Research Article | Volume: 10, Issue: 1, January, 2022

Computational ligand–receptor docking simulation of piperine with apoptosis-associated factors

Adrianne Dien-Yu Vong Siaw-San Hwang Xavier Wezen Chee Edmund Ui-Hang Sim   

Open Access   

Published:  Jan 07, 2022

DOI: 10.7324/JABB.2021.100105

Although widely known for its antioxidant properties, piperine’s (a compound from the pepper plant) physiologic involvement in apoptosis (programmed cell death) is unclear. As a prerequisite to unravel its role in this process, computational approaches simulating ligand–receptor docking are sought. Herein, we report the simulated binding of piperine with major apoptotic proteins via combined deployment of AutoDock suite (AutoDock Vina), PyMOL, and LigPlot + software. Our results demonstrated varied binding affinity toward the different apoptosis-associated proteins with a higher to lower affinity pattern in the order of TNFR-1 > Caspase-3 > TNF-α > Caspase-8 > Bcl-2 > Caspase-9 > Bax. Docking scores for all receptor–ligand interactions indicate a strong likelihood of impromptu receptor–ligand binding. Molecularly, the simulated analysis revealed hydrophobic interactions in all receptor–ligand models studied. Receptor–piperine complexes involving TNFR-1 and Caspase-8 showed single hydrogen bonding whereas amino acid residues of TNF-α exhibited double hydrogen bonding to piperine. In the TNFR-1-piperine complex (receptor–ligand docked model with strongest binding affinity) the hydrophobic interaction involves amino acid residues of SER74, LYS75, ASN110 (2), THR94, CYS96, VAL95, and PHE112. Our findings provide novel in silico evidence of piperine’s binding affinity toward apoptosis-associated proteins and the high likelihood of its influence on apoptosis reaction via the extrinsic pathway.

Keyword:     Apoptotic proteins AutoDock docking simulation piperine TNFR-1


Vong ADY, Hwang SS, Chee XW, Sim EUH. Computational ligand–receptor docking simulation of piperine with apoptosis-associated factors. J Appl Biol Biotech. 2022;10(01):38–44.

Copyright: Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike license.

HTML Full Text


1. Tiwari A, Mahadik KR, Gabhe SY. Piperine: a comprehensive review of methods of isolation, purification and biological properties. Med Drug Discov 2020;7:100027.

2. Shityakov S, Bigdelian E, Hussien AA, Hussain MB, Tripathi YC, Khan MU, et al. Phytochemical and pharmacologiacal attributes of piperine: a bioactive ingredient of black pepper. Euro J Med Chem 2019;176:149-61.

3. Siddiqui S, Ahamad MD, Jafri A, Afzal M, Arshad M. Piperine triggers apoptosis of human oral squamous carcinoma through cell cycle arrest and mitochondrial oxidative stress. Nutr Cancer 2017;69(5):791-9.

4. George K, Thomas NS, Malathi R. Piperine blocks voltage gated K+ current and inhibits proliferation in androgen sensitive and insensitive human prostate cancer cell lines. Arch Biochem Biophys 2019;667:36-48.

5. Jafri A, Siddiqui S, Rais J, Ahmad MS, Kumar S, Jafar T, et al. Induction of apoptosis by piperine in human cervical adenocarcinoma via Ros mediated mitochondrial pathway and caspase-3 activation. EXCLI J, Int Online J Adv Sci 2019;18:154-64.

6. Song L, Wang Y, Zhen Y, Li D, He X, Yang H, et al. Piperine inhibits colorectal cancer migration and invasion by regulating STAT3/ snail-mediated epithelial mesenchymal transition. Biotechnol Lett 2020;42(10):2049-58.

7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646-74.

8. Yanumula A, Cusick JK. Biochemistry, extrinsic pathway of apoptosis [Internet]. StatPearls Publishing LLC, Treasure Island, Florida, 2020. Available via (Accessed 27 March 2021).

