Prediction of a Stable Complex of Compounds in the Ethanol Extract of Celery Leaves (Apium graveolens L.) Function as a VKORC1 Antagonist


  • Aiyi Asnawi Faculty of Pharmacy, Universitas Bhakti Kencana, Jl. Soekarno Hatta No.754, Bandung, West Java, 40617, Indonesia
  • Marselina Nedja Faculty of Pharmacy, Universitas Bhakti Kencana, Jl. Soekarno Hatta No.754, Bandung, West Java, 40617, Indonesia
  • Ellin Febrina Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang Km. 21, Jatinangor, Sumedang, West Java, 45363, Indonesia.
  • Purwaniati Purwaniati Faculty of Pharmacy, Universitas Bhakti Kencana, Jl. Soekarno Hatta No.754, Bandung, West Java, 40617, Indonesia


VKORC1, Molecular Dynamics, Molecular Docking, Celery Leaves, Anticoagulants


The vitamin K cycle, specifically the protein VKORC1 (Vitamin K epoxide reductase complex subunit 1), is closely linked to coagulation mechanisms in the body. Disruptions in this cycle will be associated with vascular diseases such as myocardial infarction and stroke. Warfarin is commonly used as an anticoagulant, but it still has side effects in interactions with numerous drug compounds; thus, it is necessary to search for safer candidate compounds. The ethanol extract of celery leaves (Apium graveolens L.) has potential anticoagulant activity, but the compound responsible for this activity has not been identified yet. The CADD method has been developed to predict in silico a compound's potential to interact with binding sites. This study aimed to predict interactions and obtain a stable complex of the compounds in the ethanol extract of celery leaves, which function as a VKORC1 antagonist. A total of 23 compounds were simulated using Autodock 4.2, and AMBER 18 was then used to simulate the stability of the five compounds with the best interactions. The docking simulation results of 17 test compounds (ligands) yielded five selected compounds, namely 6-isopentenyloxy-isobergapten (S1), Heratomin (S2), Apigenin (S3), Lanatin (S4), and Isoimperatorin (S5), with G values of −9.27, −9.26, −9.22, −9.13, and −8.94 kcal/mol, respectively. The MD simulation continued to produce 6-isopentenyloxy-isobergapten  as the most effective ligand for stabilizing the complex for 100 ns from these five ligands. In conclusion, the 6-isopentenyloxy-isobergapten from celery leaf has the potential as a candidate anticoagulant, VKORC1. 


Saner FH, Kirchner C. Monitoring and Treatment of Coagulation Disorders in End-Stage Liver Disease. Visc Med. 2016;32(4):241-248. doi:10.1159/000446304

Laslett LJ, Alagona P, Clark BA, Drozda JP, Saldivar F, Wilson SR, Poe C, Hart M. The worldwide environment of cardiovascular disease: Prevalence, diagnosis, therapy, and policy issues: A report from the american college of cardiology. J Am Coll Cardiol. 2012;60(25 SUPPL.). doi:10.1016/J.JACC.2012.11.002

Gbyli R, Mercaldi A, Sundaram H, Amoako KA. Achieving Totally Local Anticoagulation on Blood Contacting Devices. Adv Mater Interfaces. 2018;5(4):1700954. doi:10.1002/ADMI.201700954

Johnson JA, Gong L, Whirl‐Carrillo M, Gage BF, Scott SA, Stein CM, Anderson JL, Kimmel SE, Lee MTM,Pirmohamed M, Wadelius M, Klein TE, Altman RB. Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther. 2011;90(4):625-629. doi:10.1038/clpt.2011.185

Sikka P, Bindra VK. Newer antithrombotic drugs. Indian J Crit Care Med. 2010;14(4):188-195. doi:10.4103/0972-5229.76083

Guven H, Arici A, Simsek O. Flavonoids in our foods: a short review. J Basic Clin Heal Sci. 2019;3(2):96-106.

