., Omaka, E.E., Iseghohi, F.O., Otitoju, A.P., Uzor, P.F., and Okoyeh, J.N., 2022, Rhamnetin is a better inhibitor of SARS-CoV-2 2’-O-methyltransferase than dolutegravir: A computational prediction, Afr. J. Infect. Dis., 16 (2), 80–96.

[14] Kirtishanti, A., Siswandono, S., Hardjono, S., and Kesuma, D., 2020, Molecular docking of benzoylurea derivatives as potential anti-breast cancer agent and its ADMET profiles, J. Global Pharma Technol., 12 (6), 726–735.

[15] Abdullah, M.A., Al Dajah, S., Abu Murad, A., El-Salem, A.M., and Khafajah, A.M., 2019, Extraction, purification, and characterization of lycopene from jordanian vine tomato cultivar, and study of its potential natural antioxidant effect on samen baladi, Curr. Res. Nutr. Food Sci., 7 (2), 532–546.

[16] Bettaiah, A., and Prabhushankar, H.B., 2021, Screening of novel source for genistein by rapid and sensitive UPLC-APCI-TOF mass spectrometry, Int. J. Food Sci., 2021, 5537917.

[17] Fatchiyah, F., Sari, D.R.T., Safitri, A., and Cairns, J.R.K., 2020, Phytochemical compound and nutritional value in black rice from Java Island, Indonesia, Syst. Rev. Pharm., 11 (7), 414–421.

[18] Oresanya, I.O., Sonibare, M.A., Gueye, B., Balogun, F.O., Adebayo, S., Ashafa, A.O.T., and Morlock, G., 2020, Isolation of flavonoids from Musa acuminata Colla (Simili radjah, ABB) and the in vitro inhibitory effects of its leaf and fruit fractions on free radicals, acetylcholinesterase, 15-lipoxygenase, and carbohydrate hydrolyzing enzymes, J. Food Biochem., 44 (3), e13137.

[19] Agustin, A.T., Safitri, A., and Fatchiyah, F., 2021, Java red rice (Oryza sativa L.) nutritional value and anthocyanin profiles and its potential role as antioxidant and anti-diabetic, Indones. J. Chem, 21 (4), 968–978.

[20] Safitri, A., Roosdiana, A., Kurnianingsih, N., Fatchiyah, F., Mayasari, E., and Rachmawati, R., 2022, Microencapsulation of Ruellia tuberosa L. aqueous root extracts using chitosan-sodium tripolyphosphate and their in vitro biological activities, Scientifica, 2022, 9522463.

[21] Fatchiyah, F., Safitri, A., Palis, C.N., Sari, D.R.T., Suyanto, E., Fajriani, S., Kurnianingsih, N., Nugraha, Y., Sitaresmi, T., Kusbiantoro, B., and Ketudat-Cairns, J.R., 2023, Bioactive compound profile and their biological activities of endogenous black rice from Java and East Nusa Tenggara, CyTA - J. Food, 21 (1), 159–170.

[22] Agustin, A.T., Safitri, A., and Fatchiyah, F., 2020, An in silico approach reveals the potential function of cyanidin-3-O-glucoside of red rice in inhibiting the advanced glycation end products (AGES)-receptor (RAGE) signaling pathway, Acta Inform. Med., 28 (3), 170–179.

[23] Grahadi, R., Fatchiyah, F., and Kurniawan, N., 2022, Virtual prediction of potential immunogenic epitope of candoxin protein from Malayan krait (Bungarus candidus) venom, J. Pharm. Pharmacogn. Res., 10 (6), 1046–1057.

[24] Dallakyan, S., and Olson, A.J., 2015, “Small-Molecule Library Screening by Docking with PyRx” in Chemical Biology: Methods and Protocols, Eds. Hempel, J.E., Williams, C.H., and Hong, C.C., Springer, New York, US, 243–250.

[25] Trott, O., and Olson, A.J., 2010, AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, J. Comput. Chem., 31 (2), 455–461.

[26] Haque, A., Baig, G.A., Alshawli, A.S., Sait, K.H.W., Hafeez, B.B., Tripathi, M.K., Alghamdi, B.S., Mohammed Ali, H.S.H., and Rasool, M., 2022, Interaction Analysis of MRP1 with anticancer drugs used in ovarian cancer: In silico approach, Life, 12 (3), 383.

[27] Yuan, S., Chan, H.C.S., and Hu, Z., 2017, Using PyMOL as a platform for computational drug design, WIREs Comput. Mol. Sci., 7 (2), e1298.

[28] Wargasetia, T.L., Ratnawati, H., Widodo, N., and Widyananda, M.H., 2023, Antioxidant and anti-inflammatory activity of sea cucumber (Holothuria scabra) active compounds against KEAP1 and iNOS protein, Bioinf. Biol. Insights, 17, 11779322221149613.

[29] Kurnianingsih, N., Harbiyanti, N.T., Prakosa, A.G., Ratnawati, R., and Fatchiyah, F., 2022, Materials in life sciences in silico study of the 5-hydroxytryptamine-2C receptor antagonist activity of anthocyanins as antidepressant therapy, J. Mater. Life Sci., 2 (1), 88–95.

[30] Sampat, G., Suryawanshi, S.S., Palled, M.S., Patil, A.S., Khanal, P., and Salokhe, A.S., 2022, Drug likeness screening and evaluation of physicochemical properties of selected medicinal agents by computer aided drug design tools, Adv. Pharmacol. Pharm., 10 (4), 234–246.

[31] Padmi, H., Kharisma, V.D., Ansori, A.N.M., Sibero, M.T., Widyananda, M.H., Ullah, M.E., Gumenyuk, O., Chylichcova, S., Bratishko, N., Prasedya, E.S., Sucipto, T.H., and Rahadian, Z., 2022, Macroalgae bioactive compounds for the potential antiviral of SARS-CoV-2: An in silico study, J. Pure Appl. Microbiol., 16 (2), 1018–1027.

