Structure-based screening of inhibitor platelet-derived growth factor from ethanol extract of Uncaria gambir (Hunter) Roxb. as an antifibrotic in keloid fibroblast cells

Sri Widia A. Jusman Maftuhatun Fista Amalia Reni Paramita Sri Ningsih Fadilah Fadilah   

Open Access   

Published:  Nov 19, 2022

DOI: 10.7324/JAPS.2023.59304
Abstract

This study aimed to determine the potency of the compounds in gambir [Uncaria gambir (Hunter) Roxb.] to inhibit the proliferation of keloid fibroblasts using an in silico study with molecular docking and an in vitro assay. In this study, the interaction between compounds found in the gambir plant and platelet-derived growth factor subunit A (PDGF-α) as the target protein and the percentage inhibition were analyzed to determine its potential as a candidate for herbal-based keloid therapy. The compounds found in the plant gambir [(+)-catechin, gambirin A1, gambirin A2, gambirin B1, gambirin B2, gambirin C, procyanidin B1, procyanidin B2, epigallocatechin gallate, and (+)-epicatechin] were docked to the target protein PDGF-α (PBD ID: 3MJK). An MTT assay was conducted to determine the cytotoxicity of each compound. The three compounds gambirin A1, procyanidin B2, and neooxygambirtannine had the best affinity values of −12.8324, −13.4987, and −14.5446 and PKI values of 8.962, 10.218, and 9.129, respectively. The IC50 of the ethanolic extract of gambir was 22.40 ± 0.071 ug/ml against keloid fibroblast cells. The potential bioactive compounds as PDGF inhibitors have been identified, namely, gambirin A1, procyanidin B2, and neooxygambirtannine. These compounds can be isolated for further research. IC50 can be used to understand the molecular mechanism of the inhibition of the gambir extract against keloid fibroblast cells.


Keyword:     Molecular docking keloid PDGF receptors gambir compounds


Citation:

Jusman SWA, Amalia MF, Paramita R, Ningsih S, Fadilah F. Structure-based screening of inhibitor platelet-derived growth factor from ethanol extract of Uncaria gambir (Hunter) Roxb. as an antifibrotic in keloid fibroblast cells. J Appl Pharm Sci, 2022. https://doi.org/10.7324/JAPS.2023.59304

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

Al-Attar A, Mess S, Thomassen JM, Kauffman CL, Davison SP. Keloid pathogenesis and treatment. Plast Reconstr Surg, 2006; 117(1):286- 300; doi:10.1097/01.prs.0000195073.73580.46 https://doi.org/10.1097/01.prs.0000195073.73580.46

Andrews JP, Marttala J, Macarak E, Rosenbloom J, Uitto J. Keloids: The paradigm of skin fibrosis - Pathomechanisms and treatment. Matrix Biol, 2016; 51:37-46; doi:10.1016/j.matbio.2016.01.013 https://doi.org/10.1016/j.matbio.2016.01.013

Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic- Canic M. Growth factors and cytokines in wound healing: Growth factors and cytokines in wound healing. Wound Repair Regen, 2008; 16(5):585- 601; doi:10.1111/j.1524-475X.2008.00410.x https://doi.org/10.1111/j.1524-475X.2008.00410.x

Cohen BE, Geronemus RG, McDaniel DH, Brauer JA. The role of elastic fibers in scar formation and treatment. Dermatol Surg, 2017; 43(1):S19-24; doi:10.1097/dss.0000000000000840 https://doi.org/10.1097/DSS.0000000000000840

Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep, 2017; 7:42717; doi:10.1038/srep42717 https://doi.org/10.1038/srep42717

Desdiani D. Fibropreventive and fibrolysis effects of gambir (Uncaria gambir (Hunter) roxb.) in the lung and pleural rat of fibrosis models. Chest, 2019; 155(4):207A; doi:10.1016/j.chest.2019.02.377 https://doi.org/10.1016/j.chest.2019.02.377

