Anticancer activities of bioactive compounds from Paracaudina australis: an in-silico study targeting AKT1 and NOS2
DOI:
https://doi.org/10.17844/m8s22h81Keywords:
bioactivity, docking, ligands, pharmaceuticals, sea cucumberAbstract
Sea cucumber isolates (Paracaudina australis) have shown potential as agents with various bioactivities. Bioactivity refers to the ability of a substance to interact with biological tissues and elicit positive physiological responses. This study aimed to analyze the interaction between the target proteins RAC-alpha serine/threonine-protein kinase (AKT1) and Nitric Oxide Synthase 2 (NOS2) with compounds identified in P. australis. The methods employed included ligand preparation using the Open Babel 2.3.1 plug-in, bioactivity prediction via the PASS Online web server, ADMET analysis using Canonical SMILES, pathway prediction using the DAVID (Database for Annotation, Visualization, and Integrated Discovery) web server, prediction of active or functional sites in proteins using BIOVIA Discovery Studio software, molecular docking using AutoDock Vina integrated in PyRx 0.8, visualization with BIOVIA Discovery Studio 2019, and molecular dynamics simulation using the WebGro web server. The results revealed that the P. australis sea cucumber isolate contained 38 compounds predicted to exhibit bioactivities related to the target proteins, including anticancer, anti-proliferative, pro-apoptotic, anti-inflammatory, anti-type 2 diabetes, and anti-obesity effects. Based on five ADMET parameters, all compounds satisfied several pharmacokinetic and toxicity criteria. Protein interaction analysis indicated that AKT1 and NOS2 interacted with other proteins, such as MTCP1, TCL1A, and NOX1. Molecular docking results showed that the compounds Ergosta-7,22-dien-3-ol, (3β,5α,22E); Ergostan-3-ol; Ergost-7-en-3-ol, (3β,5α); and Stigmasta-7,16-dien-3-ol, (3β,5α) exhibited the most stable binding to AKT1. Additionally, the compounds Ergosta-7,22-dien-3-ol, (3β,5α,22E) and Ergosta-7,22-dien-3-ol, (3β,22E) demonstrated lower binding affinity values than the control NOS2 inhibitor, indicating strong potential as NOS2 inhibitors.
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Seo Hyo-Deok, Ji-Young Lee, So-Hyun Park, Eunyoung Lee, Jeong-Hoon Hahm, Jiyun Ahn, A Ra Jang, So Hee An, Jang Ho Ha. (2024). Identification of novel anti-obesity saponins from the ovary of sea cucumber (Stichopus japonicus). Heliyon, 10, e36943.
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Srivastava V, Yadav A, Sarkar P. (2020). Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc.49:2999-3007. doi: 10.1016/j.matpr.2020.10.055. Epub Oct 14. PMID: 33078096; PMCID: PMC7556787.
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Tripathy D, Nayak BS, Mohanty B, et al. (2019). Solid dispersion: A technology for improving aqueous solubility of drug. Journal of Pharmaceutical Advanced Research, 2(7):577-586.
Verma, C, M.A. Quraishi, K.Y. Rhee, (2022). Hydrophilicity and hydrophobicity consideration of organic surfactant compounds: Effect of alkyl chain length on corrosion protection, Advances in Colloid and Interface Science, 306, 102723, 0001-8686 https://doi.org/10.1016/j.cis.2022.102723.
Verma, C, M.A. Quraishi, K.Y. Rhee. Electronic effect vs. Molecular size effect: Experimental and computational based designing of potential corrosion inhibitors. Chemical Engineering Journal 2022, 430 (1), 132645 https://doi.org/10.1016/j.cej.2021.132645
Wang, X.; Gray, Z.; Willette-Brown, J.; Zhu, F.; Shi, G.; Jiang, Q.; Song, N.Y.; Dong, L.; Hu, Y. (2018). Macrophage inducible nitric oxide synthase circulates inflammation and promotes lung carcinogenesis. Cell Death Discov. 4, 46.
Wargasetia TL, Ratnawati H, Widodo N, et al. (2021). Bioinformatics study of sea cucumber peptides as antibreast cancer through inhibiting the activity of overexpressed protein (EGFR, PI3K, AKT1, and CDK4). Cancer Informatics, 20, 11769351211031864.
Watkins, Elyse J. (2019). DHSc, PA-C, DFAAPA Overview of breast cancer, Journal of the American Academy of Physician Assistants. 32:(10): 13-17 DOI: 10.1097/01.JAA.0000580524.95733.3d.
