Molecular Docking Analysis of Bioactive Compounds from Jatropha Curcas L. Leaves as Lipoxygenase Inhibitors and Antioxidant Candidates

Wa Ode Rufiyani, Fahmi Sadik, Muhammad Fakhrur Rajih Hi. Yusuf

Abstract

Oxidative stress results from an imbalance between reactive oxygen species (ROS) and the body's antioxidant defense system, contributing to various degenerative diseases. The enzyme Lipoxygenase (LOX) plays a crucial role in ROS formation; thus, its inhibition offers a strategic approach to mitigate oxidative damage. This study aims to evaluate the potential of bioactive compounds from Jatropha curcas L. leaves as LOX inhibitors using in silico approaches. The target protein (Human 15-LOX, PDB ID: 7LAF) and ligand structures were retrieved from the Protein Data Bank and PubChem. Flexible molecular docking simulations were performed using YASARA Structure to accommodate receptor side-chain adjustments, validated against the native ligand (XRP) and a positive control (Zileuton). The results revealed that Naringenin-7-O-β-D-glucopyranoside exhibited the strongest binding affinity (–10.41 kcal/mol), surpassing both the native ligand (–9.03 kcal/mol) and Zileuton (–7.48 kcal/mol), driven by extensive hydrogen bond networks with residues ASN173 and ASP625. Meanwhile, the aglycone (-)-Pinoresinol demonstrated competitive affinity (–8.80 kcal/mol) stabilized by hydrophobic interactions with PHE88 and TRP109. While glycosides showed superior potency, (-)-Pinoresinol and Epicatechin were identified as the most rational oral drug candidates, fulfilling Lipinski’s Rule of Five and demonstrating high intestinal absorption (>90%) in ADMET analysis. These findings provide a structure-based rationale for selecting J. curcas metabolites as promising LOX inhibitor candidates for further in vitro validation.

Keywords

Molecular docking; Jatropha curcas; Lipoxygenase; Antioxidant; Oxidative stress

References

[1] N. Chandimali et al., “Free radicals and their impact on health and antioxidant defenses: a review,” Cell Death Discov., vol. 11, no. 1, p. 19, 2025, https://doi.org/10.1038/s41420-024-02278-8.

[2] P. Rajak et al., “In silico targeting of lipoxygenase, CYP2C9, and NAD(P)H oxidase by major green tea polyphenols to subvert oxidative stress,” Adv. Redox Res., vol. 7, p. 100061, 2023, https://doi.org/10.1016/j.arres.2023.100061.

[3] İ. Gulcin, “Antioxidants: a comprehensive review.,” Arch. Toxicol., vol. 99, no. 5, pp. 1893–1997, May 2025, https://doi.org/10.1007/s00204-025-03997-2.

[4] S. A. B. Galal, M. Madhat Mousa, E. S. Elzanfaly, E. M. Hussien, E. A. H. Amer, and H. E. Zaazaa, “Quantitative analysis of residual butylated hydroxytoluene and butylated hydroxyanisole in Salmo salar, milk, and butter by liquid chromatography–tandem mass spectrometry,” Food Chem., vol. 453, p. 139653, 2024, doi: https://doi.org/10.1016/j.foodchem.2024.139653.

[5] L. Méndez, J. Rojas, C. Izaguirre, B. Contreras, and R. Gómez, “Jatropha curcas leaves analysis, reveals it as mineral source for low sodium diets,” Food Chem., vol. 165, pp. 575–577, 2014, doi: https://doi.org/10.1016/j.foodchem.2014.05.124.

[6] S. Rahman, E. P. Toepak, dan S. C. Angga, “Uji aktivitas antioksidan dan sitotoksik ekstrak daun Jarak Pagar (Jatropha curcas),” Jurnal SAGO Gizi dan Kesehatan, vol. 4, no. 2, hlm. 239–244, 2023.

[7] S. Yakubu and G. Yebpella, “Antioxidant Activity of Bioactive and Mineral Constituents of Jatropha curcas Linn. (Euphorbiaceae) Leaf and Seed Extract,” J. Chem. Nat. Resour., vol. 6, pp. 1–9, May 2024, doi: https://doi.org/10.32734/jcnar.v6i1.15658.

