Endophytic fungus Paecylomyces subglobosus CBK3 as a natural source of ACE inhibitors: A phytochemical and in silico study

Yulianis Yulianis; Rustini Rustini; Agus Supriyono; Muhammad Azhari Herli; Herland Satriawan; Dian Handayani

doi:10.7324/JAPS.2025.235025

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Abstract

Paecilomyces subglobosus CBK3, an endophytic fungus isolated from the traditional medicinal fern Cyathea contaminans (Hook.) Copel. has been recognized for its capacity to produce bioactive secondary metabolites. Chromatographic separation of the dichloromethane fraction of P. subglobosus CBK3 led to the isolation of two major compounds: O-methylcorypaline (OMC, 0.25%) and phenylglyoxylic acid (PGA, 0.02%). Structural elucidation was confirmed using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. To assess their therapeutic potential, molecular docking simulations were performed against cyclooxygenase-2, angiotensin II receptor type 1 (AT1 ), and angiotensin-converting enzyme (ACE). OMC demonstrated a stronger binding affinity to ACE (−5.54 kcal/mol) compared to the reference drug captopril (−4.92 kcal/mol) and was comparable to the natural ligand (−5.40 kcal/mol). However, its affinity for AT1 was relatively lower (−5.49 kcal/mol). Furthermore, the analysis of absorption, distribution, metabolism, excretion, and toxicity revealed that OMC possesses a more favorable pharmacokinetic profile than PGA. These findings underscore the potential of OMC as a promising lead compound for developing novel antihypertensive agents derived from fungal endophytes.

Keyword: O-methylcorypaline phenylglyoxylic acid LC-QToF-MS/MS molecular docking natural product drug discovery

Citation:

Yulianis Y, Rustini R, Supriyono A, Herli MA, Satriawan H, Handayani D. Endophytic fungus Paecylomyces subglobosus CBK3 as a natural source of ACE inhibitors: A phytochemical and in silico study. J Appl Pharm Sci. 2025. Article in Press. http://doi.org/10.7324/JAPS.2025.23502

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

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1. Wijesekara T, Xu B. Health-promoting effects of bioactive Compounds from plant endophytic fungi. J Fungi. 2023;9(997):1- 14. https://doi.org/10.3390/jof9100997

2. Visagie C, Yilmaz N, Kocsubé S, Frisvad J, Hubka V, Samson R, et al. A review of recently introduced Aspergillus, Penicillium, Talaromyces and other Eurotiales species. Stud Mycol. 2024;10(107):1-66. https://doi.org/10.3114/sim.2024.107.01

3. Li XQ, Xu K, Liu XM, Zhang P. A systematic review on secondary metabolites of Paecilomyces species: chemical diversity and biological activity. Planta Med. 2020;86(12):805-21. https://doi.org/10.1055/a-1196-1906

4. Dai ZB, Wang X, Li GH. Secondary metabolites and their bioactivities produced by Paecilomyces. Molecules. 2020;25(21):1-18. https://doi.org/10.3390/molecules25215077

5. Ramos G da C, Silva-Silva JV, Watanabe LA, Siqueira JE de S, Almeida-Souza F, Calabrese KS, et al. Phomoxanthone A, compound of endophytic fungi Paecilomyces sp. and its potential antimicrobial and antiparasitic. Antibiotics 2022;11(10):1332. https://doi.org/10.3390/antibiotics11101332

6. Yulianis, Rustini, Supriyono A, Sandrawati N, Handayani D. Ethyl acetate extracts endophytic fungi from the medicinal tree fern Cyathea Contaminans (Hook) Copel with antimicrobial activity. TRENDS Sci. 2024;21(10):1-10. https://doi.org/10.48048/tis.2024.8232

7. Yang X, Miao X, Dai L, Guo X, Jenis J, Zhang J, et al. Isolation, biological activity, and synthesis of isoquinoline alkaloids. Nat Prod Rep. 2024;41:1652-722. https://doi.org/10.1039/D4NP00023D

8. Mustafa YF, Zain Al-Abdeen SH, Khalil RR, Mohammed ET. Novel functionalized phenyl acetate derivatives of benzo [e]-bispyrone fused hybrids: synthesis and biological activities. Results Chem. 2023;5:100942. https://doi.org/10.1016/j.rechem.2023.100942