Wicaksono A, Raihandhany R, Zen TV, et al. (2021). Screening Rafflessia and Sapria metabolites using a bioinformatics approach to assess their potential as drugs. Philippine Journal of Science. 151(5):1771-1791.
Widyananda MH, Pratama SK, Samoedra RS, et al. (2021). Molecular docking study of sea urchin (Arbacia lixula) peptides as multi-target inhibitor for non-small cell lung cancer (NSCLC) associated proteins. Journal of Pharmacy and Pharmacognosy Research. 9(4):484-496.
Widyananda MH, Wicaksono ST, Rahmawati K, et al. (2022). A Potential Anticancer Mechanism of Finger Root (Boesenbergia rotunda) Extracts against a Breast Cancer Cell Line. Scientifica, 2022.
Yang Z-Y, Di M-Y, Yuan J-Q , et al. (2015). The prognostic value of phosphorylated Akt in breast cancer: a systematic review. Sci Rep.;5:7758. doi:10.1038/ srep07758.
Zhao Y, Lin G, Li R, Yubo L, Congcong M, Xianming L. (2022). Factors influencing the blood-brain barrier permeability. Brain Research, 1788, 147937.
Zrieq R, Ahmad I, Snoussi M, Noumi E, Iriti M, Algahtani FD, Patel H, Saeed M, Tasleem M, Sulaiman S, et al. (2021). Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations. International Journal of Molecular Sciences.; 22(19):10693. https://doi.org/10.3390/ijms221910693
Aini NS., Kharisma VD., Ansori A., (2023). Bioactive compounds screening of Rafflessia sp. and Sapria sp. (Family: Rafflesiaceae) as anti-SARS-CoV-2 via tetra inhibitors: An in silico research. Journal of Pharmacy and Pharmacognosy Research, 11(4):611-624. DOI: 10.56499/jppres23.1620_11.4.611.
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Cao, L., Coventry, B., Goreshnik, I. et al. (2022). Design of protein-binding proteins from the target structure alone. Nature 605, 551–560 https://doi.org/10.1038/s41586-022-04654-9
Carletti A, Cardoso C, Lobo-Arteaga J, Sales S, Juliao D, Ferreira I, Chainho P, Dionísio MA, Gaudêncio MJ, Afonso C, Lourenço H, Cancela ML, Bandarra NM and Gavaia PJ. (2022). Antioxidant and Anti-inflammatory Extracts From Sea Cucumbers and Tunicates Induce a Pro-osteogenic Effect in Zebrafish Larvae. Front. Nutr. 9:888360. doi: 10.3389/fnut.2022.888360.
Chen L, Lu D, Zhang Y. (2022). Organic Compounds as Corrosion Inhibitors for Carbon Steel in HCl Solution: A Comprehensive Review. Materials.; 15(6):2023. https://doi.org/10.3390/ma15062023
Christina YI, Nafisah W, Atho’illah MF, et al. (2021). Anti-breast cancer potential activity of Phaleria macrocarpa (Scheff.) Boerl. leaf extract through in silico studies. Journal of Pharmacy and Pharmacognosy Research, 9(6):824-845.
Ebenso Eno E., Chandrabhan Verma, Lukman O. Olasunkanmi, Ekemini D. Akpan, Dakeshwar Kumar Verma,Hassane Lgaz, Lei Guo, Savas Kayah and M. A. Quraishi. (2021). Molecular modelling of compounds used for corrosion inhibition studies: a review. Phys. Chem. Chem. Phys., ,23, 19987-20027
Esteves F, Rueff J, Kranendonk M. (2021). The Central Role of Cytochrome P450 in Xenobiotic Metabolism—A Brief Review on a Fascinating Enzyme Family. Journal of Xenobiotics.; 11(3):94-114. https://doi.org/10.3390/jox11030007.
Grahadi R, Widyananda MH, Rahayu. (2023). In-silico screening of bioactive compounds from nut grass (Cyperus rotundus) to inhibit the α-bungarotoxin from Kraits (Bungarus spp.) venom. Egyptian Journal of Basic and Applied Sciences. 11(1):92-103. DOI: 10.1080/2314808X.2024.2317024.
Groeneveld CS, Virginia SQ, Florent D, Mingjun S, Florent D, Rémy N, Elodie C, Patrick P, Daniel J, Clémentine K, Pascale M, Francis V, Dimitri V, Simone B, Thierry L, Olivier M, Andrei Z, Damarys L, Yves A, Aurélien de R, Isabelle BP, François R. (2024). Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor–related Apoptosis-inducing Ligand in FGFR3-mutated Tumors, European Urology, 85, Issue 5, 483-494, https://doi.org/10.1016/j.eururo.2023.05.037.