9. Campbell KJ, Tait SWG. Targeting BCL-2 regulated apoptosis in cancer. Open Biol 2018;8:1-1.

10. Singh R, Letai A, Sarosiek K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat Rev Mol Cell Biol 2019;20(3):175-93.

11. Zhu J, Jin M, Wang J, Zhang H, Wu Y, Li D, et al. TNFα induces Ca2+ influx to accelerate extrinsic apoptosis in hepatocellular carcinoma cells. J Exp Clin Cancer Res 2018;37(1):43.

12. Jan R, Chaudhry, G. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull 2019;9(2):205-18.

13. Wang Y, Hu S, Tuerdi M, Yu X, Zhang H, Zhou Y, et al. Initiator and executioner caspases in salivary gland apoptosis of Rhipicephalus haemaphysaloides. Parasit Vectors 2020;13(1):288.

14. Neves BJ, Braga RC, Melo-Filho CC, Moreira-Filho JT, Muratov EN, Andrade CH. QSAR-based virtual screening: advances and applications in drug discovery. Front Pharmacol 2018;9:1275.

15. Forli S, Huey R, Pique ME, Sanner MF, Goodsell DS, Olson AJ. Computational protein-ligand docking and virtual drug screening with the AutoDock suite. Nat Protoco 2016;11(5):905-19.

16. Pandurangan M, Enkhtaivan G, Kim DH. Therapeutic efficacy of natural dipeptide carnosine against human cervical carcinoma cells. J Mol Recognit 2016;29(9):426-35.

17. Murthy SS, Narsaiah TB. Molecular docking studies of phytocompounds with transcriptional factors in hepatocellular carcinoma. Rasayan J Chem 2019;14(4):2030-8.

18. Kuo SZ, Honda CO, Li WT, Honda TK, Kim E, Altuna X, et al. Metformin results in diametrically opposed effects by targeting non-stem cancer cells but protecting cancer stem cells in head and neck squamous cell carcinoma. Int J Mol Sci 2019;20(1):193.

19. Adegoke RO, Oyebamiji AK, Semire B. Dataset on the DFT-QSAR, and docking approaches for anticancer activities of 1, 2, 3-triazole-pyrimidine derivatives against human esophageal carcinoma (EC- 109). Data Brief 2020;31:105963.

20. Xue ST, Li K, Gao Y, Zhao LY, Gao Y, Yi H, et al. The role of the key autophagy kinase ULK1 in hepatocellular carcinoma and its validation as a treatment target. Autophagy 2020;16(10):1823-37.

21. Schrödinger LLC. The PyMOL molecular graphics system, Schrödinger Inc., New York, NY, USA, version 1.8. 2015.

22. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimisation and multithreading, J Comput Chem 2010;31:455-61.

23. Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J Chem Inf Model 2011;51(10):2778-86.

24. Edlich F. BCL-2 proteins and apoptosis: recent insights and unknowns. Biochem Biophys Res Commun 2018;500(1):26-34.

25. Warren CFA, Wong-Brown MW, Bowden NA. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis 2019;10(3):177.

26. Kominami K, Nakabayashi J, Nagai T, Tsujimura Y, Chiba K, Kimura H, et al. The molecular mechanism of apoptosis upon caspase-8 activation: quantitative experimental validation of a mathematical model. Biochimica Biophysica Acta 2012;1823(10):1825-40.

27. Raudenska M, Balvan J, Masarik M. Cell death in head and neck cancer pathogenesis and treatment. Cell Death Dis 2021;12(2):192.

28. McComb S, Chan PK, Guinot A, Hartmannsdottir H, Jenni S, Dobay MP, et al. Efficient apoptosis requires feedback amplification of upstream apoptotic signals by effector caspase-3 or -7. Sci Adv 2019;5(7):eaau9433.

29. Tian W, Chen C, Lei X, Zhao JL, Liang J. CASTp 3.0: computed atlas of surface topography of proteins. Nucleic Acids Res 2018;46(W1):W363-7.

