Potential of bioactive compounds Piper betle L. as angiotensin converting enzyme inhibitors: molecular docking study and in silico analysis evaluation of physicochemical properties, drug-likeness, and toxicity

Agus Kurniawan; Ernawati Sinaga; Muhammad Hanafi; Puspa Dewi Narrij Lotulung; Syamsudin Abdillah

doi:10.35814/jifi.v24i1.2083

Penulis

Agus Kurniawan Department of Pharmaceutical Biology, Faculty of Health Sciences and Pharmacy, Universitas Gunadarma, Depok City, 16424, Indonesia
Ernawati Sinaga Department of Biology, Faculty of Biology and Agriculture, Universitas Nasional, Jakarta, 12520, Indonesia
Muhammad Hanafi Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), KST B. J. Habibie, South Tangerang, 15314, Indonesia
Puspa Dewi Narrij Lotulung Research Center for Pharmaceutical Ingredients and Traditional Medicine, National Research and Innovation Agency (BRIN), KST B. J. Habibie, South Tangerang, 15314, Indonesia
Syamsudin Abdillah Department of Biomedicine and Clinical Pharmacy, Faculty of Pharmacy, Universitas Pancasila, Jakarta, 12640, Indonesia

DOI:

https://doi.org/10.35814/jifi.v24i1.2083

Kata Kunci:

ACE inhibitors, drug-likeness, hypertension, in silico, Piper betle L.

Abstrak

Hypertension remains a major global health burden, with angiotensin converting enzyme (ACE) representing a central therapeutic target in blood pressure regulation via the RAAS. Although synthetic ACE inhibitors are clinically effective, their long-term use is frequently associated with adverse effects, motivating the search for safer alternative agents. Piper betle L. is a medicinal plant rich in diverse bioactive phytochemicals with reported cardiovascular benefits. This study aimed to systematically evaluate the ACE inhibitory potential of Piper betle leaf constituents using an integrated in silico approach. A total of 43 compounds were docked against human ACE (PDB ID: 1UZF) using the PLANTS algorithm, with protocol validation performed by captopril redocking. Binding affinities and key interactions were analyzed, followed by prediction of physicochemical properties, drug-likeness, and toxicity using ADMETlab 3.0 and ProTox-3.0. Docking results revealed that several compounds, including cerebrosides, lignans, and long-chain esterified phenolics, exhibited strong predicted binding to ACE. However, many high-affinity ligands showed unfavorable physicochemical characteristics, low quantitative estimates of drug-likeness, and multiple medicinal chemistry rule violations. In contrast, Piperenamide A and Piperenamide B demonstrated a balanced profile, combining stable ACE binding with favorable physicochemical properties, compliance with Lipinski’s Rule of Five, and low predicted toxicity. Simple phenolic compounds displayed good safety profiles despite moderate binding affinity. Overall, this integrative in silico analysis highlights compounds derived from Piper betle L. leaves as a promising natural source of ACE-inhibitory scaffolds and provides a rational framework for subsequent experimental validation and lead optimization in antihypertensive drug discovery.

Referensi

[1] K. T. Mills, A. Stefanescu, and J. He, “The global epidemiology of hypertension,” Nat. Rev. Nephrol., vol. 16, pp. 223–237, 2020.

[2] A. Durante, A. Mazzapicchi, and M. B. Redaelli, “Systemic and Cardiac Microvascular Dysfunction in Hypertension,” Int. J. Mol. Sci., vol. 25, no. 24, pp. 1–16, 2024.

[3] X. Y. Zhu, M. Q. Shi, Z. M. Jiang, X. Li, J. W. Tian, and F. F. Su, “Global , regional , and national burden of cardiovascular diseases attributable to metabolic risks across all age groups from 1990 to 2021 : an analysis of the 2021 global burden of disease study data,” BMC iPublic Heal., vol. 25, no. 1704, pp. 1–21, 2025, doi: 10.1186/s12889-025-22702-7.