9. Tang CD, Shi HL, Xu JH, Jiao ZJ, Liu F, Ding PJ, et al. Biosynthesis of phenylglyoxylic acid by LhDMDH, a novel d -mandelate dehydrogenase with high catalytic activity. J Agric Food Chem. 2018;66(11):2805-11. https://doi.org/10.1021/acs.jafc.7b05835

10. Wei X, Zhang M, Yang M, Ogutu C, Li J, Deng X. Lotus (Nelumbo nucifera) benzylisoquinoline alkaloids: advances in chemical profiling, extraction methods, pharmacological activities, and biosynthetic elucidation. Veg Res. 2024;4:e005. https://doi.org/10.48130/vegres-0024-0004

11. Wu WN, Huang CH. Structural elucidation of isoquinoline, isoquinolone, benzylisoquinoline, aporphine, and phenanthrene alkaloids using API-ion spray tandem mass spectrometry. Chinese Pharm J. 2006;58(1):41-55.

12. Crestey F, Jensen AA, Borch M, Andreasen JT, Andersen J, Balle T, et al. Design, synthesis, and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists. J Med Chem. 2013;56(23):9673-82. https://doi.org/10.1021/jm4013592

13. Usmanov PB, Jumayev IZ, Rustamov SY, Zaripov AA, Esimbetov AT, Zhurakulov SN, et al. The combined inotropic and vasorelaxant effect of DHQ-11, a conjugate of flavonoid dihydroquercetin with isoquinoline alkaloid 1-aryl-6,7-dimethoxy-1,2.3,4- tetrahydroisoquinoline. Biomed Pharmacol J. 2021;14(2):651-61. https://doi.org/10.13005/bpj/2167

14. Amir M, Shikha K. Synthesis and anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities of some new 2-[(2,6-dichloroanilino) phenyl]acetic acid derivatives. Eur J Med Chem. 2004;39(6):535-45. https://doi.org/10.1016/j.ejmech.2004.02.008

15. Ko SC, Kim JY, Lee JM, Yim MJ, Kim HS, Oh GW, et al. Angiotensin I-converting enzyme (ACE) inhibition and molecular docking study of meroterpenoids isolated from brown alga, Sargassum macrocarpum. Int J Mol Sci. 2023;24(13):11065. https://doi.org/10.3390/ijms241311065

16. Agostini L da C, Silva NNT, Belo V de A, Luizon MR, Lima AA, da Silva GN. Pharmacogenetics of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in cardiovascular diseases. Eur J Pharmacol [Internet]. 2024;981:176907. https://doi.org/10.1016/j.ejphar.2024.176907

17. Kirkby NS, Sampaio W, Etelvino G, Alves DT, Anders KL, Temponi R, et al. Cyclooxygenase-2 selectively controls renal blood flow through a novel PPARβ/δ-dependent vasodilator Pathway. Hypertension 2018;71:297-305. https://doi.org/10.1161/HYPERTENSIONAHA.117.09906

18. Kjer J, Debbab A, Aly AH, Proksch P. Methods for isolation of marine-derived endophytic fungi and their bioactive secondary products. Nat Protoc. 2010;5(3):479-90. https://doi.org/10.1038/nprot.2009.233

19. Handayani D, Muslim RI, Syafni N, Artasasta MA, Riga R. Endophytic fungi from medicinal plant Garcinia cowa Roxb. ex Choisy and their antibacterial activity. J Appl Pharm Sci. 2024;14(9):182-8. https://doi.org/10.7324/JAPS.2024.180510

20. Handayani D, Dwinatrana K, Rustini R. Antibacterial compound from marine sponge derived fungus Aspergillus sydowii DC08. Rasayan J Chem. 2022;15(4):2485-92. https://doi.org/10.31788/RJC.2022.1546971

21. Handayani D, Aminah I, Pontana Putra P, Eka Putra A, Arbain D, Satriawan H, et al. The depsidones from marine sponge-derived fungus Aspergillus unguis IB151 as an anti-MRSA agent: molecular docking, pharmacokinetics analysis, and molecular dynamic simulation studies. Saudi Pharm J. 2023;31(9):101744. https://doi.org/10.1016/j.jsps.2023.101744

22. Kilicaslan OS, Cretton S, Quir L, Bella MA, Kaiser M, Mäser P, et al. Isolation and structural elucidation of compounds from Pleiocarpa bicarpellata and their in vitro antiprotozoal activity. Molecules. 2022;27(7):2200. https://doi.org/10.3390/molecules27072200

