IN SILICO STUDY OF JATI (Tectona grandis) LEAF CONSTITUENTS AS TRADITIONAL WOUND CARE
Downloads
HIGHLIGHTS
- T. grandis leaf methanolic extract contains 82 compounds, with 17 being predominant.
- Epigallocatechin 3-O cinnamate, epigallocatechin 3-O-p-coumarate, and tectograndinol predicted as the potential bioactive compounds in wound healing
- Molecular docking suggests inhibitory activities against NF-κB, MMP-2, and MMP-9, and stimulatory activity against EGFR-1 that comparable to commercial drugs.
ABSTRACT
Wound-healing process involves a physiological cascade to restore skin integrity, which includes inflammatory response, cell proliferation, and tissue reconstruction. Prolonged inflammation in wound-healing process may lead to a chronic wound stage. Proper wound care is needed to prevent wound-caused mortality. Several studies showed the potential of T. grandis leaf in wound-healing process. However, the bioactive compounds and the molecular mechanism of T. grandis leaf remains unknown. This study aimed to identify bioactive compounds and biological activity contained in T. grandis leaf extract as well as analyze its molecular mechanism in wound-healing process by conducting in silico study using NF-κB, MMP-2, MMP-9, and EGFR-1. Bioactive compounds of T. grandis leaf extract were identified with LC-MS. Three potential compounds, epigallocatechin 3-O cinnamate, epigallocatechin 3-O-p-coumarate, and tectograndinol, were selected based on the Pa score screening with the PASS prediction. Drug-likeness and pharmacokinetics properties of the selected compounds were virtually identified by SwissADME and Protox. The interactions of T. grandis bioactive compounds toward NF-κB, MMP-2, MMP-9, and EGFR-1 were compared to those of curcumin, phenytoin, and nitrofurazone as control. Molecular docking to identify the protein-ligand interaction was performed by Autodock Vina integrated in PyRx v.0.8. Among 82 bioactive compounds detected in the LC-MS analysis, epigallocatechin 3-O-cinnamate, epigallocatechin 3-O-p coumarate, and tectograndinol exhibited anti-inflammatory, antioxidant, free radical scavenger, and MMP-9 inhibitor activities. According to Lipinski’s rule of five, bioactive compounds are possible to be administered as medication. Molecular docking showed that bioactive compounds potentially bound to the active sites of NF-κB, MMP-2, and MMP-9, resulting in proteins inhibition. This study suggested that the wound-healing mechanism of T. grandis bioactive compounds were driven by EGFR-1 stimulation indicated by the ability of bioactive compounds to interact with EGFR-1 in similar manner to those of nitrofurazone. We concluded that bioactive compounds of T. grandis leaf extract has significant potential to be used as traditional wound treatment and therapy. These compounds demonstrated wound-healing activity in silico by interacting with the key molecular targets, including NF-κB, MMP-2, MMP-9, and EGFR-1.
Akiki RK, Anand RS, Borrelli M, Sarkar IN, Liu PY, Chen ES. 2021. Predicting open wound mortality in the ICU using machine learning. J Emerg Crit Care Med 5:13. DOI: 10.21037/jeccm-20-154 DOI: https://doi.org/10.21037/jeccm-20-154
Al Mousa AA, Abouelela ME, Mansour A, Nasr M, Ali YH, Al Ghamidi NS, …, Hassane AM. 2024. Wound healing, metabolite profiling, and in silico studies of Aspergillus terreus. Curr Issues Mol Biol 46(10):11681–699. DOI: 10.3390/cimb46100694 DOI: https://doi.org/10.3390/cimb46100694
Arief II, Suryati T, Afiyah DN, Wardhani DP. 2014. Physicochemical and organoleptic of beef sausages with teak leaf extract (Tectona grandis) addition as preservative and natural dye. Int Food Res J 21(5):2033–42.
