β-glucogallin from (Muntingia calabura L.) as glaucoma inhibitor: an in silico study

Year 2026, Volume: 30 Issue: 1, 13 - 27, 11.01.2026

Darlah Immaria Ulfa , Eko Suyanto , Turhadi Turhadi , Nia Kurnianingsih , Fatchiyah Fatchiyah

https://doi.org/10.12991/jrespharm.1630476

Abstract

Glaucoma causes permanent vision loss by damaging the optic nerve and retinal ganglion cells, increasing intraocular pressure, and involving toxic inflammatory factors that contribute to cell death and disease progression. Owing to the frequent adverse effects of current medicines, safer alternatives are required. Cherry fruit (Muntingia calabura L.) contains β-glucogallin, which has antioxidant and anti-inflammatory properties; however, the potential of β-glucogallin as a neurodegenerative inhibitor in glaucoma has not been thoroughly examined in in silico studies. The potential of β-glucogallin in inhibiting the signaling pathway of TNFR1, matrix metalloproteinase 9 (MMP9), and endothelin receptor B (ETRB) linked to neurodegenerative illnesses in glaucoma is investigated in this work. The Protein Data Bank database provided ETRB, TNFR1, and MMP9, whereas the PubChem database provided the β-glucogallin. PyRx was used for molecular docking, which was visualized using PyMOL and Biovia Discovery Studio. YASARA software was used for molecular dynamics simulations. According to the molecular prediction, β-glucogallin and drug control of ETRB, TNFR1, and MMP9 had comparable interactions and equivalent binding affinities. Residues of Asn158 and Trp336 were identified in the interaction between β-glucogallin and the drug control on ETRB, Ser74, Arg77, and Lys75 in the interaction on TNFR1, Val145, and Pro146 in the interaction on MMP9. According to the RMSD backbone, number of hydrogen bonds, and RMSF value, the protein was stable and the interaction between β-glucogallin and TNFR-1 and MMP9 was stable; these results demonstrate the potential of β-glucogallins from Muntingia calabura L. as neurodegenerative glaucoma inhibitors.

Keywords

β-glucogallin , fruits , glaucoma , Muntingia calabura L. , molecular docking and dynamics