Desdiani D, Rengganis I, Djauzi S, Setiyono A, Sadikin M, Jusman SWA, Siregar NC, Eyanoer PC, Fadilah F. Vitro Assay and Study Interaction of Uncaria gambir. Pharmacogn J, 2020; 12(6):1232-40. https://doi.org/10.5530/pj.2020.12.172

Dewi, S. R. P., Pratiwi, A., & Teodorus, T. The effect of gambier extracts (Uncaria gambir [Roxb.]) as antiseptic on gingival wound in rats. ODONTO Dental Journal, 2018; 5(1):80-88; doi: 10.30659/odj.5.1.%p. https://doi.org/10.30659/odj.5.1

Elokely KM, Doerksen RJ. Docking challenge: protein sampling and molecular docking performance. J Chem Infor Model, 2013; 53(8):1934-45; doi:10.1021/ci400040d https://doi.org/10.1021/ci400040d

Eming SA, Martin P, Tomic-Canic M. Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med, 2014; 6(265):265sr6; doi:10.1126/scitranslmed.3009337 https://doi.org/10.1126/scitranslmed.3009337

Ertl P, Rohde B, Selzer P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J Med Chem, 2000; 43(20):3714- 7; doi:10.1021/jm000942e https://doi.org/10.1021/jm000942e

Fahrudin F, Solihin DD, Kusumorini N, Ningsih S. Isolasi efektivitas ekstrak gambir (Uncaria gambir (Hunter) Roxb.) sebagai hepatoprotektor pada tikus (Rattus norvegicus L.) yang diinduksi CCl4. J Ilmu Kefarm Indo, 2015; 13(2):115-22.

Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules, 2015; 20(7):13384-421; doi:10.3390/molecules200713384 https://doi.org/10.3390/molecules200713384

Gallin JI, Wright DG, Schiffmann E. Role of secretory events in modulating human neutrophil chemotaxis. J Clin Invest, 1978; 62(6):1364-74. https://doi.org/10.1172/JCI109257

Gao Z, Sasaoka T, Fujimori T, Oya T, Ishii Y, Sabit H, Kawaguchi M, Kurotaki Y, Naito M, Wada T, Ishizawa S, Kobayashi M, Nabeshima Y, Sasahara M. Deletion of the PDGFR-beta gene affects key fibroblast functions important for wound healing. J Biol Chem, 2005; 280(10):9375- 89; doi:10.1074/jbc.M413081200 https://doi.org/10.1074/jbc.M413081200

Gschwend DA, Good AC, Kuntz ID. Molecular docking towards drug discovery. J Mol Recognit, 1996; 9(2), 175-86; doi:10.1002/ (sici)1099-1352(199603)9:2<175::aid-jmr260>3.0.co;2-d https://doi.org/10.1002/(SICI)1099-1352(199603)9:2<175::AID-JMR260>3.0.CO;2-D

Hsu CK, Lin HH, Harn HI, Hughes MW, Tang MJ, Yang CC. Mechanical forces in skin disorders. J Dermatol Sci, 2018; 90(3):232-40; doi:10.1016/j.jdermsci.2018.03.004 https://doi.org/10.1016/j.jdermsci.2018.03.004

Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science, 1991; 253(5018):407-14; doi:10.1126/science.1862342 https://doi.org/10.1126/science.1862342

Lamb ML, Jorgensen WL. Computational approaches to molecular recognition. Curr Opin Chem Biol, 1997; 1(4):449-57; doi:10.1016/s1367-5931(97)80038-5 https://doi.org/10.1016/S1367-5931(97)80038-5

Li X, Zhai Y, Xi B, Ma W, Zhang J, Ma X, Miao Y, Zhao Y, Ning W, Zhou H, Yang C. Pinocembrin ameliorates skin fibrosis via inhibiting TGF-β1 signaling pathway. Biomolecules, 2021; 11(8):1240; doi:10.3390/ biom11081240 https://doi.org/10.3390/biom11081240