Asdaq SMB, Nayeem N, Abida, Alam MT, Alaqel SI, Imran M, …, Rabbani SI. 2022. Tectona grandis L.f: A comprehensive review on its patents, chemical constituents, and biological activities. Saudi J Biol Sci 29(3):1456–64. DOI: 10.1016/j.sjbs.2021.11.026 DOI: https://doi.org/10.1016/j.sjbs.2021.11.026
Ayuk SM, Abrahamse H, Houreld NN. 2016. The role of matrix metalloproteinases in diabetic wound healing in relation to photobiomodulation. J Diabetes Res 2897656. DOI: 10.1155/2016/2897656 DOI: https://doi.org/10.1155/2016/2897656
Banerjee P, Kemmler E, Dunkel M, Preissner R. 2024. ProTox 3.0: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res 52(W1): W513–W520. DOI: 10.1093/nar/gkae303. DOI: https://doi.org/10.1093/nar/gkae303
Bergant Suhodolčan A, Luzar B, Kecelj Leskovec N. 2021. Matrix metalloproteinase (MMP)-1 and MMP-2, but not COX-2 serve as additional predictors for chronic venous ulcer healing. Wound Repair Regen 29(5):725–31. DOI: 10.1111/wrr.12915 DOI: https://doi.org/10.1111/wrr.12915
Bodnar RJ. 2013. Epidermal growth factor and epidermal growth factor receptor: the yin and yang in the treatment of cutaneous wounds and cancer. Adv Wound Care 2(1):24–9. DOI: 10.1089/wound.2011.0326 DOI: https://doi.org/10.1089/wound.2011.0326
Budianto P, Suroto S, Wasita B, Mirawati DK. 2023. Tectona grandis leaves: determination of total flavonoid content, phenolic content, characterization of the leaves, and compound identification in GC-MS. Pharmacogn J 15(1):165–70. DOI: https://doi.org/10.5530/pj.2023.15.24
Cabral-Pacheco GA, Garza-Veloz I, Castruita-De la Rosa C, Ramirez-Acuña JM, Perez-Romero BA, Guerrero-Rodriguez JF, …, Martinez-Fierro ML. 2020. The roles of matrix metalloproteinases and their inhibitors in human diseases. Int J Mol Sci 21(24):9739. DOI: 10.3390/ijms21249739 DOI: https://doi.org/10.3390/ijms21249739
Caley MP, Martins VL, O’Toole EA. 2015. Metalloproteinases and wound healing. Adv Wound Care 4(4):225–34. DOI: 10.1089/wound.2014.0581 DOI: https://doi.org/10.1089/wound.2014.0581
Casanova ML, Larcher F, Casanova B, Murillas R, Fernández-Aceñero MJ, Villanueva C, …, Jorcano JL. 2002. A critical role for ras-mediated, epidermal growth factor receptor-dependent angiogenesis in mouse skin carcinogenesis. Cancer Res 62(12):3402–07.
