Investigation ethanol extract of Piper crocatum leaves as condyloma acuminata inhibitor using protein interaction and molecular simulation

Idrianti Idrus; Wresti Indriatmi; Rasiha Rasiha; Fadilah Fadilah

doi:10.7324/JAPS.2025.203484

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Abstract

Condyloma acuminata (CA) is a sexually transmitted infection that is mainly caused by the Human papillomavirus. Condyloma exhibits a considerable rate of recurrence, necessitating repeated therapies. Protein-protein network was implemented to see the underlying mechanism of CA, while molecular modeling approaches investigated the bioactive compound structure from Piper crocatum as an X-linked inhibitor of apoptosis protein (XIAP) inhibitor on CA. These simulations aid in investigating protein-protein interactions, how the enriched pathways align with the known mechanism of CA, and whether they reveal any novel insight and connection to the immune system, cytokine signaling, and intrinsic pathways for apoptosis. The results from in-silico showed the most potent compounds from P. crocatum with the lowest binding free energy for binding to XIAP included N-trans-feruloyltyramine 4′-O-β- D-glucopyranoside (NFT) and Vitexin 2″-rhamnoside (VTR) compounds (−8.62 Kcal/mol and −8.6 Kcal/mol, respectively). Investigation of bonds between NFT-XIAP of complexes showed that Asn252, Thr254, Arg258, Gly305, Ser347, Leu348, and Pro352 of the XIAP domain were essential for protein binding. NFT and VTR compounds could reduce the binding ability of XIAP proteins to NFT. Therefore, these phytochemicals from P. crocatum may be feasible drug candidates against XIAP inhibitors on CA.

Keyword: Condyloma acuminata P. crocatum XIAP inhibitor molecular simulation

Citation:

Idrus I, Indriatmi W, Rasiha R, Fadilah F. Investigation ethanol extract of Piper crocatum leaves as condyloma acuminata inhibitor using protein interaction and molecular simulation. J Appl Pharm Sci. 2025. Online First. http://doi.org/10.7324/JAPS.2025.203484

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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4. Rego CMA, Francisco AF, Boeno CN, Paloschi MV, Lopes JA, Silva MDS, et al. Inflammasome NLRP3 activation induced by convulxin, a C-type lectin-like isolated from Crotalus durissus terrificus snake venom. Sci Rep. 2022;12(1):4706. https://doi.org/10.1038/s41598-022-08735-7
5. Mesquita KDSM, Feitosa BS, Cruz JN, Ferreira OO, Franco CJP, Cascaes MM, et al. Chemical composition and preliminary toxicity evaluation of the essential oil from Peperomia circinnata link var. circinnata. (Piperaceae) in Artemia salina leach. Mol Basel Switz. 2021;26(23):7359. https://doi.org/10.3390/molecules26237359
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20. YASARA. Yet another scientific artificial reality application [Internet]. [cited 2024 May 16]. Available from: https://www.yasara.org/
21. Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;47(W1):W357-64. https://doi.org/10.1093/nar/gkz382
22. PharmMapper [Internet]. [cited 2024 May 16]. Available from: https://www.lilab-ecust.cn/pharmmapper/
23. KEGG PATHWAY. KEGG PATHWAY Database [Internet]. [cited 2024 May 16]. Available from: https://www.genome.jp/kegg/pathway.html
24. Bugnon M, Röhrig UF, Goullieux M, Perez MAS, Daina A, Michielin O, et al. SwissDock 2024: major enhancements for small-molecule docking with attracting cavities and AutoDock vina. Nucleic Acids Res. 2024;2024:gkae300. https://doi.org/10.1093/nar/gkae300
25. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9(10):679-91. https://doi.org/10.1038/nri2622
26. Ma W, Melief CJ, van der Burg SH. Control of immune escaped human papilloma virus is regained after therapeutic vaccination. Curr Opin Virol. 2017;23:16-22. https://doi.org/10.1016/j.coviro.2017.02.005
27. Pahne-Zeppenfeld J, Schröer N, Walch-Rückheim B, Oldak M, Gorter A, Hegde S, et al. Cervical cancer cell-derived interleukin-6 impairs CCR7-dependent migration of MMP-9-expressing dendritic cells. Int J Cancer. 2014;134(9):2061-73. https://doi.org/10.1002/ijc.28549
28. Saeki H, Moore AM, Brown MJ, Hwang ST. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol. 1999;162(5):2472-5. https://doi.org/10.4049/jimmunol.162.5.2472
29. Badovinac VP, Porter BB, Harty JT. Programmed contraction of CD8(+) T cells after infection. Nat Immunol. 2002;3(7):619-26. https://doi.org/10.1038/ni804
30. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516. https://doi.org/10.1080/01926230701320337
31. McComb S, Mulligan R, Sad S. Caspase-3 is transiently activated without cell death during early antigen driven expansion of CD8+ T cells in vivo. PLoS One. 2010;5(12):e15328. https://doi.org/10.1371/journal.pone.0015328
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33. Feng Y, Daley-Bauer LP, Roback L, Guo H, Koehler HS, Potempa M, et al. Caspase-8 restricts antiviral CD8 T cell hyperaccumulation. Proc Natl Acad Sci U S A. 2019;116(30):15170-7. https://doi.org/10.1073/pnas.1904319116
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1. Henri K, Eljona X, Frenki V, Asfloral H, Bledi H, Eriol B, et al. Surgical treatment of a severe anogenital condyloma acuminata- case report. J Educ Pract. 2023;14(16):1.

