Potency of Bisindoles from Caulerpa racemosa in Handling Diabetes-Related Complications: In silico ADMET Properties and Molecular Docking Simulations

Year 2024, , 99 - 107, 19.09.2024

Muhammad Aswad , Resky Nugraha Risfah Yulianty

https://doi.org/10.33435/tcandtc.1396721

Abstract

Diabetes mellitus and its complications are among the primary causes of death and disability. Retinopathy, cardiovascular disease, and neuropathy develop progressively with prolonged hyperglycemia. Finding an effective and secure drug with fewer side effects to handle diabetes-related complications is necessary. Numerous scientists are launching new initiatives to investigate plant sources, which are known to contain a vast array of active agents. An edible marine algae, Caulerpa racemosa, was reported to have bioactivities including antidiabetes, anti-inflammatory and neuroprotective. Consequently, the current study was conducted to investigate bisindoles from Caulerpa racemosa using in silico method. Five bisindoles such as caulerpin, caulersin, racemosin A, racemosin B and racemosin C were selected to be anticipated their interaction binding mode and interaction energies toward protein targets associated with NF−κB such as TAK1 (7NTI), NIK (4IDV) and MMP−9 (4H3X) using AutoDock Vina integrated with Chimera, while their predicted ADMET were proceeded using web tool pkCSM. The result indicated that caulerpin
all the compounds were predicted to interact molecularly with amino acids surrounding the binding site of protein targets. indicating the most favorable interaction with targets Predicted pharmakokinetics showed that most of the compounds meet the minimum standard parameters in ADMET properties. The findings suggested that bisindoles contained in Caulerpa racemosa might potentially to be used in treatment of diabetes-related complications

Keywords

ADMET, Caulerpa, bisindole, docking, diabetes

Ethical Statement

The authors declare that there are no conflict of interest

Supporting Institution

This is was supported by grants provide by Hasanuddin University

Project Number

00323/UN4.22/PT.01.03/2023

Thanks

The authors thank Hasanuddin University for the research grant (00323/UN4.22/PT.01.03/2023) in the scheme Collaborative Fundamental Research in 2023.