Chakraborty S, Li L, Puliyappadamba VT, Guo G, Hatanpaa KJ, Mickey B, …, Habib AA. 2014. Constitutive and ligand-induced EGFR signalling triggers distinct and mutually exclusive downstream signalling networks. Nat Commun 5(1):5811. DOI: 10.1038/ncomms6811 DOI: https://doi.org/10.1038/ncomms6811
Chiang YT, Xiao YB, Hsu SH, Chang SW, Chou CC. 2023. Molecular interactions of tannic acid and matrix metalloproteinases 2 and 9. Comput Struct Biotechnol J 21:2792–2800. DOI: 10.1016/j.csbj.2023.04.011 DOI: https://doi.org/10.1016/j.csbj.2023.04.011
Comino-Sanz IM, López-Franco MD, Castro B, Pancorbo-Hidalgo PL. 2021. The role of antioxidants on wound healing: a review of the current evidence. J Clin Med 10(16):3558. DOI: 10.3390/jcm10163558 DOI: https://doi.org/10.3390/jcm10163558
Dégbé M, Debierre-Grockiego F, Tété-Bénissan A, Débare H, Aklikokou K, Dimier-Poisson I, Gbeassor M. 2018. Extract of Tectona grandis and Vernonia amygdalina have anti-toxoplasma and pro-inflammatory properties in vitro. Parasite 25:11. DOI: 10.1051/parasite/2018014 DOI: https://doi.org/10.1051/parasite/2018014
Elkins PA, Ho YS, Smith WW, Janson CA, D’Alessio KJ, McQueney MS, …, Romanic AM. 2002. Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase. Acta Crystallogr D Biol Crystallogr 58(Pt 7):1182–92. DOI: https://doi.org/10.1107/S0907444902007849
Erdur B, Ersoy G, Yilmaz O, Ozkutuk A, Sis B, Karcioglu O, …, Guryay M. 2008. A comparison of the prophylactic uses of topical mupirocin and nitrofurazone in murine crush contaminated wounds. Am J Emerg Med 26(2):137–43. DOI: 10.1107/s0907444902007849 DOI: https://doi.org/10.1016/j.ajem.2007.03.030
Fernand VE, Dinh DT, Washington SJ, Fakayode SO, Losso JN, van Ravenswaay RO, Warner IM. 2009. Determination of pharmacologically active compounds in root extracts of Cassia alata L. by use of high performance liquid chromatography. Talanta. 74(4):896–902. DOI: 10.1016/j.talanta.2007.07.033 DOI: https://doi.org/10.1016/j.talanta.2007.07.033
Filimonov DA, Lagunin AA, Gloriozova TA, Rudik AV, Druzhilovskii DS, Pogodin PV, Poroikov VV. 2014. Prediction of the biological activity spectra of organic compounds using the PASS online web resource. Chem Heterocycl Comp 50(3):444–57. DOI: 10.1007/s10593-014-1496-1 DOI: https://doi.org/10.1007/s10593-014-1496-1
Gan C, Langa E, Ballestero D, Pino-Otín MR. 2024. Comparative ecotoxicity assessment of highly bioactive isomeric monoterpenes carvacrol and thymol on aquatic and edaphic indicators and communities. Chemosphere 368:143666. DOI: 10.1016/j.chemosphere.2024.143666 DOI: https://doi.org/10.1016/j.chemosphere.2024.143666
González Y, Torres-Mendoza D, Jones GE, Fernandez PL. 2015. Marine diterpenoids as potential anti-inflammatory agents. Mediators Inflamm. 2015:263543. DOI: 10.1155/2015/263543 DOI: https://doi.org/10.1155/2015/263543
Groblewska M, Mroczko B, Gryko M, Pryczynicz A, Guzińska-Ustymowicz K, Kędra B, …, Szmitkowski M. 2014. Serum levels and tissue expression of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinases 2 (TIMP-2) in colorectal cancer patients. Tumour Biol 35(4):3793–3802. DOI: 10.1007/s13277-013-1502-8 DOI: https://doi.org/10.1007/s13277-013-1502-8
Han M, Yang F, Zhang K, Ni J, Zhao X, Chen X, …, Zhang Y. 2023. Antioxidant, anti-inflammatory and anti-diabetic activities of Tectona grandis methanolic extract, fractions, and isolated compounds. Antioxidants 12(3):664. DOI: 10.3390/antiox12030664 DOI: https://doi.org/10.3390/antiox12030664
Hasan AEZ, Artike IM, Suryani, Ramadhani DL. 2023. Molecular docking analysis of selected Curcuma xanthorrhiza constituents as potential anticancer drug. BIOTROPIA 30(1):11–20. DOI: 10.11598/btb.2023.30.1.1386 DOI: https://doi.org/10.11598/btb.2023.30.1.1386
Hingorani DV, Lippert CN, Crisp JL, Savariar EN, Hasselmann JPC, Kuo C, …, Ellies LG. 2018 Impact of MMP-2 and MMP-9 enzyme activity on wound healing, tumor growth and RACPP cleavage. PLoS One 13(9):e0198464. DOI: 10.1371/journal.pone.0198464 DOI: https://doi.org/10.1371/journal.pone.0198464
Irinmwinuwa EO, Cherechi NC, Oyate GB, Ifeyinwa OC, Chinedu JO, John-Iganga AA. 2023. A comprehensive review of phytochemistry and antibacterial action of Tectona grandis. Int J Sci Res Arch 9(2):133–43. DOI: 10.30574/ijsra.2023.9.2.0527 DOI: https://doi.org/10.30574/ijsra.2023.9.2.0527
Kandhwal M, Behl T, Singh S, Sharma N, Arora S, Bhatia S, …, Bungau S. 2022. Role of matrix metalloproteinase in wound healing. Am J Transl Res 14(7):4391–4405.