Hays E, Bonavida B. (2019). YY1 regulates cancer cell immune resistance by modulating PDL1 expression. Drug Resist Update. 43:10-28. DOI: 10.1016/j.drup.2019.04.001. Epub 2019 Apr 9. PMID: 31005030.
Kang JH, Ko YT. (2023). Intraosseous administration into the skull: Potential blood–brain barrier bypassing route for brain drug delivery. Bioeng Transl Med. 8(2):e10424. doi:10.1002/btm2.10424
Klomp F, Wenzel C, Drozdzik M, Oswald S. (2020). Drug–Drug Interactions Involving Intestinal and Hepatic CYP1A Enzymes. Pharmaceutics.; 12(12):1201. https://doi.org/10.3390/pharmaceutics12121201
Liu L, Xiaomin Li, Xiaofen Wu, Juan Feng, Xiangxing Zhu, Dongsheng Tang, Xiao Jiang, Wenjie Pan, Jiasheng Huang, Ting Chen, Chunhua Ren, Aifen Yan. (2023). Genome-wide analysis of the intrinsic apoptotic pathway in the tropical sea cucumber Holothuria leucospilota. Aquaculture Reports, , 31,101665 https://doi.org/10.1016/j.aqrep.2023.101665.
Lombardo F, Jörg B, Giuliano B, Ingo M. (2021). In Silico Models of Human PK Parameters. Prediction of Volume of Distribution Using an Extensive Data Set and a Reduced Number of Parameters. Journal of Pharmaceutical Sciences, 110(1): 500-509. https://doi.org/10.1016/j.xphs.2020.08.023.
Onyango H, Odhiambo P, Angwenyi D, et al. (2022). In Silico identification of new anti-sars-cov-2 main protease (Mpro) molecules with pharmacokinetic properties from natural sources using molecular dynamics (MD) simulations and hierarchical virtual screening. J Trop Med. 3697498. doi: 10.1155/2022/3697498.
Pantaleão S. Q., P. O. Fernandes, J. E. Gonçalves, V. G. Maltarollo, K. M. Honorio. (2022). Recent Advances in the Prediction of Pharmacokinetics Properties in Drug Design Studies: A Review. ChemMedChem, 17, e202100542.
Pradeepkiran JA, Sainath SB, Shrikanya KVL. (2021). In silico validation and ADMET analysis for the best lead molecules. In: Brucella Melintesis: Identification and Characterization of Potential Drug Targets. 133-176. Doi: 10.1016/B978-0-323-85681-2.00008-2.
Qin, A.; Chen, S.; Wang, P.; Huang, X.; Zhang, Y.; Liang, L.; Du, L.R.; Lai, D.H.; Ding, L.; Yu, X.; et al. (2021). Knockout of NOS2 Promotes Adipogenic Differentiation of Rat MSCs by Enhancing Activation of JAK/STAT3 Signaling. Front. Cell Dev. Biol. 9, 638518.
Rudrapal M, Celik I, Khan J, et al. (2022). Identification of bioactive molecules from Triphala (Ayurvedic herbal formulation) as potential inhibitors of SARS-CoV-2 main protease (Mpro) through computational investigations. Journal of King Saud University—Science, 34(3):101826. Doi: 10.1016/j.jksus.2022.101826.
Seo Hyo-Deok, Ji-Young Lee, So-Hyun Park, Eunyoung Lee, Jeong-Hoon Hahm, Jiyun Ahn, A Ra Jang, So Hee An, Jang Ho Ha. (2024). Identification of novel anti-obesity saponins from the ovary of sea cucumber (Stichopus japonicus). Heliyon, 10, e36943.
Song M, Bode AM, Dong Z, Lee M-H. (2019). AKT as a therapeutic target for cancer. Cancer Res, 79:1019-1031. doi:10.1158/0008-5472.CAN-18-2738.
Srivastava V, Yadav A, Sarkar P. (2020). Molecular docking and ADMET study of bioactive compounds of Glycyrrhiza glabra against main protease of SARS-CoV2. Mater Today Proc.49:2999-3007. doi: 10.1016/j.matpr.2020.10.055. Epub Oct 14. PMID: 33078096; PMCID: PMC7556787.