References

• [1] Allison K, Patel D, Alabi O. Epidemiology of glaucoma: the past, present, and predictions for the future. Cureus. 2020;12(11):e11686. https://doi.org/10.7759/cureus.11686.
• [2] Kemenkes RI 2023. https://kemkes.go.id/id/pnpk-2023---tata-laksana-glaukoma (accessed January 30, 2024).
• [3] JEC World Glaucoma Week & Bakti Katarak 2020. https://jec.co.id/id/article/jec-world-glaucoma-week-bakti-katarak-2020 (accessed May 6, 2024).
• [4] Thomas CN, Berry M, Logan A, Blanch RJ, Ahmed Z. Caspases in retinal ganglion cell death and axon regeneration. Cell Death Discov. 2017; 3: 17032. https://doi.org/10.1038/cddiscovery.2017.32.
• [5] Minton AZ, Phatak NR, Stankowska DL, He S, Ma HY, Mueller BH, Jiang M, Luedtke R, Yang S, Brownlee C, Krishnamoorthy RR. Endothelin b receptors contribute to retinal ganglion cell loss in a rat model of glaucoma. PLoS One. 2012;7(8):e43199. https://doi.org/10.1371/journal.pone.0043199.,
• [6] Schlotzer‐Schrehardt KAU, Lommatzsch J, Kuchle M, GO N. Matrix metalloproteinases and their inhibitors in aqueous humor of patients with pseudoexfoliation syndrome/glaucoma and primary open‐angle glaucoma. Invest Ophthalmol Vis Sci. 2003; 44(3): 1117‐1125. https://doi.org/10.1167/iovs.02-0365.
• [7] Tsai CL, Chen WC, Hsieh HL, Chi PL, Der Hsiao L, Yang CM. TNF-α induces matrix metalloproteinase-9-dependent soluble intercellular adhesion molecule-1 release via TRAF2-mediated MAPKs and NF-κB activation in osteoblast-like MC3T3-E1 cells. J Biomed Sci. 2014; 21(1): 12. https://doi.org/10.1186/1423-0127-21-12.
• [8] Schmickl CN, Owens RL, Orr JE, Edwards BA, Malhotra A. Side effects of acetazolamide: a systematic review and meta-analysis assessing overall risk and dose dependence. BMJ Open Respir Res. 2020;7(1):e000557. https://doi.org/ 10.1136/bmjresp-2020-000557.
• [9] Yang K, Zhang L, Liao P, Xiao Z, Zhang F, Sindaye D, Xin Z, Tan C, Deng J, Yin Y, Deng B. Impact of gallic acid on gut health: focus on the gut microbiome, immune response, and mechanisms of action. Front Immunol. 2020;11:580208. https://doi.org/10.3389/fimmu.2020.580208.
• [10] Pereira GA, Arruda HS, de Morais DR, Eberlin MN, Pastore GM. Carbohydrates, volatile and phenolic compounds composition, and antioxidant activity of calabura (Muntingia calabura L.) fruit. Food Res Int. 2018; 108: 264–273. https://doi.org/10.1016/j.foodres.2018.03.046.
• [11] Thangaraj P. Medicinal Plants Promising Future for Health and New Drugs, first ed., Boca Raton: CRC Press, USA 2018.
• [12] Suyanto E, Gorantla JG, Santi M, Fatchiyah F, Kedutat-Cairns M, Talabnin C, Kedutat Cairns JR. Enzymatic synthesis of phenolic acid glucosyl esters to test activities on cholangiocarcinoma cells. Appl Microbiol Biotechnol. 2024; 108(1): 69. https://doi.org/10.1007/s00253-023-12895-5.
• [13] Khan AN, Bhattacharya A, Chakravarti R, Sing R. A short review on glucogallin and its pharmacological activities. Mini Rev Med Chem. 2022; 22(22): 2820–2830. https://doi.org/10.2174/1389557522666220513150907.
• [14] Panchal SS, Patidar RK, Jha AB, Allam AA, Ajarem J, Butani SB. Anti-inflammatory and antioxidative stress effects of oryzanol in glaucomatous rabbits. J Ophthalmol. 2017;2017:1468716. https://doi.org/10.1155/2017/1468716.
• [15] Cao T, Wang J, Wu Y, Wang L, Zhang H. Antiglaucoma potential of β-glucogallin is mediated by modulating mitochondrial responses in experimentally induced glaucoma. Neuroimmunomodulation. 2021; 27(3): 142-151. https://doi.org/10.1159/000512992.
• [16] Ortí-Casañ N, Boerema AS, Köpke K, Ebskamp A, Keijser J, Zhang Y, Chen T, Dolga AM, Broersen K, Fischer R, Pfizenmaier K, Kotermann RE, Eisel ULM. The TNFR1 antagonist atrosimab reduces neuronal loss, glial activation and memory deficits in an acute mouse model of neurodegeneration. Sci Rep. 2023; 13(1): 10622. https://doi.org.10.1038/s41598-023-36846-2.
