Molecular docking and flexibility analysis of vitamin D3 with microenvironment-associated protein targets in colorectal cancer
Keywords:
Vitamin D3, colorectal cancer, tumor microenvironment, molecular docking, Matrix metalloproteinasesAbstract
Colorectal cancer (CRC) remains a major global health burden, with high mortality largely driven by tumor metastasis, angiogenesis, and chronic inflammation within the tumor microenvironment. Vitamin D3 (cholecalciferol) has been widely investigated for its pleiotropic anticancer properties, yet its interactions with proteins involved in the CRC tumor microenvironment remain insufficiently explored. This study aimed to evaluate the molecular interactions of vitamin D3 with key proteins associated with the CRC tumor microenvironment, including matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), and interleukin-1β (IL-1β). Molecular docking simulations were conducted using AutoDock Vina to predict binding affinities and interaction patterns between vitamin D3 and the selected proteins. The stability and flexibility of the resulting complexes were further analyzed through coarse-grained simulations using CABS-flex 2.0, generating root mean square fluctuation (RMSF) and radius of gyration (Rg) values, while docking poses and structural dynamics were visualized using PyMOL. The results showed that vitamin D3 exhibited favorable binding affinities toward all targets, with docking scores of –7.9 kcal/mol (MMP-9), –7.7 kcal/mol (MMP-2), –7.3 kcal/mol (VEGF), and –6.3 kcal/mol (IL-1β). RMSF analysis indicated low to moderate residue fluctuations (<1.5 Å), suggesting stable protein–ligand complexes, with VEGF showing the lowest RMSF value (0.87 Å), reflecting enhanced structural stability upon vitamin D3 binding. Rg values remained within the expected range for compact protein structures (0.25–0.35 nm), indicating no significant unfolding during simulation. These findings suggest that vitamin D3 may act as a multi-target modulator of the CRC tumor microenvironment by influencing extracellular matrix degradation, angiogenesis, and inflammatory signaling, although further in vitro and in vivo validation is required to confirm these computational predictions.
References
1. Zhou J, Ge X, Fan X, Wang J, Miao L, Hang D. Associations of vitamin D status with colorectal cancer risk and survival. Int J Cancer. 2021;149(3):606–14.
2. Sharma R, Abbasi-Kangevari M, Abd-Rabu R, Abidi H, Abu-Gharbieh E, Acuna JM, et al. Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Gastroenterol Hepatol. 2022 Jul;7(7):627–47.
3. Wang Y, Wei Y, Huang J, Li X, You D, Wang L, et al. Prognostic value of matrix metalloproteinase-2 protein and matrix metalloproteinase-9 protein in colorectal cancer: a meta-analysis. BMC Cancer. 2024;24(1):1065.
4. Park JY, Park DH, Jeon Y, Kim YJ, Lee J, Shin MS, et al. Eupatilin inhibits angiogenesis-mediated human hepatocellular metastasis by reducing MMP-2 and VEGF signaling. Bioorg Med Chem Lett. 2018;28(19):3150–4.
5. Pore N. Vascular endothelial growth factor and tumor immune microenvironment. In: Endothelial Signaling in Vascular Dysfunction and Disease. Elsevier; 2021. p. 105–11.
6. Wang Z, Yuan Y, Ji X, Xiao X, Li Z, Yi X, et al. The Hippo-TAZ axis mediates vascular endothelial growth factor C in glioblastoma-derived exosomes to promote angiogenesis. Cancer Lett. 2021;513:1–13.
7. Muthusami S, Ramachandran IK, Babu KN, Krishnamoorthy S, Guruswamy A, Queimado L, et al. Role of Inflammation in the Development of Colorectal Cancer. Endocrine, Metab Immune Disord - Drug Targets. 2021;21(1):77–90.
8. Shakhpazyan NK, Mikhaleva LM, Sadykhov NK, Bedzhanyan AL, Gioeva ZV, Mikhalev AI, et al. Altered proinflammatory cytokine response in colorectal cancer patients: insights into immune dysregulation. Clin Exp Morphol. 2024;13(4):29–35.
9. Blasiak J, Chojnacki J, Pawlowska E, Jablkowska A, Chojnacki C. Vitamin D May Protect against Breast Cancer through the Regulation of Long Noncoding RNAs by VDR Signaling. Int J Mol Sci. 2022;23(6):3189.
10. Wiecheć O. The role of vitamin D3 in signaling pathways – potential anticancer properties of calcitriol and its analogues. Postepy Hig Med Dosw. 2019;73:920–36.
