Evaluation of natural compounds as VEGFR-2 inhibitors for breast cancer therapy: insights from molecular docking and drug-likeness analysis

  • Vika Aprilia Department of Pharmacy, Faculty of Health Sciences, Universitas Jenderal Soedirman, Purwokerto 53123, Indonesia
  • Sarmoko Department of Pharmacy, Faculty of Science, Institut Teknologi Sumatera, South Lampung 35365, Indonesia https://orcid.org/0000-0002-1315-6085
  • Muhamad Salman Fareza Department of Pharmacy, Faculty of Health Sciences, Universitas Jenderal Soedirman, Purwokerto 53123, Indonesia https://orcid.org/0000-0003-2414-1249
  • Hanif Nasiatul Baroroh Department of Pharmacy, Faculty of Health Sciences, Universitas Jenderal Soedirman, Purwokerto 53123, Indonesia https://orcid.org/0000-0003-2199-6727
  • Nur Amalia Choironi Department of Pharmacy, Faculty of Health Sciences, Universitas Jenderal Soedirman, Purwokerto 53123, Indonesia
Keywords: curcumin, KDR, VEGFR2, molecular docking

Abstract

Breast cancer remains one of the most common cancers worldwide, with VEGFR-2 (KDR) playing a key role in tumor angiogenesis. Inhibiting VEGFR-2 is a promising therapeutic strategy. Natural compounds are increasingly studied for their potential to inhibit VEGFR-2. This study aims to assess the binding affinity of 11 natural compounds (andrographolide, alpha-mangostin, pinostrobin, pinocembrin, ethyl-p-methoxycinnamate (EPMS), xanthorrhizol, galangin, gamma-mangostin, curcumin, cinnamaldehyde, and alashanoid B) to the VEGFR-2 protein through molecular docking and Lipinski's rule analysis, identifying promising candidates for breast cancer treatment. Molecular docking simulations were performed for 11 compounds and sunitinib as a control, with binding energies and interactions analyzed. The compounds were also evaluated for drug-likeness using Lipinski’s rule of five. Curcumin showed the highest binding affinity to VEGFR-2 with a binding energy of -9.9 kcal/mol, surpassing sunitinib (-9.4 kcal/mol). Key interactions were observed with active site residues Cys919 and Asp1046. All tested compounds met the criteria for oral bioavailability per Lipinski’s rules. Curcumin demonstrates potential as a VEGFR-2 inhibitor due to its favorable binding affinity and drug-like properties. Enhancing curcumin’s bioavailability is recommended for effective therapeutic application.

References

WHO. 2021. Breast cancer worldwide.pdf. Available at:https://www.who.int/news-room/fact-sheets/detail/breast-cancer

Zhu, X., Zhou, W. The emerging regulation of VEGFR-2 in triple-negative breast cancer. Frontiers in Endocrinology. 2015; 6: 1-7. https://doi.org/10.3389/fendo.2015.00159

Yang, F. et al. Increased VEGFR-2 gene copy is associated with chemoresistance and shorter survival in patients with non-small-cell lung carcinoma who receive adjuvant chemotherapy. Cancer Research. 2011; 71(16): 5512-5521. https://doi.org/10.1158/0008-5472.CAN-10-2614

Zhang, H. et al. Apatinib suppresses breast cancer cells proliferation and invasion via angiomotin inhibition. American journal of translational research. 2019; 11(7): 4460-4469.

Liu, Y. et al. Targets and Mechanism Used by Cinnamaldehyde, the Main Active Ingredient in Cinnamon, in the Treatment of Breast Cancer. Frontiers in Pharmacology. 2020; 11: 1-12. https://doi.org/10.3389/fphar.2020.582719

Wiyono, L. et al. Isolation, synthesis nanoparticle, and in-vitro test of pinostrobin from kaempferia pandurata on mcf-7 and mdamb-231 breast cancer cell. Research Journal of Pharmacy and Technology. 2020; 13(6): 2797-2801. https://doi.org/10.5958/0974-360X.2020.00497.7

Peng, Y. et al. Andrographolide inhibits breast cancer through suppressing COX-2 expression and angiogenesis via inactivation of p300 signaling and VEGF pathway 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis. Journal of Experimental and Clinical Cancer Research. 2018; 37(1): 1-14. https://doi.org/10.1186/s13046-018-0926-9

Lara-Sotelo, G. et al. α-Mangostin Synergizes the Antineoplastic Effects of 5-Fluorouracil Allowing a Significant Dose Reduction in Breast Cancer Cells. Processes, 2021; 9(3): 1-12. https://doi.org/10.3390/pr9030458