[4] C. P. McCarthy, R. M. Bruno, K. Rahimi, R. M. Touyz, and J. W. Mcevoy, “What Is New and Different in the 2024 European Society of Cardiology Guidelines for the Management of Elevated Blood Pressure and Hypertension?,” Hypertension, vol. 82, no. 3, pp. 432–444, 2025, doi: 10.1161/HYPERTENSIONAHA.124.24173.

[5] H. Triebel and H. Castrop, “The renin angiotensin aldosterone system,” Pflügers Arch. - J. Physiol., vol. 476, no. 5, pp. 705–713, 2024, doi: 10.1007/s00424-024-02908-1.

[6] F. Bioletto, M. Bollati, C. Lopez, S. Arata, M. Procopio, and F. Ponzetto, “Primary Aldosteronism and Resistant Hypertension : A Pathophysiological Insight,” Int. J. Mol. Sci., vol. 23, no. 4803, pp. 1–16, 2022.

[7] S. Cutrell, I. S. Alhomoud, A. Mehta, A. H. Talasaz, and B. Van Tassell, “ACE ‑ Inhibitors in Hypertension : A Historical Perspective and Current Insights,” Curr. Hypertens. Rep., vol. 25, no. 9, pp. 243–250, 2023, doi: 10.1007/s11906-023-01248-2.

[8] H. Ahmad, H. Khan, S. Haque, S. Ahmad, N. Srivastava, and A. Khan, “Angiotensin-Converting Enzyme and Hypertension: A Systemic Analysis of Various ACE Inhibitors , Their Side Effects , and Bioactive Peptides as a Putative Therapy for Hypertension,” J. Renin-Angiotensin-Aldosterone Syst., no. 7890188, pp. 1–9, 2023.

[9] M. N. Takuathung et al., “Adverse Effects of Angiotensin-Converting Enzyme Inhibitors in Humans : A Systematic Review and Meta-Analysis of 378 Randomized Controlled Trials,” Int. J. Environ. Res. Public Heal., vol. 19, no. 14, pp. 1–13, 2022.

[10] D. J. Newman and G. M. Cragg, “Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019,” J. Nat. Prod., vol. 83, no. 3, pp. 770–803, 2020, doi: 10.1021/acs.jnatprod.9b01285.

[11] R. Chakraborty and S. Roy, “Angiotensin-converting enzyme inhibitors from plants : A review of their diversity , modes of action , prospects , and concerns in the management of diabetes-centric complications,” J. Integr. Med., vol. 19, no. 6, pp. 478–492, 2021, doi: 10.1016/j.joim.2021.09.006.

[12] T. A. F. T. Anuar and A. Ismail, “Southeast Asian Medicinal Plants with Angiotensin Converting Enzyme (ACE) Inhibition Properties,” Pharmacogn J., vol. 12, no. 6, pp. 1429–1439, 2020.

[13] A. Riany, A. P. Permatasari, N. Salsabila, N. Rahayu, S. Endarti, and M. Marcelina, “Ethnobotanical Study of Medicinal Plants in Bangbayang Village, Sumedang, West Java,” J. Trop. Biodivers., vol. 4, no. 2, pp. 89–111, 2024.

[14] E. Singarimbun, E. Elfrida, and I. Indriaty, “Indigenous Knowledge and Herbal Medicine: Exploring the Ethnobotany of the Karo Tiganderket Tribe in Indonesia,” Heca J. Appl. Sci., vol. 2, no. 2, pp. 74–86, 2024, doi: 10.60084/hjas.v2i2.208.

[15] C. A. I. Nufus et al., “Ethnobotanical Study and Medicinal Plant Bioprospecting in Tamiang Tribal Community, Aceh,” J. Trop. Ethnobiol., vol. 7, no. 1, pp. 1–20, 2024.