2. Peixoto A, Silva M, Castro R, Coelho R, Sarmento A, Macedo G. Anal condylomas: predictors of recurrence and progression to high-grade dysplasia/carcinoma in situ. J Gastrointest Oncol. 2017;8(6):1114-5. https://doi.org/10.21037/jgo.2017.09.09

3. Calik J, Zawada T, Bove T. Treatment of condylomata acuminata using a new non-vapor-generating focused ultrasound method following imiquimod 5% cream. Case Rep Dermatol. 2022;14(3):275-82. https://doi.org/10.1159/000525896

4. Rego CMA, Francisco AF, Boeno CN, Paloschi MV, Lopes JA, Silva MDS, et al. Inflammasome NLRP3 activation induced by convulxin, a C-type lectin-like isolated from Crotalus durissus terrificus snake venom. Sci Rep. 2022;12(1):4706. https://doi.org/10.1038/s41598-022-08735-7

5. Mesquita KDSM, Feitosa BS, Cruz JN, Ferreira OO, Franco CJP, Cascaes MM, et al. Chemical composition and preliminary toxicity evaluation of the essential oil from Peperomia circinnata link var. circinnata. (Piperaceae) in Artemia salina leach. Mol Basel Switz. 2021;26(23):7359. https://doi.org/10.3390/molecules26237359

6. Santana de Oliveira M, Pereira da Silva VM, Cantão Freitas L, Gomes Silva S, Nevez Cruz J, de Aguiar Andrade EH. Extraction yield, chemical composition, preliminary toxicity of Bignonia nocturna (Bignoniaceae) essential oil and in silico evaluation of the interaction. Chem Biodivers. 2021;18(4):e2000982. https://doi.org/10.1002/cbdv.202000982

7. Costa EB, Silva RC, Espejo-Román JM, Neto MFDA, Cruz JN, Leite FHA, et al. Chemometric methods in antimalarial drug design from 1,2,4,5-tetraoxanes analogues. SAR QSAR Environ Res. 2020;31(9):677-95. https://doi.org/10.1080/1062936X.2020.1803961

8. Zhong Y, Wei J, Song W, Wang Q, Zhang Z, Liu H, et al. Identification of novel biomarkers and key pathways of condyloma acuminata. Genomics. 2022;114(2):110303. https://doi.org/10.1016/j.ygeno.2022.110303