• [17] Caban M, Owczarek K, Lewandowska U. The role of metalloproteinases and their tissue inhibitors on ocular diseases: focusing on potential mechanisms. Int J Mol Sci. 2022; 23(8): 4256. https://doi.org/10.3390/ijms23084256.
• [18] Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL. Quantifying the chemical beauty of drugs. Nat Chem. 2012; 4(2): 90–98. https://doi.org/10.1038/nchem.1243.
• [19] Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018; 46: W257–W263. https://doi.org/10.1093/nar/gky318.
• [20] Adams L, Afiadenyo M, Kwofie SK, Wilson MD, Kusi KA, Obiri-Yeboah D, Moane S, McKeon-Bennett M. In silico screening of phytochemicals from Dissotis rotundifolia against Plasmodium falciparum dihydrofolate reductase. Phytomed Plus. 2023; 3(2): 100447. https://doi.org/10.1016/j.phyplu.2023.100447.
• [21] Cascone AA, Lamberti S, Marra G, Titomanlio F, d’amore G, Barba M. Gastrointestinal behavior and ADME phenomena: i. in vitro simulation. J Drug Deliv Sci Technol. 2016; 35: 272–283. https://doi.org/10.1016/j.jddst.2016.08.002.
• [22] Chagas L, Moss CM, Alisaraie S. Drug metabolites and their effects on the development of adverse reactions: revisiting Lipinski’s rule of five. Int J Pharm. 2018; 549(1–2): 133–149. https://doi.org/10.1016/j.ijpharm.2018.07.046.
• [23] Tanchuk G, Tanin VY, Vovk VO, Poda AI. A new, improved hybrid scoring function for molecular docking and scoring based on AutoDock and AutoDock Vina. Chem Biol Drug Des. 2016; 87(4): 618–625. https://doi.org/10.1111/cbdd.12697.
• [24] Galiè N, Hoeper MM, Gibbs JSR, Simonneau G. Liver toxicity of sitaxentan in pulmonary arterial hypertension. Eur Heart J. 2011; 32(4): 386–387. https://doi.org/10.1093/eurheartj/ehr001.
• [25] Pantsar T, Poso A. Binding affinity via docking: fact and fiction. Molecules. 2018; 23(8): 1899. https://doi.org/ 10.3390/molecules23081899.
• [26] Davenport AP, Kuc RE, Southan C, Maguire JJ. New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res. 2018; 67(1): S37–S54. https://doi.org/10.33549/physiolres.933872.
• [27] Dhaun N, Moorhouse R, Macintyre IM, Melville V, Oozthuyzen W, Kimmitt RA, Brown KE, Kennedy ED, Goddard J, Webb DJ. Diurnal variation in blood pressure and arterial stiffness in chronic kidney disease: the role of endothelin-1. Hypertension. 2014; 64(2): 296–304. https://doi.org/10.1161/HYPERTENSIONAHA.114.03533.
• [28] Weinelt N, Karathanasis C, Sonja S, Medler J, Malkusch S, Fulda S, Wajant H, Heilemann H, van Wijk SJL. Quantitative single-molecule imaging of TNFR1 reveals zafirlukast as antagonist of TNFR1 clustering and TNFα-induced NF-ĸB signaling. J Leukoc Biol. 2021; 109(2): 363–371. https://doi.org/ 10.1002/JLB.2AB0420-572RR.
• [29] Saddala MS, Huang H. Identification of novel inhibitors for TNFα, TNFR1 and TNFα-TNFR1 complex using pharmacophore-based approaches. J Transl Med. 2019; 17(1): 215. https://doi.org/10.1186/s12967-019-1965-5.
• [30] Paschalis EI, Zhou C, Sharma J, Dohlman TH, Kim S, Lei F, Chodosh J, Vavvas D, Urtti A, Papaliodis G, Dohlman CH. The prophylactic value of TNF-α inhibitors against retinal cell apoptosis and optic nerve axon loss after corneal surgery or trauma. Acta Ophthalmol. 2024; 102(3): e381–e394. https://doi.org/10.1111/aos.15786.
• [31] Thoh SK, Kumar M, Nagarajaram P, Manna AH. Azadirachtin interacts with the tumor necrosis factor (TNF) binding domain of its receptors and inhibits TNF-induced biological responses. J Biol Chem. 2012; 287(17): 8561 htpps://doi.org/ 10.1074/jbc.A109.065847.
• [32] Alves R, Pires A, Jorge J, Balça-Silva J, Gonçalves AC, Sarmento-Ribeiro AB. Batimastat induces cytotoxic and cytostatic effects in in vitro models of hematological tumors. Int J Mol Sci. 2024; 25(8): 4554. https://doi.org/ 10.3390/ijms25084554.