[16] P. Biswas et al., “Betelvine (Piper betle L.): A comprehensive insight into its ethnopharmacology , phytochemistry , and pharmacological , biomedical and therapeutic attributes,” J Cell Mol Med., vol. 26, pp. 3083–3119, 2022, doi: 10.1111/jcmm.17323.

[17] J. Seo et al., “Anti-inflammatory and antioxidant activities of methanol extract of Piper betle Linn. (Piper betle L.) leaves and stems by inhibiting NF- κ B/MAPK/Nrf2 signaling pathways in RAW 264.7 macrophages,” Biomed. Pharmacother., vol. 155, p. 113734, 2022, doi: 10.1016/j.biopha.2022.113734.

[18] B. Somanadhan et al., “An ethnopharmacological survey for potential angiotensin converting enzyme inhibitors from Indian medicinal plants,” J. Ethnopharmacol., vol. 65, no. 2, pp. 103–112, 1999, doi: 10.1016/S0378-8741(98)00201-3.

[19] S. S. Çınaroğlu and E. Timuçin, “Comparative Assessment of Seven Docking Programs on a Nonredundant Metalloprotein Subset of the PDBbind Refined,” J. Chem. Inf. Model., vol. 59, no. 9, p. 3846−3859, 2019, doi: 10.1021/acs.jcim.9b00346.

[20] J. Li, A. Fu, and L. Zhang, “An Overview of Scoring Functions Used for Protein – Ligand Interactions in Molecular Docking,” Interdiscip. Sci. Comput. Life Sci., vol. 11, no. 2, pp. 320–328, 2019, doi: 10.1007/s12539-019-00327-w.

[21] N. Patel and J. Mohan, “Isolation and characterization of potential bioactive compounds from Piper betle varieties Banarasi and Bengali leaf extract,” Int. J. Herb. Med., vol. 5, no. 5, pp. 182–191, 2017.

[22] A. Atiya, B. N. Sinha, and U. R. Lal, “New chemical constituents from the Piper betle Linn. (Piperaceae),” Nat. Prod. Res., pp. 1–9, 2017, doi: 10.1080/14786419.2017.1380018.

[23] T. T. San et al., “A new sesquineolignan and four new neolignans isolated from the leaves of Piper betle, a traditional medicinal plant in Myanmar,” Bioorganic Med. Chem. Lett., vol. 31, pp. 1–19, 2021, doi: 10.1016/j.bmcl.2020.127682.

[24] D. Z. Chen, H. Bin Xiong, K. Tian, J. M. Guo, X. Z. Huang, and Z. Y. Jiang, “Two new sphingolipids from the leaves of Piper betle L.,” Molecules, vol. 18, no. 9, pp. 11241–11249, 2013, doi: 10.3390/molecules180911241.

[25] I. Ali et al., “In vitro antifungal activity of hydroxychavicol isolated from Piper betle L,” Ann. Clin. Microbiol. Antimicrob., vol. 9, no. 7, pp. 1–9, 2010.

[26] M. Nagabhushan, A. J. Amonkar, U. J. Nair, A. V. D’souza, and S. V. Bhide, “Hydroxychavicol: A new anti-nitrosating phenolic compound from betel leaf,” Mutagenesis, vol. 4, no. 3, pp. 200–204, 1989, doi: 10.1093/mutage/4.3.200.

[27] F. Prasetya et al., “Novel amides derivative with antimicrobial activity of Piper betle var. nigra leaves from Indonesia,” Molecules, vol. 26, no. 2, pp. 1–8, 2021, doi: 10.3390/molecules26020335.

[28] H. Zeng, Y.-Y. Jiang, D. Cai, K. Long, and Z. Chen, “Piperbetol, Methylpiperbetol, Piperol A and Piperol B: A New Series of Highly Specific PAF Receptor Antagonists from Piper betle,” Planta Med., vol. 63, pp. 296–298, 1997.

[29] M. Madhumita, P. Guha, and A. Nag, “Bio-actives of betel leaf (Piper betle L.): A comprehensive review on extraction, isolation, characterization, and biological activity,” Phyther. Res., vol. 34, no. 10, pp. 2609–2627, 2020, doi: 10.1002/ptr.6715.