9. Liu D, Wang X, Du Z, Liu J, Zhong Y, Tian Q. The binding affinity prediction of PI3K/Akt/mTOR signaling pathway proteins with drugs based on deep learning method. Proceedings of the 2021 IEEE International Conference on Bioinformatics and Biomedicine (BIBM); [cited 2024 May 13]. pp. 1667-72. Houston, TX: IEEE; 2021. Available from: https://ieeexplore.ieee.org/document/9669786 https://doi.org/10.1109/BIBM52615.2021.9669786

10. Sagerman PM, Kadish AS, Niedt GW. Condyloma acuminatum with superficial spirochetosis simulating condyloma latum. Am J Dermatopathol. 1993;15(2):176-9. https://doi.org/10.1097/00000372-199304000-00015

11. Li H, Yi T, Zhao S, Chen P, Cheng C, Wei Y, et al. The anti-condyloma acuminatum effects of interferon-inducible protein 10 in vitro. Int J Dermatol. 2009;48(2):136-41. https://doi.org/10.1111/j.1365-4632.2009.03776.x

12. Astuti PDY, Fadilah F, Promsai S, Bahtiar A. Integrating molecular docking and molecular dynamics simulations to evaluate active compounds of Hibiscus schizopetalus for obesity. J Appl Pharm Sci. 2024;14(4):176-87. https://doi.org/10.7324/JAPS.2024.158550

13. Elcock AH, Sept D, McCammon JA. Computer simulation of protein−protein interactions. J Phys Chem B. 2001;105(8):1504-18. https://doi.org/10.1021/jp003602d

14. GeneCards. Condyloma acuminata related genes-GeneCards search results [Internet]. [cited 2024 May 16]. Available from: https://www.genecards.org/Search/Keyword?queryString=condyloma%20acuminata

15. STRING. Functional protein association networks [Internet]. [cited 2024 May 16]. Available from: https://string-db.org/

16. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(Web Server issue):W90-7. https://doi.org/10.1093/nar/gkw377

17. Bank RPD. RCSB PDB-5OQW: XIAP in complex with small molecule [Internet]. [cited 2024 May 16]. Available from: https://www.rcsb.org/structure/5OQW

18. Marvin. The only chemical drawing tool you will ever need [Internet]. [cited 2024 May 16]. Available from: https://chemaxon.com/marvin

19. Bugnon M, Röhrig UF, Goullieux M, Perez MAS, Daina A, Michielin O, et al. SwissDock 2024: major enhancements for small-molecule docking with attracting cavities and AutoDock Vina. Nucleic Acids Res. 2024 Apr 30;gkae300. https://doi.org/10.1093/nar/gkae300

20. YASARA. Yet another scientific artificial reality application [Internet]. [cited 2024 May 16]. Available from: https://www.yasara.org/

21. Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;47(W1):W357-64. https://doi.org/10.1093/nar/gkz382

22. PharmMapper [Internet]. [cited 2024 May 16]. Available from: https://www.lilab-ecust.cn/pharmmapper/

23. KEGG PATHWAY. KEGG PATHWAY Database [Internet]. [cited 2024 May 16]. Available from: https://www.genome.jp/kegg/pathway.html

24. Bugnon M, Röhrig UF, Goullieux M, Perez MAS, Daina A, Michielin O, et al. SwissDock 2024: major enhancements for small-molecule docking with attracting cavities and AutoDock vina. Nucleic Acids Res. 2024;2024:gkae300. https://doi.org/10.1093/nar/gkae300

25. Nestle FO, Di Meglio P, Qin JZ, Nickoloff BJ. Skin immune sentinels in health and disease. Nat Rev Immunol. 2009;9(10):679-91. https://doi.org/10.1038/nri2622

26. Ma W, Melief CJ, van der Burg SH. Control of immune escaped human papilloma virus is regained after therapeutic vaccination. Curr Opin Virol. 2017;23:16-22. https://doi.org/10.1016/j.coviro.2017.02.005