Eichsteininger, J. et al. Structural insight into the in vitro anti-intravasative properties of flavonoids. Scientia Pharmaceutica. 2019; 87(3). https://doi.org/10.3390/scipharm87030023

Zhu, X. et al. Pinocembrin Inhibits the Proliferation and Metastasis of Breast Cancer via Suppression of the PI3K/AKT Signaling Pathway. Frontiers in Oncology. 2021; 11: 1-13. https://doi.org/10.3389/fonc.2021.661184

Noomhorm, N. et al. In vitro and in vivo effects of xanthorrhizol on human breast cancer MCF-7 cells treated with tamoxifen. Journal of Pharmacological Sciences. 2015; 125(4): 375-385. https://doi.org/10.1254/jphs.14024FP

Koohpar, Z. K. et al. Anticancer activity of curcumin on human breast adenocarcinoma: Role of Mcl-1 gene. International Journal of Cancer Management. 2015; 8(3). https://doi.org/10.17795/ijcp2331

Omar, M. N., Hasali, N. H. M., Yarmo, M. A. Cytotoxicity activity of biotransformed ethyl p-methoxycinnamate by Aspergillus niger. Oriental Journal of Chemistry. 2016; 32(5): 2731-2734. https://doi.org/10.13005/ojc/320547

Rizaldy, D. et al. Chemical compounds and pharmacological activities of mangosteen (Garcinia mangostana L.)-updated review. Biointerface Research in Applied Chemistry. 2022; 12(2): 2503-2516. https://doi.org/10.33263/BRIAC122.25032516

O'Boyle, N. M. et al. Open Babel: An Open Chemical Toolbox. Journal of Cheminformatics; 2011; 3(33): 1-14. https://doi.org/10.1186/1758-2946-3-33

Kolina, J., Sumiwi, S. A. Levita, J. Mode Ikatan Metabolit Sekunder di Tanaman Akar Kuning (Arcangelisia Flava L.) dengan Nitrat Oksida Sintase. Fitofarmaka: Jurnal Ilmiah Farmasi. 2019; 8(1): 45-52. https://doi.org/10.33751/jf.v8i1.1171

Hartanti, I. R., Putri, A. A., Auliya AS, N. N., Triadenda, A. L., Laelasari, E., Suhandi, C., Muchtaridi, M. Molecular Docking Senyawa Xanton, Benzofenon, Dan Triterpenoid Sebagai Antidiabetes Dari Ekstrak Tumbuhan Garcinia Cowa. Jurnal Kimia. 2022; 16(1): 72-83. https://doi.org/10.24843/JCHEM.2022.v16.i01.p10

Fadilla, Didi, Arifian, Hanggara, Rahmadai, Agung, Rusli, R. Kajian In Silico Senyawa Turunan Kalkon sebagai Antikanker. Proceeding of Mulawarman Pharmaceuticals Conferences. 2018; 9: 45-50. https://doi.org/10.25026/mpc.v9i1.309

Modi, S. J., Kulkarni, V. M. Vascular Endothelial Growth Factor Receptor (VEGFR-2)/KDR Inhibitors: Medicinal Chemistry Perspective. Medicine in Drug Discovery. 2019; 2. https://doi.org/10.1016/j.medidd.2019.100009

Song, X. et al. Molecular targets of curcumin in breast cancer (Review). Molecular Medicine Reports. 2019; 19(1): 23-29. https://doi.org/10.3892/mmr.2018.9665

Chang, H. F., Yang, L. L. Gamma-mangostin, a micronutrient of mangosteen fruit, induces apoptosis in human colon cancer cells. Molecules. 2012; 17(7): 8010-8021. https://doi.org/10.3390/molecules17078010

Adriani. Prediksi Senyawa Bioaktif dari Tanaman Sanrego (Lunasia amara Blanco) sebagai Inhibitor enzim Siklooksigenase-2 (COX-2) melalui Pendekatan Molecular Docking. Jurnal Ilmiah Pena. 2018; 1: 6-11.

Syahputra, G., Ambarsari L. Simulasi docking kurkumin enol, bisdemetoksikurkumin dan analognya sebagai inhibitor enzim12-lipoksigenase. Biofisika. 2014; 10(1): 55-67

Published
2024-10-30
How to Cite
Aprilia, V., Sarmoko, Fareza, M. S., Baroroh, H. N., & Choironi, N. A. (2024). Evaluation of natural compounds as VEGFR-2 inhibitors for breast cancer therapy: insights from molecular docking and drug-likeness analysis. Pharmacy Reports, 4(2), 82. https://doi.org/10.51511/pr.82