11. Prasanth D, Khan PA, Jamal‐E‐Fatima, Durgawale TP, Siddique FA, Khan SL, et al. Vitamin D‐induced mechanisms in cancer prevention and therapy: Recent advances and future opportunities. Anim Model Exp Med. 2025;8(11):1935-1946.
12. Shobahah J, Wahyuningsih S, Winarni D, Herdiansyah M, Aly M. In Silico Evaluation of Vitamin D3 as a Dual Inhibitor of CDK2 and Bcl-2 in Colorectal Cancer. Open Vet J. 2025;15(8):3759.
13. de Oliveira Gonçalves GB, de Almeida Belo V, Ceron CS. Gel Zymography for the Evaluation of Matrix Metalloproteinase-2 and -9 in Aorta and Kidney Tissues. 2025. p. 87–97.
14. Wolosowicz M, Prokopiuk S, Kaminski TW. The Complex Role of Matrix Metalloproteinase-2 (MMP-2) in Health and Disease. Int J Mol Sci. 2024;25(24):13691.
15. Zhu M, Ma Y, Tang M, Pan L, Liu W. Hypoxia-induced upregulation of matrix metalloproteinase 9 increases basement membrane degradation by downregulating collagen type IV alpha 1 chain. Physiol Res. 2022;71(6):825–34.
16. Barabás L, Hritz I, István G, Tulassay Z, Herszényi L. The Behavior of MMP-2, MMP-7, MMP-9, and Their Inhibitors TIMP-1 and TIMP-2 in Adenoma-Colorectal Cancer Sequence. Dig Dis. 2021;39(3):217–24.
17. Bajbouj K, Al-Ali A, Shafarin J, Sahnoon L, Sawan A, Shehada A, et al. Vitamin D Exerts Significant Antitumor Effects by Suppressing Vasculogenic Mimicry in Breast Cancer Cells. Front Oncol. 2022;12:918340.
18. Gupta B, Chandra S, Raj V, Gupta V. Immunohistochemical expression of vascular endothelial growth factor in orofacial lesions – A review. J Oral Biol Craniofacial Res. 2016;6(3):231–6.
19. Kang Y, Li H, Liu Y, Li Z. Regulation of VEGF-A expression and VEGF-A-targeted therapy in malignant tumors. J Cancer Res Clin Oncol. 2024;150(5):221.
20. El-Toukhy SE, Abdel-Salam OME, Ibrahim AMM, Youness ER. Oxidative, Inflammatory, Angiogenic Markers and Vitamin D Status in Pre- and Postmenopausal Breast Cancer Egyptian Patients. Biomed Pharmacol J. 2021;14(02):829–44.
21. Shi H, Qin Y, Tian Y, Wang J, Wang Y, Wang Z, et al. Interleukin-1beta triggers the expansion of circulating granulocytic myeloid-derived suppressor cell subset dependent on Erk1/2 activation. Immunobiology. 2022;227(1):152165.
22. Khan A, Zhang Y, Ma N, Shi J, Hou Y. NF-κB role on tumor proliferation, migration, invasion and immune escape. Cancer Gene Ther. 2024;31(11):1599–610.
23. Lu L, Wang P, Zou Y, Zha Z, Huang H, Guan M, et al. IL-1β Promotes Stemness of Tumor Cells by Activating Smad/ID1 Signaling Pathway. Int J Med Sci. 2020;17(9):1257–68.
24. Wei J, Zhang J, Jiang Y, Lian T, Zhang P, Hoffman RM, et al. Elevated Pro-inflammatory Cytokine Levels in Acute Reflux Esophagitis Are Reduced by 1,25 Dihydroxy Vitamin D3. In Vivo (Brooklyn). 2023;37(1):79–87.
25. Jin A, Zhao Y, Yuan Y, Ma S, Chen J, Yang X, et al. Single Treatment of Vitamin D3 Ameliorates LPS‐Induced Acute Lung Injury through Changing Lung Rodentibacter abundance. Mol Nutr Food Res. 2022;66(3). e2100952
26. Prafitriyanti W, Wibowo S, Sulistijono E. The role of vitamin D3 administration on IFN-γ, IL-1β expression and repair of colonic mucosa at mice models of ulcerative colitis. 2021. p. 030112.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 M. Ainun Najib Aly, Jauharotus Shobahah
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Abstract views: 70
,
PDF Downloads: 47