[32] Ivanović, V., Rančić, M., Arsić, B., and Pavlović, A., 2020, Lipinski’s rule of five, famous extensions and famous exceptions, Chem. Naissensis, 3 (1), 171–177.

[33] Adianingsih, O.R., Khasanah, U., Anandhy, K.D., and Yurina, V., 2022, In silico ADME-T and molecular docking study of phytoconstituents from Tithonia diversifolia (Hemsl.) A. Gray on various targets of diabetic nephropathy, J. Pharm. Pharmacogn. Res., 10 (4), 571–594.

[34] Izatunnafis, I., Murti, Y.B., and Sudarmanto, B.S.A., 2023, In silico Pharmacokinetic and toxicity prediction of compounds from Andrographis paniculata (Burm.f.) Nees., J. Food. Pharm. Sci., 11 (2), 830–838.

[35] Zackria, A.A., Pattabiraman, R., Murthy, T.P.K., Kumar, S.B., Mathew, B.B., and Biju, V.G., 2022, Computational screening of natural compounds from Salvia plebeia R. Br. for inhibition of SARS-CoV-2 main protease, Vegetos, 35 (2), 345–359.

[36] Okafor, S.N., Angsantikul, P., and Ahmed, H., 2022, Discovery of novel HIV protease inhibitors using modern computational techniques, Int. J. Mol. Sci., 23 (20), 12149.

[37] Elshamaa, S.M., Taha, N.M., Lebda, M.A., Hashem, A.E., and Elfeky, M.S., 2022, Zinc oxide nanoparticles alleviated hepatic oxidative stress induced by cadmium chloride toxicity in rats, Alexandria J. Vet. Sci., 73 (1), 1–7.

[38] van Sloun, B., Goossens, G.H., Erdos, B., Lenz, M., van Riel, N., and Arts, I.C.W., 2020, The impact of amino acids on postprandial glucose and insulin kinetics in humans: A quantitative overview, Nutrients, 12 (10), 3211.

[39] Vangipurapu, J., Stancáková, A., Smith, U., Kuusisto, J., and Laakso, M., 2019, Nine amino acids are associated with decreased insulin secretion and elevated glucose levels in a 7.4-year follow-up study of 5,181 Finnish men, Diabetes, 68 (6), 1353–1358.

[40] Ningsih, I.Y., Wardhani, L.K., Nuryuanda, A.R.E., Puspitasari, E., and Hidayat, M.A., 2022, Genistein content and tyrosinase inhibitory activity of edamame (Glycine max) extracts, J. Trop. Pharm. Chem., 6 (2), 92–100.

[41] Wijayanti, E.D., Safitri, A., Siswanto, D., and Fatchiyah, F., 2023, Indonesian purple rice ferulic acid as a candidate for anti-aging through the inhibition of collagenase and tyrosinase activities, Indones. J. Chem., 23 (2), 475–488.

[42] Telagari, M., and Hullatti, K., 2015, In-vitro α-amylase and α-glucosidase inhibitory activity of Adiantum caudatum Linn. and Celosia argentea Linn. extracts and fractions, Indian J. Pharmacol., 47 (4), 425–429.

[43] Srivalli, R., Kumari, A., Maheswari, U., Prabhakar, N., and Suneetha, J., 2013, In vitro studies on alpha amylase and alpha glucosidase inhibitory activities of selected plant extracts, Int. J. Curr. Res., 8 (12), 42739–42742.

[44] Guedes, I.A., de Magalhães, C.S., and Dardenne, L.E., 2014, Receptor-ligand molecular docking, Biophys. Rev., 6 (1), 75–87.

[45] Fatchiyah, F., Hardiyanti, F., and Widodo, N., 2015, Selective inhibition on RAGE-binding AGEs required by bioactive peptide alpha-S2 case in protein from goat Ethawah breed milk: Study of biological modeling, Acta Inform. Med., 23 (2), 90–96.

[46] Friedman, R., 2022, Computational studies of protein–drug binding affinity changes upon mutations in the drug target, WIREs Comput. Mol. Sci., 12 (1), e1563.

[47] Moysa, A., Steczkiewicz, K., Niedzialek, D., Hammerschmid, D., Zhukova, L., Sobott, F., and Dadlez, M., 2021, A model of full-length RAGE in complex with S100B, Structure, 29 (9), 989–1002.e6.

[48] Faisal, M.A., Oktaviyanti, I.K., Sujuti, H., and Rudijanto, A., 2020, Virtual screening of the active components of Garcinia mangostana Linn. Potentially inhibiting the interaction of advanced glycation end-products and their receptor, Open Access Maced. J. Med. Sci., 8 (A), 921–927.

[49] Patil, R., Das, S., Stanley, A., Yadav, L., Sudhakar, A., and Varma, A.K., 2010, Optimized hydrophobic interactions and hydrogen bonding at the target-ligand interface leads the pathways of drug-designing, PLoS One, 5 (8), e12029.

[50] Li, L., Song, Q., Zhang, X., Yan, Y., and Wang, X., 2022, Allicin alleviates diabetes mellitus by inhibiting the formation of advanced glycation end products, Molecules, 27 (24), 8793.

[51] Liu, K., Watanabe, E., and Kokubo, H., 2017, Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations, J. Comput.-Aided Mol. Des., 31 (2), 201–211.

[52] Yun, S., and Guy, H.R., 2011, Stability tests on known and misfolded structures with discrete and all atom molecular dynamics simulations, J. Mol. Graphics Modell., 29 (5), 663–675.

DOI: https://doi.org/10.22146/ijc.93505