• [33] Belal A, Elanany MA, Santali EY, Al-Karmalawy AA, Aboelez MO, Amin AH, Abdellattif MH, Mehany ABM, Elkady H. Screening a aanel of topical ophthalmic medications against MMP-2 and MMP-9 to investigate their potential in Keratoconus management. Molecules. 2022; 27(11): 3584. https://doi.org/10.3390/molecules27113584.
• [34] Appleby TC, Greenstein AW, Hung M, Liclican A, Velazquez M, Villaseñor AG, Wang R, Wong MH, Liu X, Papalia GA, Schultz BE, Sakowicz R, Smith V, Kwon HJ. Biochemical characterization and structure determination of a potent, selective antibody inhibitor of human MMP9. J Biol Chem. 2017; 292(16): 6810–6820. https://doi.org/10.1074/jbc.M116.760579.
• [35] Lommatzsch C, Rothauzs K, Schopmeyer L, Feldmenn M, Bauer D, Grisanti S, Heinz C, Kasper M. Elevated endothelin-1 levels as risk factor for an impaired ocular blood flow measured by OCT-A in glaucoma. Sci Rep. 2022; 12(1): 11801. https://doi.org/10.1038/s41598-022-15401-5.
• [36] Jung Y, Ohn K, Shin H, Oh SE, Park CK, Park HYL. Factors associated with elevated tumor necrosis factor-α in aqueous humor of patients with open-angle glaucoma. J Clin Med. 2022; 11(17): 5232. https://doi.org/ 10.3390/jcm11175232.
• [37] Sahay P, Rao A, Padhy D, Sarangi S, Das G, Reddy MM, Modak R. Functional activity of matrix metalloproteinases 2 and 9 in tears of patients with glaucoma. Invest Ophthalmol Vis Sci. 2017; 58(6): 106–113. https://doi.org/10.1167/iovs.17-21723.
• [38] Munemasa Y, Kitaoka Y. Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection. Front Cell Neurosci. 2012; 6: 60. https://doi.org/ 10.3389/fncel.2012.00060.
• [39] Kim BK, Goncharov T, Archaimbault SA, Roudnicky F, Webster JD, Westenskow PD, Vucic D. RIP1 inhibition protects retinal ganglion cells in glaucoma models of ocular injury. Cell Death Differ. 2025; 32: 353–368. https://doi.org/10.1038/s41418-024-01390-7.
• [40] Wathon S, Oktarianti R, Senjarini K. Molecular docking of interaction between D7 protein from the salivary gland of Aedes aegypti and Leukotriene A4 for developing thrombolytic agent. BIO Web Conf. 2024; 101: 14. https://doi.org/ 10.1051/bioconf/202410104002.
• [41] Fatima I, Ihsan H, Masoud MS, Kalsoom S, Aslam S, Rehman A, Ashfaq UA, Qasim M. Screening of drug candidates against Endothelin-1 to treat hypertension using computational based approaches: Molecular docking and dynamics simulation. PLoS One. 2022;17(8):e0269739. https://doi.org/ 10.1371/journal.pone.0269739. Retraction in: PLoS One. 2023;18(4):e0284670. https://doi.org/10.1371/journal.pone.0284670.
• [42] Tani K, Maki-Yonekura S, Kanno R, Negami T, Hamaguchi T, Hall M, Mizoguchi A, Humbel BM, Terada T, Yonekura K, Doi T. Structure of endothelin ETB receptor–Gi complex in a conformation stabilized by unique NPxxL motif. Commun Biol. 2024; 7(1): 1303. https://doi.org/10.1038/s42003-024-06905-z.
• [43] Nagiri C, Shihoya W, Inoue A, Kadji FMN, Aoki J, Nureki O. Crystal structure of human endothelin ETB receptor in complex with peptide inverse agonist IRL2500. Commun Biol. 2019; 2: 236. https://doi.org/10.1038/s42003-019-0482-7.
• [44] Mathpal S, Sharma P, Joshi T, Pande V, Mahmud S, Jeong MK, Obaidullah AJ, Chandra S, Kim B. Identification of zinc-binding inhibitors of matrix metalloproteinase-9 to prevent cancer through deep learning and molecular dynamics simulation approach. Front Mol Biosci. 2022; 9: 857430. https://doi.org/ 10.3389/fmolb.2022.857430.
• [45] Amrulloh LSWF, Harmastuti N, Prasetiyo A, Herowati R. Analysis of molecular docking and dynamics simulation of mahogany (Swietenia macrophylla King) compounds against the PLpro Enzyme SARS-COV-2. JFIKI. 2023; 10(3): 347–359. https://doi.org/10.20473/jfiki.v10i32023.347-359.