Karapolat S, Karapolat B, Buran A, Okatan BK, Turkyilmaz A, Set T, Tekinbas C. 2020. The effects of nitrofurazone on wound healing in thoracoabdominal full-thickness skin defects. Wounds 32(5):134–41.
Katajamaa M, Oresic M. 2005. Processing methods for differential analysis of LC/MS profile data. BMC bioinformatics 6:179. DOI: 10.1186/1471-2105-6-179 DOI: https://doi.org/10.1186/1471-2105-6-179
Krisnamurti GC, Sari DRT, Bare Y. 2021. Capsaicinoids from Capsicum annuum as an alternative FabH inhibitor of Mycobacterium tuberculosis: In silico study. Makara J Sci 25(4). DOI: 10.7454/mss.v25i4.1248 DOI: https://doi.org/10.7454/mss.v25i4.1248
Lee HS, Kim WJ. 2022. The role of matrix metalloproteinase in inflammation with a focus on infectious diseases. Int J Mol Sci 23(18):10546. DOI: 10.3390/ijms231810546 DOI: https://doi.org/10.3390/ijms231810546
Liu N, Wang X, Wu H, Lv X, Xie H, Guo Z, …, Sun M. 2021. Computational study of effective matrix metalloproteinase 9 (MMP9) targeting natural inhibitors. Aging 13(19):22867–882. DOI: 10.18632/aging.203581 DOI: https://doi.org/10.18632/aging.203581
Liu Z, Mi Z, Han N, Zhai J, Li S, Yin J. 2023. Diterpenoid glucosides with anti-inflammatory activity from Rubi Fructus. Fitoterapia 164:105325. DOI: 10.1016/j.fitote.2022.105325 DOI: https://doi.org/10.1016/j.fitote.2022.105325
Lv QW, Zhang W, Shi Q, Zheng WJ, Li X, Chen H, …, Zhang X. 2015. Comparison of Tripterygium wilfordii Hook F with methotrexate in the treatment of active rheumatoid arthritis (TRIFRA): A randomised, controlled clinical trial. Ann Rheum Dis 74(6):1078–86. DOI: 10.1136/annrheumdis-2013-204807 DOI: https://doi.org/10.1136/annrheumdis-2013-204807
Maleki SJ, Crespo JF, Cabanillas B. 2019. Anti-inflammatory effects of flavonoids. Food Chem 299:125124. DOI: 10.1016/j.foodchem.2019.125124 DOI: https://doi.org/10.1016/j.foodchem.2019.125124
Martin YC. 2005. A bioavailability score. J Med Chem 48(9):3164–70. DOI: 10.1021/jm0492002 DOI: https://doi.org/10.1021/jm0492002
Mikhal’chik EV, Anurov MV, Titkova SM, Miroshnikova EA, Lukasheva EV, Deeva IB, …, Korkina LG. 2006. Activity of antioxidant enzymes in the skin during surgical wounds. Bull Exp Biol Med 142(6):667–9. DOI: 10.1007/s10517-006-0446-z DOI: https://doi.org/10.1007/s10517-006-0446-z
Murukan G, Murugan K. 2018. Hepatoprotective activity of purified anthocyanin from teak leaves against CCL-4 induced hepatotoxicity in wistar albino rats and its analysis by LC-MS/MS. J. Global Trends Pharm Sci 9(2):5244–60.