[8] M. Lončarić, I. Strelec, T. Moslavac, D. Šubarić, V. Pavić, and M. Molnar, “Lipoxygenase Inhibition by Plant Extracts.,” Biomolecules, vol. 11, no. 2, January. 2021, doi: https://doi.org/10.3390/biom11020152.

[9] H. Slika et al., “Therapeutic potential of flavonoids in cancer: ROS-mediated mechanisms.,” Biomed. Pharmacother., vol. 146, p. 112442, February. 2022, doi: https://doi.org/10.1016/j.biopha.2021.112442.

[10] K. N. Hemavathi, S. Skariyachan, R. Raju, T. S. Keshava Prasad, and C. S. Abhinand, “Computational screening of potential anti-inflammatory leads from Jeevaneeya Rasayana plants targeting COX-2 and 5- LOX by molecular docking and dynamic simulation approaches,” Comput. Biol. Med., vol. 171, p. 108164, 2024, doi: https://doi.org/10.1016/j.compbiomed.2024.108164.

[11] G. Zengin et al., “Chemical Composition and Biological Properties of Two Jatropha Species: Different Parts and Different Extraction Methods,” Antioxidants, vol. 10, no. 5. p. 792, 2021. doi: https://doi.org/10.3390/antiox10050792.

[12] Y. Wang et al., “Chemical constituents from leaves of Jatropha curcas,” Chinese Herb. Med., vol. 15, no. 3, pp. 463–469, 2023, doi: https://doi.org/10.1016/j.chmed.2022.08.010.

[13] E. Navarrete et al., “Development of Ferrocenyl and Ruthenocenyl Zileuton Analogs with Enhanced Bioactivity toward Human 5-Lipoxygenase: Innovation in Drugs for Inflammatory Diseases,” Inorg. Chem., vol. 64, no. 7, pp. 3495–3505, February. 2025, doi: https://doi.org/10.1021/acs.inorgchem.4c05103.

[14] E. Krieger dan G. Vriend, “Increasing the Precision of Comparative Models with YASARA NOVA - a Self-Parameterizing Force Field,” Proteins: Structure, Function, and Bioinformatics, vol. 47, no. 3, hlm. 393–402, 2002, doi: https://doi.org/10.1002/prot.10104.

[15] T. A. Nyijime et al., “Computational design, pharmacokinetics, molecular docking and molecular dynamic simulation of novel anti-tubercular inhibitors,” Silico Res. Biomed., vol. 1, p. 100012, 2025, doi: https://doi.org/10.1016/j.insi.2025.100012.

[16] H. Land and M. S. Humble, “YASARA: A Tool to Obtain Structural Guidance in Biocatalytic Investigations BT - Protein Engineering: Methods and Protocols,” U. T. Bornscheuer and M. Höhne, Eds., New York, NY: Springer New York, 2018, pp. 43–67. doi: https://doi.org/10.1007/978-1-4939-7366-8_4.

[17] E. J. Millan-Casarrubias, Y. V García-Tejeda, C. H. González-De la Rosa, L. Ruiz-Mazón, Y. M. Hernández-Rodríguez, and O. E. Cigarroa-Mayorga, “Molecular Docking and Pharmacological In Silico Evaluation of Camptothecin and Related Ligands as Promising HER2-Targeted Therapies for Breast Cancer,” Current Issues in Molecular Biology, vol. 47, no. 3. p. 193, 2025. doi: https://doi.org/10.3390/cimb47030193.

[18] C. A. Lipinski, F. Lombardo, B. W. Dominy, and P. J. Feeney, “Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25.1,” Adv. Drug Deliv. Rev., vol. 46, no. 1, pp. 3–26, 2001, doi: https://doi.org/10.1016/S0169-409X(00)00129-0.

[19] D. E. V Pires, T. L. Blundell, and D. B. Ascher, “pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures,” J. Med. Chem., vol. 58, no. 9, pp. 4066–4072, May 2015, doi: https://doi.org/10.1021/acs.jmedchem.5b00104.