23. Weng G, Gao J, Wang Z, Wang E, Hu X, Yao X, et al. Comprehensive evaluation of fourteen docking programs on protein-peptide complexes. J Chem Theory Comput. 2020;16(6):3959-69. https://doi.org/10.1021/acs.jctc.9b01208

24. Khachatryan H, Matevosyan M, Harutyunyan V, Gevorgyan S, Shavina A, Tirosyan I, et al. Computational evaluation and benchmark study of 342 crystallographic holo-structures of SARS-CoV-2 Mpro enzyme. Sci Rep. 2024;14(1):1-15. https://doi.org/10.1038/s41598-024-65228-5

25. Kurumbail RG, Stevens AM, Gierse JK, McDonald JJ, Stegeman RA, Pak JY, et al. Structure basis for selective inhibitionof cyclooxygenase-2 by anti-inflammatory agents. Nat Publ Gr. 1996;384(19):644-8. https://doi.org/10.1038/384644a0

26. Akif M, Masuyer G, Bingham RJ, Sturrock ED, Isaac RE, Acharya KR. Structural basis of peptide recognition by the angiotensin-1 converting enzyme homologue AnCE from Drosophila melanogaster. FEBS J. 2012;279:4525-34. https://doi.org/10.1111/febs.12038

27. Zhang H, Unal H, Desnoyer R, Han GW, Patel N, Katritch V, et al. Structural basis for ligand recognition and functional selectivity at angiotensin receptor. JBS Pap. 2015;90(49):29127-39. https://doi.org/10.1074/jbc.M115.689000

28. Alnajjar R, Mostafa A, Kandeil A, Al-Karmalawy AA. Molecular docking, molecular dynamics, and in vitro studies reveal the potential of angiotensin II receptor blockers to inhibit the COVID-19 main protease. Heliyon 2020;6(12):e05641. https://doi.org/10.1016/j.heliyon.2020.e05641

29. Ahmed MZ, Hameed S, Ali M, Zaheer A. Computational analysis of the interaction of limonene with the fat mass and obesity-associated protein. Sci J Informatics. 2021;8(1):154-60. https://doi.org/10.15294/sji.v8i1.29051

30. 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 3:7:42717. https://doi.org/10.1038/srep42717

31. Hadni H, Elhallaoui M. Heliyon 3D-QSAR, docking and ADMET properties of aurone analogues as antimalarial agents. HLY. 2020;6(4):e03580. https://doi.org/10.1016/j.heliyon.2020.e03580

32. Menachery MD, Lavanier GL, Wetherly ML, Guinaudeau H, Shamma M. Simple isoquinoline alkaloids. J Natl Prod. 1986;49(5):745 -78. https://doi.org/10.1021/np50047a001

33. Silverstein RM, Webster FX, Kiemle DJ. Spectrometric identification of organic compounds. 7th ed. New York, NY: United States of America; 2005. 1-502 pp.

34. Rouessac F, Rouessac A. Chemical analysis: modern instrumentation methods and techniques. 2nd ed. Willey, UK: John Wiley & Sons Ltd; 2007. 1-574 pp.

35. Ohashi Y, Mamiya T, Mitani K, Wang B, Takigawa T, Kira S, et al. Simultaneous determination of urinary hippuric acid, o-, m- and p-methylhippuric acids, mandelic acid and phenylglyoxylic acid for biomonitoring of volatile organic compounds by gas chromatography-mass spectrometry. Anal Chim Acta. 2006;566(2):167-71. https://doi.org/10.1016/j.aca.2006.03.018

36. Tang C, Ding P, Shi H, Jia Y, Zhou M, Yu H, et al. One-pot synthesis of phenylglyoxylic acid from racemic mandelic acids via cascade biocatalysis. J Agric Food Chem. 2019;67:2946-53. https://doi.org/10.1021/acs.jafc.8b07295

37. Aalinezhad S, Dabaghian F, Namdari A, Akaberi M, Emami SA. Phytochemistry and pharmacology of alkaloids from Papaver spp.: a structure-activity based study. Phytochem Rev. 2025;24:585-657. https://doi.org/10.1007/s11101-024-09943-x

38. Jumayev I, Usmanov P, Rustamov S, Zhurakulov S. Comparative inotropic effects of the some isoquinoline alkaloids. Biomed Pharmacol J. 2020;13(1):325-333. https://doi.org/10.13005/bpj/1892

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