Sains Malaysiana 53(3)(2024): 653-665

http://doi.org/10.17576/jsm-2024-5303-13

Formation of Inclusion Complex of Curcumin and Tetrahydrocurcumin Prevents Angiogenesis by Inhibiting VEGF Activity: An in-silico Study

(Pembentukan Kompleks Rangkuman Kurkumin dan Tetrahidrokurkumin Menghalang Angiogenesis dengan Merencat Aktiviti VEGF: Suatu Kajian in silico)

FIRLI RAHMAH PRIMULA DEWI^1,*, ULIE VIANISSA DWIUTAMI TAMBUNAN¹, PUTRI AMATUL BARI¹, MUHAMMAD ARDIANSYAH FARID¹, NADIRA AISHA ANJANI¹, SRI PUJI ASTUTI WAHYUNINGSIH¹, AMY YI HSAN SAIK², YONG YOKE KEONG³, VUANGHAO LIM⁴, WEN NEE TAN⁵ & MOHAMMED ABDULLAH MAHDI ALSHAWSH⁶

¹Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Indonesia

²Department of Pre-Clinical Sciences, M. Kandiah Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Sungai Long City Campus, Bandar Sungai Long, Cheras, 43000 Kajang, Selangor, Malaysia

³Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

⁴School of Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, 13200 Kepala Batas, Pulau Pinang, Malaysia

⁵Chemical Sciences Programme, School of Distance Education, Universiti Sains Malaysia, 11800 USM Penang, Pulau Pinang, Malaysia

⁶Department of Pharmacology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia

Diserahkan: 17 Julai2023/Diterima: 6 Februari2024

Abstract

Curcumin and tetrahydrocurcumin (THC) are known for their anticancer properties, but limited solubility in water hinders their effectiveness against cancer. In this study, we conducted an in silico exploration of β-cyclodextrin's potential to form inclusion complexes with curcumin or THC. The aim of this study was to assess the potential of curcumin and THC inclusion complexes to inhibit vascular endothelial growth factor (VEGF) signaling pathway, a key element in carcinogenesis. The in silico analysis involved multiple stages, such as bioactive compound preparation, biological activity prediction, 3D structure retrieval of VEGF and VEGFR, protein-ligand docking, and visualization. The results of the study demonstrated that both the curcumin- and THC-inclusion complexes exhibit a lower requirement for binding free energy to interact with VEGFR compared to curcumin or THC molecules alone. When VEGFR binds with curcumin, the curcumin-inclusion complex, or the THC-inclusion complex before interacting with VEGF, there is a notable increase in the binding free energy for the VEGF-VEGFR interaction. Specifically, the presence of THC-inclusion complex demonstrates the highest binding free energy for the VEGF-VEGFR interaction. The molecular dynamic simulation study shows that when VEGFR binds with curcumin, curcumin-inclusion complex, or THC-inclusion complex, the fluctuation of amino acid residues in VEGFR decreases compared to the VEGFR protein structure before binding with these molecules. In conclusion, this study suggests that the formation of inclusion complexes holds considerable promise for enhancing the anticancer potential of curcumin and THC by augmenting their anti-angiogenic activity.

Keywords: Angiogenesis; cancer; curcumin; inclusion complex; tetrahydrocurcumin

ABSTRAK

Kurkumin dan tetrahidrokurkumin (THC) terkenal dengan sifat antikansernya, tetapi keterlarutan terhad dalam air menghalang keberkesanannya terhadap kanser. Dalam kajian ini, kami menjalankan penyelidikan in silico terhadap potensi β-siklodekstrin untuk membentuk kompleks rangkuman dengan kurkumin atau THC. Matlamat kajian ini adalah untuk menilai potensi kompleks rangkuman kurkumin dan THC untuk menghalang laluan isyarat faktor pertumbuhan endoteliaum vaskular (VEGF), unsur utama dalam karsinogenesis. Analisis in silico melibatkan pelbagai peringkat seperti penyediaan sebatian bioaktif, ramalan aktiviti biologi, struktur 3D temuan semulaVEGF dan VEGFR, dok protein-ligan dan visualisasi. Hasil kajian menunjukkan bahawa kedua-dua kompleks rangkuman kurkumin dan THC menunjukkan keperluan yang lebih rendah untuk mengikat tenaga bebas untuk berinteraksi dengan VEGFR berbanding dengan molekul kurkumin atau THC sahaja. Apabila VEGFR diikat dengan kurkumin sebelum kompleks rangkuman kurkumin atau kompleks rangkuman THC berinteraksi dengan VEGF, terdapat peningkatan ketara dalam tenaga bebas pengikat untuk interaksi VEGF-VEGFR. Khususnya, kehadiran kompleks rangkuman THC menunjukkan tenaga bebas pengikat tertinggi untuk interaksi VEGF-VEGFR. Kajian simulasi dinamik molekul menunjukkan bahawa apabila VEGFR mengikat dengan kurkumin, kompleks rangkuman kurkumin atau kompleks rangkuman THC, turun naik sisa asid amino dalam VEGFR berkurangan berbanding dengan struktur protein VEGFR sebelum diikat dengan molekul ini. Kesimpulannya, kajian ini mencadangkan bahawa pembentukan kompleks rangkuman berpotensi untuk meningkatkan potensi antikanser kurkumin dan THC dengan menambah aktiviti anti-angiogenik mereka.

Kata kunci: Angiogenesis; kanser; kurkumin; kompleks rangkuman; tetrahidrokurkumin

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*Pengarang untuk surat-menyurat; email: firli.rahmah@fst.unair.ac.id