[20] F. Wu et al., “Computational Approaches in Preclinical Studies on Drug Discovery and Development.,” Front. Chem., vol. 8, p. 726, 2020, doi: https://doi.org/10.3389/fchem.2020.00726.

[21] J. P. B. Arango, D. Y. M. Rodriguez, S. L. Cruz, and G. T. Ocampo, “In silico evaluation of pharmacokinetic properties and molecular docking for the identification of potential anticancer compounds,” Comput. Biol. Chem., vol. 120, p. 108626, 2026, doi: https://doi.org/10.1016/j.compbiolchem.2025.108626.

[22] W.-C. Tsai et al., “Kinetic and structural investigations of novel inhibitors of human epithelial 15-lipoxygenase-2,” Bioorg. Med. Chem., vol. 46, p. 116349, 2021, doi: https://doi.org/10.1016/j.bmc.2021.116349.

[23] H. Rimac, M. Grishina, and V. Potemkin, “Use of the Complementarity Principle in Docking Procedures: A New Approach for Evaluating the Correctness of Binding Poses.,” J. Chem. Inf. Model., vol. 61, no. 4, pp. 1801–1813, Apr. 2021, doi: https://doi.org/10.1021/acs.jcim.0c01382.

[24] M. K. Mandal, W. Gan, and A. J. Domb, “Phenolate-based bioactive compounds: Design, delivery and biomedical applications,” Coord. Chem. Rev., vol. 544, p. 216941, 2025, doi: https://doi.org/10.1016/j.ccr.2025.216941.

[25] H. Zhang et al., “Molecular Mechanisms Underlying the Absorption of Aglycone and Glycosidic Flavonoids in a Caco-2 BBe1 Cell Model.,” ACS omega, vol. 5, no. 19, pp. 10782–10793, May 2020, doi: https://doi.org/10.1021/acsomega.0c00379.

[26] A. Chen, Z. Jiang, and M. D. Burkart, “Enzymology of standalone elongating ketosynthases,” Chem. Sci., vol. 13, no. 15, pp. 4225–4238, 2022, doi: https://doi.org/10.1039/D1SC07256K.

[27] Y. Wang, J. Li, X. Li, B. Gao, J. Chen, and Y. Song, “Spectroscopic and molecular docking studies on binding interactions of camptothecin drugs with bovine serum albumin,” Sci. Rep., vol. 15, no. 1, p. 8055, 2025, doi: https://doi.org/10.1038/s41598-025-92607-3.

[28] H. Meuzelaar, J. Vreede, and S. Woutersen, “Influence of Glu/Arg, Asp/Arg, and Glu/Lys Salt Bridges on α-Helical Stability and Folding Kinetics.,” Biophys. J., vol. 110, no. 11, pp. 2328–2341, Jun. 2016, doi: https://doi.org/10.1016/j.bpj.2016.04.015.

[29] R. Calinsky and Y. Levy, “Aromatic Residues in Proteins: Re-Evaluating the Geometry and Energetics of π–π, Cation−π, and CH−π Interactions,” J. Phys. Chem. B, vol. 128, no. 36, pp. 8687–8700, Sep. 2024, doi: https://doi.org/10.1021/acs.jpcb.4c04774.

[30] R. Laczko and K. Csiszar, “Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways.,” Biomolecules, vol. 10, no. 8, July. 2020, doi: https://doi.org/10.3390/biom10081093.

[31] V. S. Shilpa et al., “Phytochemical Properties, Extraction, and Pharmacological Benefits of Naringin: A Review.,” Molecules, vol. 28, no. 15, July. 2023, doi: https://doi.org/10.3390/molecules28155623.

[32] L. Guo, J. Qiao, J. Huo, and H. P. V. Rupasinghe, “Plant iridoids: Chemistry, dietary sources and potential health benefits,” Food Chem. X, vol. 27, p. 102491, 2025, doi: https://doi.org/10.1016/j.fochx.2025.102491.

DOI: https://doi.org/10.20961/jkpk.v10i3.110639

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