Sternbeck, A.K.S and Ylva T. (2022). Evaluation of ADMET Predictor in Early Discovery Drug Metabolism and Pharmacokinetics Project Work. Drug Metabolism and Disposition. 50 (2) 95-104; DOI: https://doi.org/10.1124/dmd.121.000552.
Sukmiwati M, Susilawati S, Rahmawati N and Islami D. (2024).Cytotoxic Potential of Berunok Sea Cucumber (Paracaudina australis) Against Breast Cancer Cells (T47D) [version 1; peer review: awaiting peer review]. F1000Research , 13:340 (https://doi.org/10.12688/f1000research.145350.1).
Tayyeb JZ, Mondal S, Anisur Rahman M, (2024). Identification of Helicobacter pylori-carcinogenic TNF-alpha-inducing protein inhibitors via daidzein derivatives through computational approaches. J Cell Mol Med. ; 28:e18358. doi:10.1111/jcmm.18358
Tripathy D, Nayak BS, Mohanty B, et al. (2019). Solid dispersion: A technology for improving aqueous solubility of drug. Journal of Pharmaceutical Advanced Research, 2(7):577-586.
Verma, C, M.A. Quraishi, K.Y. Rhee, (2022). Hydrophilicity and hydrophobicity consideration of organic surfactant compounds: Effect of alkyl chain length on corrosion protection, Advances in Colloid and Interface Science, 306, 102723, 0001-8686 https://doi.org/10.1016/j.cis.2022.102723.
Verma, C, M.A. Quraishi, K.Y. Rhee. Electronic effect vs. Molecular size effect: Experimental and computational based designing of potential corrosion inhibitors. Chemical Engineering Journal 2022, 430 (1), 132645 https://doi.org/10.1016/j.cej.2021.132645
Wang, X.; Gray, Z.; Willette-Brown, J.; Zhu, F.; Shi, G.; Jiang, Q.; Song, N.Y.; Dong, L.; Hu, Y. (2018). Macrophage inducible nitric oxide synthase circulates inflammation and promotes lung carcinogenesis. Cell Death Discov. 4, 46.
Wargasetia TL, Ratnawati H, Widodo N, et al. (2021). Bioinformatics study of sea cucumber peptides as antibreast cancer through inhibiting the activity of overexpressed protein (EGFR, PI3K, AKT1, and CDK4). Cancer Informatics, 20, 11769351211031864.
Watkins, Elyse J. (2019). DHSc, PA-C, DFAAPA Overview of breast cancer, Journal of the American Academy of Physician Assistants. 32:(10): 13-17 DOI: 10.1097/01.JAA.0000580524.95733.3d.
Wicaksono A, Raihandhany R, Zen TV, et al. (2021). Screening Rafflessia and Sapria metabolites using a bioinformatics approach to assess their potential as drugs. Philippine Journal of Science. 151(5):1771-1791.
Widyananda MH, Pratama SK, Samoedra RS, et al. (2021). Molecular docking study of sea urchin (Arbacia lixula) peptides as multi-target inhibitor for non-small cell lung cancer (NSCLC) associated proteins. Journal of Pharmacy and Pharmacognosy Research. 9(4):484-496.
Widyananda MH, Wicaksono ST, Rahmawati K, et al. (2022). A Potential Anticancer Mechanism of Finger Root (Boesenbergia rotunda) Extracts against a Breast Cancer Cell Line. Scientifica, 2022.
Yang Z-Y, Di M-Y, Yuan J-Q , et al. (2015). The prognostic value of phosphorylated Akt in breast cancer: a systematic review. Sci Rep.;5:7758. doi:10.1038/ srep07758.
Zhao Y, Lin G, Li R, Yubo L, Congcong M, Xianming L. (2022). Factors influencing the blood-brain barrier permeability. Brain Research, 1788, 147937.
Zrieq R, Ahmad I, Snoussi M, Noumi E, Iriti M, Algahtani FD, Patel H, Saeed M, Tasleem M, Sulaiman S, et al. (2021). Tomatidine and Patchouli Alcohol as Inhibitors of SARS-CoV-2 Enzymes (3CLpro, PLpro and NSP15) by Molecular Docking and Molecular Dynamics Simulations. International Journal of Molecular Sciences.; 22(19):10693. https://doi.org/10.3390/ijms221910693
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Sukmiwati, M., Susilawati, S., & Islami, D. . (2025). Anticancer activities of bioactive compounds from Paracaudina australis: an in-silico study targeting AKT1 and NOS2. Jurnal Pengolahan Hasil Perikanan Indonesia, 28(8), 721-737. https://doi.org/10.17844/m8s22h81