• [46] Pace CN, Fu H, Fryar KL, Landua J, Trevino SR, Schell D, Thurlkill RL, Imura S, Scholtz JM, Gajiwala K, Sevcik J, Urbanikova L, Myers JK, Takano K, Hebert EJ, Shirley BA, Grimsley GR. Contribution of hydrogen bonds to protein stability. Protein Sci. 2014; 23(5): 652–661. https://doi.org/ 10.1002/pro.2449.
• [47] Martínez L. Automatic identification of mobile and rigid substructures in molecular dynamics simulations and fractional structural fluctuation analysis. PLoS One. 2015; 10(3): e0119264. https://doi.org/10.1371/journal.pone.0119264.
• [48] Fatchiyah F, Meidinna HN, Suyanto E. The cyanidin-3-O-glucoside of Black Rice inhibits the interaction of HMG-CoA and HMG-CoA reductase: three-and two-dimension structure. J Phys Conf Ser. 2020; 1665: 1-5. https://doi.org/10.1088/1742-6596/1665/1/012005.
• [49] Narwasthu S, Fahmi M, Kurnianingsih N, Wihastuti TA, Fatchiyah F. Screening of potential compounds in tomato (Solanum lycopersicum) as candidates for anti diabetes mellitus complications. Indones J Chem. 2024; 24(4): 1170. https://doi.org/10.22146/ijc.93505.
• [50] Caasi JMN, Baldoza RIDG, Bauzon MSC, Odtohan MAF, Santiago LA, Santiago-Bautista MR. In silico prediction of selected bioactive compounds present in Alpinia elegans (C.Presl) K.Schum seed oil as potential drug candidates against human cancer cell lines. Asian Pac J Cancer Prev. 2023; 24(8): 2601–2614. https://doi.org/ 10.31557/APJCP.2023.24.8.2601.
• [51] Priyadi M, Saputra RR. Anticaries potential of temu kunci-serai ethyl acetate extract combination: in vitro and molecular studies approach. Chempublish J. 2023; 7(1): 18–30. https://doi.org/10.22437/chp.v7i1.26098.
• [52] Kurnianingsih N, Harbiyanti NT, Galih Prakosa A, Ratnawati R, Fatchiyah F. In silico study of the 5-Hydroxytryptamine-2C receptor antagonist activity of anthocyanins as antidepressant therapy. JOMALISC. 2023; 2(1): 88-95. https://doi.org/10.11113/jomalisc.v2.29.
• [53] A’yunin Q, Fatchiyah F, Maftuch M, Hermanto FE, Widyananda MH, Hartana NS, Rifa'i M, Jatmiko YD. A potential of watercress Nasturtium officinale bioactive compounds in inhibiting infectious myonecrosis virus (IMNV) by targeting RNA-dependent RNA polymerase (RdRp) Virus from several countries: in silico approach. KIJOMS. 2024; 10(2): 222–231. https://doi.org/10.33640/2405-609X.3351.
• [54] Nafisah W, Fatchiyah F, Widyananda MH, Christina YI, Rifa'i M, Widodo N, Djati MS. Potential of bioactive compound of Cyperus rotundus L. rhizome extract as inhibitor of PD-L1/PD-1 interaction: an in silico study. Agric Nat Resour. 2022; 56(4): 751–760. https://doi.org/10.34044/J.ANRES.2022.56.4.09.
• [55] Widyananda MH, Fatchiyah F, Muflikhah L, Ulfa SM, Widodo N. Computational examination to reveal kaempferol as the most potent active compound from Euphorbia hirta against breast cancer by targeting AKT1 and ERα. Egypt J Basic Appl Sci. 2023; 10(1): 753–767. https://doi.org/10.1080/2314808X.2023.2272385.
• [56] Cheng S, Wang HN, Xu LJ, Li F, Miao Y, Lei B, Sun X, Wang Z. Soluble tumor necrosis factor-alpha-induced hyperexcitability contributes to retinal ganglion cell apoptosis by enhancing Nav1.6 in experimental glaucoma. J Neuroinflammation. 2021; 18(1): 182. https://doi.org/10.1186/s12974-021-02236-6.
• [57] Mahabadi N, Zeppieri M, Tripathy K. Open angle glaucoma, in National Library of Medicine, StatPearls Publishing LLC, USA 2024.
• [58] Thoh M, Kumar P, Nagarajaram HA, Manna SK. Azadirachtin interacts with the tumor necrosis factor (TNF) binding domain of its receptors and inhibits TNF-induced biological responses. J Biol Chem. 2010; 287(17): 8561. https:// doi.org/10.1074/jbc.A109.065847.
• [59] Zhang J, Zhao H, Zhou Q, Yang X, Qi H, Zhao Y, Yang L. Discovery of cyclic peptide inhibitors targeted on TNFα-TNFR1 from computational design and bioactivity verification. Molecules. 2024; 29(21): 5147. https://doi.org/10.3390/molecules29215147.