[30] T. Noshita, T. Sato, T. Iwayama, Y. Yamada, and H. Ouchi, “The proposed structures of phenolic compounds isolated from Piper betle L. differ from those of the compounds obtained by total synthesis,” Nat. Prod. Res., vol. 35, no. 21, pp. 3787–3793, 2021, doi: 10.1080/14786419.2020.1739038.

[31] A. Atiya, M. A. Salim, B. N. Sinha, and U. R. Lal, “Two new anticancer phenolic derivatives from leaves of Piper betle Linn.,” Nat. Prod. Res., vol. 36, no. 16, pp. 5021–5029, 2020, doi: 10.1080/14786419.2020.1762186.

[32] I. Bin Jantan, A. R. Ahmad, A. S. Ahmad, and N. A. M. Ali, “A comparative study of the essential oils of five piper species from Peninsular Malaysia,” Flavour Fragr. J., vol. 9, no. 6, pp. 339–342, 1994, doi: 10.1002/ffj.2730090611.

[33] N. A. Bhat, B. K. Tiwari, and A. Bhardwaj, “Isolation and identification of an aromatic compound from the Alcoholic extract of Piper betle Linn. (Leaf stalk),” J. Xi’an Univ. Archit. Technol., vol. 12, no. 6, pp. 1145–1151, 2020.

[34] D. Suryasnata, I. S. Sandeep, R. Parida, S. Nayak, and S. Mohanty, “Variation in Volatile Constituents and Eugenol Content of Five Important Betelvine (Piper betle L.) Landraces Exported from Eastern India,” J. Essent. Oil-Bearing Plants, vol. 19, no. 7, pp. 1788–1793, 2016, doi: 10.1080/0972060X.2016.1179131.

[35] A. Atiya, B. N. Sinha, and U. R. Lal, “Bioactive phenylpropanoid analogues from Piper betle L. var. birkoli leaves,” Nat. Prod. Res., vol. 31, no. 22, pp. 2604–2611, 2017, doi: 10.1080/14786419.2017.1285297.

[36] L. te Riet, J. H. M. van Esch, A. J. M. Roks, A. H. van den Meiracker, and A. H. J. Danser, “Hypertension: Renin–Angiotensin–Aldosterone System Alterations,” Circ. Res., vol. 116, no. 6, pp. 960–975, 2015, doi: 10.1161/CIRCRESAHA.116.303587.

[37] A. Valentini, R. M. Heilmann, A. Kühne, L. Biagini, D. De Bellis, and G. Rossi, “The Renin – Angiotensin – Aldosterone System (RAAS : Beyond Cardiovascular Regulation,” Vet. Sci., vol. 12, no. 8, pp. 1–18, 2025.

[38] J. Song, J. Ha, J. Lee, J. Ko, and W. Shin, “Improving docking and virtual screening performance using AlphaFold2 multi-state modeling for kinases,” Sci. Rep., vol. 14, no. 25167, pp. 1–13, 2024.

[39] J. H. Tina et al., “Molecular docking and ADMET profiling of xanthones from Securidaca longepedunculata targeting oxidative stress in hypertension,” Discov. Chem., vol. 3, no. 17, pp. 1–16, 2026.

[40] E. Mavridis and D. Hadjipavlou-litina, “Using a Novel Consensus-Based Chemoinformatics Approach to Predict ADMET Properties and Druglikeness of Tyrosine Kinase Inhibitors,” Int. J. Mol. Sci., vol. 26, no. 20, p. 10207, 2025.

[41] S. Gould and M. V Templin, “Off target toxicities and links with physicochemical properties of medicinal products , including antibiotics, oligonucleotides , lipid nanoparticles (with cationic and/or anionic charges). Data review suggests an emerging pattern,” Toxicol. Lett., vol. 384, pp. 14–29, 2023.