30. Pagadala NS, Syed K, Tuszynski J. Software for molecular docking: a review, Biophys Rev 2017;9(2):91-102.

31. Pantsar T, Poso A. Binding affinity via docking: fact and fiction. Molecules 2018;23(8):1899.

32. Freitas RF, Schapira M. Asystemic analysis of atomic protein-ligand interactions in the PDB. Med Chem Commun 2017;8(10):1970-81.

33. Afriza D, Suriyah WH, Ichwan SJA. In silico analysis of molecular interactions between the anti-apoptotic protein survivin and dentatin, nordentatin, and quercetin. J Phys Conf Ser 2018;1073(3):032001.

34. Banerjee S, Katiyar P, Kumar V, Saini SS, Varshney R, Krishnan V, et al. Black pepper and piperine induce anticancer effects on leukemia cell line. Toxicol Res 2021;10(2):169-82.

35. Kirubhanand C, Selvaraj J, Rekha UV, Vishnupriya V, Nalini D, Mohan SK, et al. Molecular docking data of piperine with Bax, Caspase 3, Cox 2 and Caspase 9. Bioinformation 2020;16(6):458-61.

36. Sethi G, Sung B, Aggarwal BB. TNF: a master switch for inflammation to cancer. Front Biosci 2008;13:5094-107.

37. Zeligs KP, Neuman MK, Annunziata CM. Molecular pathways: the balance between cancer and the immune system challenges the therapeutic specificity of targeting nuclear factor-kB signalling for cancer treatment. Clin Cancer Res 2016;22(17).

38. Jin YB, Zhang GY, Lin KR, Chen XP, Cui JH, Wang YJ, et al. Changes of plasma cytokines and chemokines expression level in nasopharyngeal carcinoma patients after treatment with definitive intensity-modulated radiotherapy (IMRT). PLoS One 2017;12(2):1-9.

39. Lu X, Qian CN, Mu YG, Li NW, Li S, Zhang HB, et al. Serum CCL2 and serum TNF-α - two new biomarkers predict bone invasion, post-treatment distant metastasis and poor overall survival in nasopharyngeal carcinoma. Euro J Cancer 2011;47(3):339-46.

40. Yu Y, Ke L, Xia WX, Xiang Y, Lv X, Bu J. Elevated levels of TNF-α and decreased levels of CD68-positive macrophages in primary tumor tissues are unfavorable for the survival of patients with nasopharyngeal carcinoma. Technol Cancer Res Treat 2019;18:1-1.

41. Farhat RA, Asnir A, Yudhistira, Susilo RR, Daulay ER, Chrestella J. Stem cell oncology: correlation of TNF-α expression to clinical stadium in nasopharyngeal carcinoma (NPC). CRC Press Taylor & Francis Group, Boca Raton, FL, pp 129-32, 2018, vol 4.

42. Santos LHS, Ferreira RS, Caffarena, ER. Integrating molecular docking and molecular dynamics simulations. Docking screens for drug discovery. Methods Mol Biol 2019;2053:13-34.

Article Metrics

9 Absract views 8 PDF Downloads 17 Total views

Related Search

By author names

    Warning: Cannot modify header information - headers already sent by (output started at /home/jabonlin/public_html/jab_php/abstract.php:245) in /home/jabonlin/public_html/jab_php/articlemodule/searchArticles.php on line 1162
    Vong A D [PubMed] [Google Scholar ]
    Hwang S [PubMed] [Google Scholar ]
    Chee X W [PubMed] [Google Scholar ]
    Sim E U [PubMed] [Google Scholar ]

    Warning: Invalid argument supplied for foreach() in /home/jabonlin/public_html/jab_php/abstract.php on line 819

Citiaion Alert By Google Scholar

Name Required
Email Required Invalid Email Address

Comment required

Notice: Undefined variable: dbq35 in /home/jabonlin/public_html/jab_php/abstract.php on line 942

Warning: mysqli_num_rows() expects parameter 1 to be mysqli_result, null given in /home/jabonlin/public_html/jab_php/articlemodule/database.php on line 379
Similar Articles