Melia S, Novia D, Juliyarsi I. Antioxidant and antimicrobial activities of gambir (Uncaria gambir roxb) extracts and their application in rendang. Pak J Nutr, 2015; 14(12):938-41; doi:10.3923/pjn.2015.938.941 https://doi.org/10.3923/pjn.2015.938.941

Morelli Coppola M, Salzillo R, Segreto F, Persichetti P. Triamcinolone acetonide intralesional injection for the treatment of keloid scars: patient selection and perspectives. Clin Cosmet Investig Dermatol, 2018; 11:387-96. https://doi.org/10.2147/CCID.S133672

Nie Z, Bayat A, Behzad F, Rhodes LE. Positive response of a recurrent keloid scar to topical methyl aminolevulinate-photodynamic therapy: MAL-PDT for keloid. Photodermatol Photoimmunol Photomed, 2010; 26(6):330-2; doi:10.1111/j.1600-0781.2010.00539.x https://doi.org/10.1111/j.1600-0781.2010.00539.x

Ningsih E, Rahayuningsih S. Extraction, isolation, characterization and antioxidant activity assay of catechin gambir (Uncaria gambir (Hunter). Roxb. Al-Kimia, 2019; 7(2):177-88. https://doi.org/10.24252/al-kimia.v7i2.7800

Oswari L, Hidayat R, Fatmawati F, Hayati L, Alisa BS. Gambir extract (Uncaria gambir) decreases inflammatory response and increases gastric mucosal integrity in Wistar rats - model gastritis. Open Access Maced J Med Sci, 2019; 7(19):3149-52; doi:10.3889/oamjms.2019.758 https://doi.org/10.3889/oamjms.2019.758

Roques C, Téot L. The use of corticosteroids to treat keloids: a review. Int J Low Extrem Wounds, 2008; 7(3):137-45; doi:10.1177/1534734608320786 https://doi.org/10.1177/1534734608320786

Saad MF, Goh HH, Rajikan R, Yusof TR, Baharum SN, Bunawan H. Uncaria gambir (W. Hunter) Roxb: From phytochemical composition to pharmacological importance. Trop J Pharm Res, 2020; 19(8):1767-73; doi:10.4314/tjpr.v19i8.28 https://doi.org/10.4314/tjpr.v19i8.28

Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking. Curr Opin Chem Biol, 2002; 6(4):439-46. https://doi.org/10.1016/S1367-5931(02)00339-3

Shih B, Garside E, McGrouther DA, Bayat A. Molecular dissection of abnormal wound healing processes resulting in keloid disease. Wound Repair Regen, 2010; 18(2):139-53; doi:10.1111/j.1524-475X.2009.00553.xShim AH, Liu H, Focia PJ, Chen X, Lin PC, He X. Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex. Proc Natl Acad Sci U S A, 2010; 107(25):11307-12; doi:10.1073/pnas.1000806107 https://doi.org/10.1073/pnas.1000806107

Trace AP, Enos CW, Mantel A, Harvey VM. Keloids and hypertrophic scars: A spectrum of clinical challenges Am J Clin Dermatol, 2016; 17(3):201-23; doi:10.1007/s40257-016-0175-7 https://doi.org/10.1007/s40257-016-0175-7

Wang X, Song K, Li L, Chen L. Structure-based drug design strategies and challenges. Curr Top Med Chem, 2018; 18(12):998-1006; do i:10.2174/1568026618666180813152921 https://doi.org/10.2174/1568026618666180813152921

Waring MJ. Lipophilicity in drug discovery. Expert Opin Drug Discov, 2010; 5(3):235-48; doi:10.1517/17460441003605098 https://doi.org/10.1517/17460441003605098

Wolfram D, Tzankov A, Pülzl P, Piza-Katzer H. Hypertrophic scars and keloids: a review of their pathophysiology, risk factors, and therapeutic management. Dermatol Surg, 2009;35:171-81. https://doi.org/10.1111/j.1524-4725.2008.34406.x

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