References

• [1] IDF, IDF Diabetes Atlas, (2022) 4-7. https://diabetesatlas.org/.
• [2] A.D. Deshpande, M. Harris-Hayes, M. Schootman, Epidemiology of diabetes and diabetes-related complications, Physical Theraphy 88 (2008) 1254–1264.
• [3] S. V. Suryavanshi, Y.A. Kulkarni, NF-κB: A potential target in the management of vascular complications of diabetes, Frontiers Pharmacology 8 (2017) 1–12.
• [4] H. Yu, L. Lin, Z. Zhang, Targeting NF-κB pathway for the therapy of diseases : mechanism and clinical study, Signal Transduction and Targeted Therapy (2020) 1-23.
• [5] K. Kanasaki, G. Taduri, D. Koya, Diabetic nephropathy : the role of inflammation in fibroblast activation and kidney fibrosis, Frontiers in Endocrinology 4 (2013) 1–15.
• [6] R.A. Kowluru, Q. Zhong, J.M. Santos, Matrix metalloproteinases in diabetic retinopathy: Potential role of MMP-9, Expert Opinion on Investigational Drugs 21 (2012) 797–805.
• [7] R.A. Kowluru, Y. Shan, M. Mishra, Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy, Laboratory Investigation (2016) 1–10.
• [8] P.K. Shihab, A. Al-roub, M. Al-ghanim, A. Al-mass, K. Behbehani, TLR2 and AP-1 / NF-κB are involved in the regulation of MMP-9 elicited by heat killed Listeria monocytogenes in human monocytic THP-1 cells, Journal of Inflammation (2015) 1–9.
• [9] Y. Li, Y. Zhang, D. Liu, H. Liu, W. Hou, Y. Dong, Curcumin Attenuates Diabetic Neuropathic Pain by Downregulating TNF-α in a Rat Model, International Journal of Medical Sciences 10 (2013) 377.
• [10] L. Daniel, C. Alberto, J. Alarc, M. Miranda, D. Manuel, F.J. Romero, V.M. Villar, Curcumin as a Therapeutic Option in Retinal Diseases, Antioxidants 9 (2020) 1–15.
• [11] F. Xu, Y. Wang, W. Cui, H. Yuan, J. Sun, M. Wu, Q. Guo, L. Kong, H. Wu, L. Miao, Resveratrol Prevention of Diabetic Nephropathy Is Associated with the Suppression of Renal Inflammation and Mesangial Cell Proliferation : Possible Roles of Akt / NF-κB Pathway, International Journal of Endocrinology 2014 (2014) 1-9.
• [12] A.Q. Aroyehun, S.A. Razak, K. Palaniveloo, T. Nagappan, N. Suraiza, N. Rahmah, G.W. Jin, Bioprospecting Cultivated Tropical Green Algae, Caulerpa racemosa (Forsskal) J. Agardh: A Perspective on Nutritional Properties, Antioxidative Capacity and Anti-Diabetic Potential, Foods 9 (2020) 1313.
• [13] R. V Mandlik, S.R. Naik, S. Zine, H. Ved, G. Doshi, Antidiabetic Activity of Caulerpa racemosa : Role of Proinflammatory Mediators , Oxidative Stress , and Other Biomarkers, Planta Medica 9 (2022) 60–71.
• [14] N. El Habitri, L. Belkacemi, Antidiabetic effect of oral supplementation with Caulerpa racemosa powder, European Journal Biological Research 12 (2022) 141–152.
• [15] I.H. Dissanayake, U. Bandaranayake, L.R. Keerthirathna, C. Manawadu, R.M. Silva, B. Mohamed, R. Ali, D.C. Peiris, Integration of in vitro and in silico analysis of Caulerpa racemosa against antioxidant , antidiabetic , and anticancer activities, Scientific Reports (2022) 1–15.
• [16] R. Kurniawan, F. Nurkolis, N.A. Taslim, D. Subali, R. Surya, W. Ben Gunawan, D. Alisaputra, N. Mayulu, N. Salindeho, B. Kim, Carotenoids Composition of Green Algae Caulerpa racemosa and Their Antidiabetic, Anti-Obesity, Antioxidant, and Anti-Inflammatory Properties, Molecules. 28 (2023) 3267.
• [17] P. Yang, D.Q. Liu, T.J. Liang, J. Li, H.Y. Zhang, A.H. Liu, Y.W. Guo, S.C. Mao, Bioactive constituents from the green alga Caulerpa racemosa, Bioorganic and Medicinal Chemistry 23 (2015) 38–45.
• [18] D.Q. Liu, S.C. Mao, H.Y. Zhang, X.Q. Yu, M.T. Feng, B. Wang, L.H. Feng, Y.W. Guo, Racemosins A and B, two novel bisindole alkaloids from the green alga Caulerpa racemosa, Fitoterapia. 91 (2013) 15–20.
• [19] H. Yang, D. Liu, T. Liang, J. Li, A. Liu, P. Yang, K. Lin, X. Yu, Y. Guo, B. Wang, Racemosin C, a novel minor bisindole alkaloid with protein tyrosine phosphatase-1B inhibitory activity from the green alga Caulerpa racemosa, Journal Asian Natural Product Research (2014) 37–41.
• [20] R. Mehra, S. Bhushan, F. Bast, S. Singh, Marine macroalga Caulerpa: role of its metabolites in modulating cancer signaling, Molecular Biology Reports 46 (2019) 3545–3555.
• [21] J.J.N. Veerman, Y.B. Bruseker, E. Damen, E.H. Heijne, W. Van Bruggen, K.F.W. Hekking, R. Winkel, C.D. Hupp, A.D. Keefe, J. Liu, H.A. Thomson, Y. Zhang, J.W. Cuozzo, A.J. McRiner, M.J. Mulvihill, P. Van Rijnsbergen, B. Zech, L.M. Renzetti, L. Babiss, G. Müller, Discovery of 2,4-1 H-Imidazole Carboxamides as Potent and Selective TAK1 Inhibitors, ACS Medicinal Chemistry Letters 12 (2021) 555–562.
• [22] K. Li, L.R. Mcgee, B. Fisher, A. Sudom, J. Liu, S.M. Rubenstein, M.K. Anwer, T.D. Cushing, Y. Shin, M. Ayres, F. Lee, J. Eksterowicz, P. Faulder, B. Waszkowycz, O. Plotnikova, E. Farrelly, S. Xiao, G. Chen, Z. Wang, Inhibiting NF-kB-inducing kinase ( NIK ): Discovery , structure-based design , synthesis , structure – activity relationship , and co-crystal structures, Bioorganic and Medicinal Chemistry Letters 23 (2013) 1238–1244.
• [23] C. Antoni, L. Vera, L. Devel, M.P. Catalani, B. Czarny, E. Cassar-Lajeunesse, E. Nuti, A. Rossello, V. Dive, E.A. Stura, Crystallization of bi-functional ligand protein complexes, Journal of Structural Biology 182 (2013) 246–254.
• [24] D.E.V. Pires, T.L. Blundell, D.B. Ascher, pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures, Journal of Medicinal Chemistry 58 (2015) 4066–4072.
• [25] D. Ramirez, J. Caballero, Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data ?, Molecules 23 (2018) 1038.
• [26] Y. Zeng, Y. Yang, Piperine depresses the migration progression via downregulating the Akt/mTOR/MMP-9 signaling pathway in DU145 cells, Molecular Medicine Repots 17 (2018) 6363–6370.