Nanney LB, Paulsen S, Davidson MK, Cardwell NL, Whitsitt JS, Davidson JM. 2000. Boosting epidermal growth factor receptor expression by gene gun transfection stimulates epidermal growth in vivo. Wound Repair Regen 8(2):117–27. DOI: 10.1046/j.1524-475x.2000.00117.x DOI: https://doi.org/10.1046/j.1524-475x.2000.00117.x
Oduola T, Bello I, Adeosun G, Ademosun AW, Raheem G, Avwioro G. 2010. Hepatotoxicity and nephrotoxicity evaluation in Wistar albino rats exposed to Morinda lucida leaf extract. N Am J Med Sci. 2(5):230–33. DOI: 10.4297/najms.2010.2230
Onivogui G, Diaby M, Chen X, Zhang H, Song Y. 2015. Antibacterial and antifungal activities of various solvent extracts from the leaves and stem bark of Anisophyllea laurina R. Br ex Sabine used as traditional medicine in Guinea. J Ethnopharmacol 168:287–90. DOI: 10.1016/j.jep.2015.03.055 DOI: https://doi.org/10.1016/j.jep.2015.03.055
Patenall BL, Carter KA, Ramsey MR. 2024. Kick-starting wound healing: a review of pro-healing drugs. Int J Mol Sci 25(2):1304. DOI: 10.3390/ijms25021304. DOI: https://doi.org/10.3390/ijms25021304
Ponugoti B, Xu F, Zhang C, Tian C, Pacios S, Graves DT. 2013. FOXO1 promotes wound healing through the up-regulation of TGF-beta1 and prevention of oxidative stress. J Cell Biol 203(2):327–43. DOI: 10.1083/jcb.201305074 DOI: https://doi.org/10.1083/jcb.201305074
Rajuri A, Rao KNV, Banji D, Chaithanya RK. 2010. A review on Tectona grandis Linn: Chemistry and medicinal uses (famili: Verbenaceae). Herbal Tech Ind 1: 6–9.
Ratzinger G, Stoitzner P, Ebner S, Lutz MB, Layton GT, Rainer C, …, Schuler G. 2002. Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin. J Immunol 168(9):4361–71. DOI: 10.4049/jimmunol.168.9.4361 DOI: https://doi.org/10.4049/jimmunol.168.9.4361
Reiss MJ, Han YP, Garcia E, Goldberg M, Yu H, Garner WL. 2010. Matrix metalloproteinase-9 delays wound healing in a murine wound model. J. Surg 147(2):295–302. DOI: 10.1016/j.surg.2009.10.016. DOI: https://doi.org/10.1016/j.surg.2009.10.016
Repertinger SK, Campagnaro E, Fuhrman J, El-Abaseri T, Yuspa SH, Hansen LA. 2004. EGFR enhances early healing after cutaneous incisional wounding. J Invest Dermatol 123(5):982–89. DOI: 10.1111/j.0022-202X.2004.23478.x DOI: https://doi.org/10.1111/j.0022-202X.2004.23478.x
Scheler S, Fahr A, Liu X. 2014. Linear combination methods for prediction of drug skin permeation. ADMET & DMPK 2(4):199–220. DOI: 10.5599/admet.2.4.147 DOI: https://doi.org/10.5599/admet.2.4.147
Shanthi Kumari K, Shivakrishna P, Ganduri VSR. 2020. Wound healing activities of the bioactive compounds from Micrococcus sp. OUS9 isolated from marine water. Saudi J Biol Sci 27(9):2398–2402. DOI: 10.1016/j.sjbs.2020.05.007 DOI: https://doi.org/10.1016/j.sjbs.2020.05.007
Shin SH, Koh YG, Lee WG, Seok J, Park KY. 2022. The use of epidermal growth factor in dermatological practice. Int Wound J 20(6):2414–23. DOI: 10.1111/iwj.14075 DOI: https://doi.org/10.1111/iwj.14075
Singh KK, Agrawal NK, Gupta SK, Mohan G, Chaturvedi S, Singh K. 2016. Increased expression of endosomal members of toll-like receptor family abrogates wound healing in patients with type 2 diabetes mellitus. Int Wound J 13(5):927–35. DOI: 10.1111/iwj.12411 DOI: https://doi.org/10.1111/iwj.12411