Rumpho ME, Edwards GE, Loescher WH. A Pathway for Photosynthetic Carbon Flow to Mannitol in Celery Leaves. Plant Physiol. 1983;73(4):869-873. doi:10.1104/PP.73.4.869

Chatron N, Chalmond B, Trouvé A, Benoit E, Caruel H, Lattard V, Tchertanov L. Identification of the functional states of human Vitamin K epoxide reductase from molecular dynamics simulations. RSC Adv. 2017;7(82):52071-52090. doi:10.1039/C7RA07463H

Nursamsiar, Nur S, Febrina E, Asnawi A, Syafiie S. Synthesis and Inhibitory Activity of Curculigoside A Derivatives as Potential AntiDiabetic Agents with β-Cell Apoptosis. J Mol Struct. 2022;1265. doi:10.1016/J.MOLSTRUC.2022.133292

Asnawi A, Aman LO, Nursamsiar, Febrina E. Molecular Docking and Molecular Dynamic Studies: Screening Phytochemicals of Acalypha Indica Against Braf Kinase Receptors For Potential Use In Melanocytic Tumours. Rasayan J Chem. 2022;15(2):1352-1361. doi:10.31788/RJC.2022.1526769

Febrina E, Asnawi A, Abdulah R, Lestari K, Supratman U. Identification of Flavonoids From Acalypha Indica L. (Euphorbiaceae) as Caspase-3 Activators Using Molecular Docking and Molecular Dynamics. Int J Appl Pharm. 2022;14(Special issue 5):162-166. doi:10.22159/IJAP.2022.V14S5.34

Ischak NI, Ode LA, Hasan H, Kilo A La, Asnawi A. In silico screening of Andrographis paniculata secondary metabolites as anti-diabetes

mellitus through PDE9 inhibition. Res Pharm Sci. 2023;18(1):100. doi:10.4103/1735-5362.363619

Febrina E, Alamhari RK, Asnawi A, Abdulah R, Lestari K, Levita J, Supratman U. Molecular Docking and Molecular Dynamics Studies of

Acalypha Indica L. Phytochemical Constituents with Caspase-3. Int J Appl Pharm. 2021;13(Special Issue 4):210-215. doi:10.22159/IJAP.2021.V13S4.43861

Ritchie TJ, McLay IM. Should medicinal chemists do molecular modelling? Drug Discov Today. 2012;17(11-12):534-537. doi:10.1016/J.DRUDIS.2012.01.005

Liu S, Li S, Shen G, Sukumar N, Krezel AM, Li W. Structural basis of antagonizing the vitamin K catalytic cycle for anticoagulation. Science

(80- ). 2021;371(6524). doi:10.1126/SCIENCE.ABC5667

Nursamsiar, Asnawi A, Kartasasmita RE, Ibrahim S, Tjahjono DH. Synthesis, biological evaluation, and docking analysis of methyl hydroquinone and bromo methyl hydroquinone as potent cyclooxygenase (COX-1 and COX-2) inhibitors. J Appl Pharm Sci. 2018;8(7):16-20. doi:10.7324/JAPS.2018.8703

Wu S, Chen X, Jin DY, Stafford DW, Pedersen LG, Tie JK. Warfarin and vitamin K epoxide reductase: a molecular accounting for observed

inhibition. Blood. 2018;132(6):647. doi:10.1182/BLOOD-2018-01-830901

Weinhold F, Klein RA. What is a hydrogen bond? Resonance covalency in the supramolecular domain. Chem Educ Res Pract. 2014;15(3):276-285. doi:10.1039/C4RP00030G

Cetin E, Atilgan AR, Atilgan C. DHFR Mutants Modulate Their Synchronized Dynamics with the Substrate by Shifting Hydrogen Bond Occupancies. J Chem Inf Model. Published online December 26, 2022. doi:10.1021/acs.jcim.2c00507

Xie H, Li Y, Yu F, Xie X, Qiu K, Fu J. An investigation of molecular docking and molecular dynamic simulation on imidazopyridines as Braf kinase inhibitors. Int J Mol Sci. 2015;16(11):27350-27361. doi:10.3390/ijms161126026

Genheden S, Ryde U. The MM/PBSA and MM/GBSA methods to estimate ligand-binding affinities. Expert Opin Drug Discov. 2015;10(5):449-461. doi:10.1517/17460441.2015.1032936

Mahmudov KT, Kopylovich MN, Guedes da Silva MFC, Pombeiro AJL. Non-covalent interactions in the synthesis of coordination compounds: Recent advances. Coord Chem Rev. 2017;345:54-72. doi:10.1016/J.CCR.2016.09.002



How to Cite

Asnawi, A., Nedja, M., Febrina, E., & Purwaniati, P. (2023). Prediction of a Stable Complex of Compounds in the Ethanol Extract of Celery Leaves (Apium graveolens L.) Function as a VKORC1 Antagonist: Tropical Journal of Natural Product Research (TJNPR), 7(2), 2362–2370. Retrieved from