27. Pahne-Zeppenfeld J, Schröer N, Walch-Rückheim B, Oldak M, Gorter A, Hegde S, et al. Cervical cancer cell-derived interleukin-6 impairs CCR7-dependent migration of MMP-9-expressing dendritic cells. Int J Cancer. 2014;134(9):2061-73. https://doi.org/10.1002/ijc.28549

28. Saeki H, Moore AM, Brown MJ, Hwang ST. Cutting edge: secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of mature dendritic cells from the skin to regional lymph nodes. J Immunol. 1999;162(5):2472-5. https://doi.org/10.4049/jimmunol.162.5.2472

29. Badovinac VP, Porter BB, Harty JT. Programmed contraction of CD8(+) T cells after infection. Nat Immunol. 2002;3(7):619-26. https://doi.org/10.1038/ni804

30. Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516. https://doi.org/10.1080/01926230701320337

31. McComb S, Mulligan R, Sad S. Caspase-3 is transiently activated without cell death during early antigen driven expansion of CD8+ T cells in vivo. PLoS One. 2010;5(12):e15328. https://doi.org/10.1371/journal.pone.0015328

32. Ch'en IL, Tsau JS, Molkentin JD, Komatsu M, Hedrick SM. Mechanisms of necroptosis in T cells. J Exp Med. 2011;208(4):633-41. https://doi.org/10.1084/jem.20110251

33. Feng Y, Daley-Bauer LP, Roback L, Guo H, Koehler HS, Potempa M, et al. Caspase-8 restricts antiviral CD8 T cell hyperaccumulation. Proc Natl Acad Sci U S A. 2019;116(30):15170-7. https://doi.org/10.1073/pnas.1904319116

34. Deveraux QL, Reed JC. IAP family proteins-suppressors of apoptosis. Genes Dev. 1999;13(3):239-52. https://doi.org/10.1101/gad.13.3.239

35. Lopes RB, Gangeswaran R, McNeish IA, Wang Y, Lemoine NR. Expression of the IAP protein family is dysregulated in pancreatic cancer cells and is important for resistance to chemotherapy. Int J Cancer. 2007;120(11):2344-52. https://doi.org/10.1002/ijc.22554

36. Obexer P, Ausserlechner MJ. X-linked inhibitor of apoptosis protein-a critical death resistance regulator and therapeutic target for personalized cancer therapy. Front Oncol. 2014;4:197. https://doi.org/10.3389/fonc.2014.00197

37. Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS. XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs. EMBO J. 2005;24(3):645-55. https://doi.org/10.1038/sj.emboj.7600544

38. Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, et al. Mechanism of XIAP-mediated inhibition of caspase-9. Mol Cell. 2003;11(2):519-27. https://doi.org/10.1016/S1097-2765(03)00054-6

39. Yin GW, Guo Y, Huang YH, Song FJ. The expression and significance of XIAP and C-jun on condyloma acuminatum. Pak J Pharm Sci. 2015;28(4 Suppl.):1551-3.

40. Stuqui B, Provazzi PJS, Lima MLD, Cabral ÁS, Leonel ECR, Candido NM, et al. Condyloma acuminata: an evaluation of the immune response at cellular and molecular levels. PLoS One. 2023;18(4):e0284296. https://doi.org/10.1371/journal.pone.0284296

41. Wu S, Chen H. Anti-condyloma acuminata mechanism of microRNAs-375 modulates HPV in cervical cancer cells via the UBE3A and IGF-1R pathway. Oncol Lett. 2018;16(3):3241-7. https://doi.org/10.3892/ol.2018.8983

42. Shi YJ, Yang J, Yang W. Mechanistic investigation of immunosuppression in patients with condyloma acuminata. Mol Med Rep. 2013;8(2):480-6. https://doi.org/10.3892/mmr.2013.1511

43. Yang Z, Xiong H, Wei S, Liu Q, Gao Y, Liu L, et al. Yes-associated protein promotes the development of condyloma acuminatum through EGFR pathway activation. Dermatol Basel Switz. 2020;236(5):454-66. https://doi.org/10.1159/000500216