Sun M, Li Z, Yang C, Lv Y, Yuan L, Shang C, …, Luo D. 2021. Nanogenerator-based devices for biomedical applications. Nano Energy 89:106461. DOI: 10.1016/j.nanoen.2021.106461 DOI: https://doi.org/10.1016/j.nanoen.2021.106461
Suryanti V, Kusumaningsih T, Marliyana SD, Setyono HA, Trisnawati EW. 2020. Identification of active compounds and antioxidant activity of teak (Tectona grandis) leaves. Biodiversitas 21(3):946–52. DOI: 10.13057/biodiv/d210313 DOI: https://doi.org/10.13057/biodiv/d210313
Takeuchi T, Hayashi M, Tamita T, Nomura Y, Kojima N, Mitani A, …, Kakinuma H. 2022. Discovery of aryloxyphenyl-heptapeptide hybrids as potent and selective Matrix Metalloproteinase-2 inhibitors for the treatment of idiopathic pulmonary fibrosis. J Med Chem 65(12):8493–8510. DOI: 10.1021/acs.jmedchem.2c00613 DOI: https://doi.org/10.1021/acs.jmedchem.2c00613
Tomas A, Futter CE, Eden ER. 2014. EGF receptor trafficking: consequences for signaling and cancer. Trends Cell Biol 24(1):26–34. DOI: 10.1016/j.tcb.2013.11.002 DOI: https://doi.org/10.1016/j.tcb.2013.11.002
Tottoli EM, Dorati R, Genta I, Chiesa E, Pisani S, Conti B. 2020. Skin wound healing process and new emerging technologies for skin wound care and regeneration. Pharm 12(8):735. DOI: 10.3390/pharmaceutics12080735 DOI: https://doi.org/10.3390/pharmaceutics12080735
Tyavambiza C, Meyer M, Meyer S. 2022. Cellular and molecular events of wound healing and the potential of silver based nanoformulations as wound healing agents. Bioengineering 9(11):712. DOI: 10.3390/bioengineering9110712 DOI: https://doi.org/10.3390/bioengineering9110712
Varma SB, Giri SP. 2013. Study of wound healing activity of Tectona grandis Linn. leaf extract on rats. Anc Sci Life 32(4):241–44. DOI: 10.4103/0257-7941.131984 DOI: https://doi.org/10.4103/0257-7941.131984
Wolosowicz M, Prokopiuk S, Kaminski TW. 2024. The complex role of matrix metalloproteinase-2 (MMP-2) in health and disease. Int J Mol Sci 25(4):13691. DOI: 10.3390/ijms252413691 DOI: https://doi.org/10.3390/ijms252413691
Yang Y, Luo R, Chao S, Xue J, Jiang D, Feng YH, …, Wang ZL. 2022. Improved pharmacodynamics of epidermal growth factor via microneedles-based self-powered transcutaneous electrical stimulation. Nat Commun 13:6908. DOI: 10.1038/s41467-022-34716-5 DOI: https://doi.org/10.1038/s41467-022-34716-5
Copyright (c) 2025 Gabriella Chandrakirana Krisnamurti, Anak Agung Sagung Alit Sukmaningsih, Cicilia Novi Primiani
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Authors who publish with this journal agree with the following terms:
- Authors retain copyright and grant the journal right of first publication, with the work 1 year after publication simultaneously licensed under a Creative Commons attribution-noncommerical-noderivates 4.0 International License that allows others to share, copy and redistribute the work in any medium or format, but only where the use is for non-commercial purposes and an acknowledgement of the work's authorship and initial publication in this journal is mentioned.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
