Malaysian Journal of Analytical Sciences, Vol 28 No 3 (2024): 586 - 602

 

SYNTHESIS AND MOLECULAR DOCKING SIMULATION OF CINNAMIC ACIDS DERIVATIVES AGAINSTS DENV2 NS2B/NS3

 

(Sintesis dan Simulasi Pengedokan Terbitan Asid Sinamik Terhadap DENV2 NS2B/NS3)

 

Nadia Mohamed Yusoff1, Siti Nor Khadijah Addis1, Nurul Huda Abdul Wahab1,2, Fauziah Abdullah3

and Asnuzilawati Asari1,2,*

 

1Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia

2Advanced Nano Materials (ANoMA) Research Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, 21030 Kuala Nerus, Terengganu, Malaysia

3Phytochemistry Programme, Natural Products Division, Forest Research Institute Malaysia (FRIM), 52109 Kepong, Selangor Darul Ehsan, Malaysia

 

*Corresponding author: asnu@umt.edu.my

 

 

Received: 18 February 2024; Accepted: 23 April 2024; Published: 29 June 2024

 

 

Abstract

Dengue virus (DENV) is known as one of the serious global threats to human health since its emergence in the past few decades. However, clinically approved antiviral drugs are still not available for DENV treatment. The increased number of cases reported yearly had led to the on-going research in finding an effective drug for dengue. Cinnamic acid is a naturally occurring compound which consists of α, β-unsaturated carboxylic acid and is known for its wide pharmacological properties. Cinnamic acid derivatives such as caffeic acid are one of constituents in Carica papaya leaf which are used as a folk remedy for dengue. Recently, cinnamic acid was reported to show a potential against dengue virus. In this study, eight cinnamic acid derivatives were synthesized by incorporating cinnamic acid and amide moieties through the reaction of cinnamic acid with corresponding amines. All compounds were characterized by using 1H and 13C nuclear magnetic resonance (NMR), Fourier transform infrared (FTIR), mass spectrometry (MS) and CHN elemental analysis. Then, the synthesized compounds were simulated for molecular docking to investigate their binding affinity with the Wichapong homology protein model crystal structure, DENV-2 NS2B/NS3pro. The lower the value of FEB of a compound, the higher its binding affinity towards protein. The in-silico study revealed that compounds 6b1-6b4, with tert-butyl substituents had the highest binding affinity and good interaction with DENV-2 NS2B/NS3 serine protease. This might be due to the presence of a tert-butyl moiety in the structure, which could interact with amino acid residue of protease, thereby increasing the binding interaction between the ligand and the protein. Compound 6b2 showed the lowest FEB value despite having less H-bond interactions as compared to compound 6b3. This was probably due to the presence of more non-covalent interaction and closer bond distance which helped to enhance its binding stability. In summary, this study showed that cinnamic acid could be a promising candidate for the development of antiviral drugs to target DENV.

 

Keywords: cinnamic acid, synthesis, anti-dengue virus, docking

 

Abstrak

Virus denggi (DENV) telah dikenali sebagai salah satu ancaman global yang serius terhadap kesihatan manusia setelah kemunculannya beberapa dekad yang lalu. Walau bagaimanapun, masih belum ada ubat antiviral yang diluluskan secara klinikal bagi rawatan DENV. Peningkatan jumlah kes yang dilaporkan setiap tahun telah membawa kepada penyelidikan yang berterusan dalam pencarian ubat yang berkesan untuk rawatan denggi. Asid sinamik adalah bahan semulajadi yang mempunyai kumpulan asid karbosilik α, β-tak tepu dan dikenali dengan pelbagai sifat farmakologinya. Asid sinamik seperti asid kafeik merupakan antara komposisi yang terkandung di dalam daun Carica papaya yang digunakan secara tradisional untuk rawatan denggi. Kebelakangan ini, asid sinamik telah dilapor menunjukkan potensi terhadap DENV. Di dalam kajian ini, lapan terbitan asid sinamik telah disintesis dengan menggabungkan asid sinamik dan amida melalui tindak balas asid sinamik dengan amina yang bersesuaian. Semua sebatian dicirikan dengan menggunakan 1H and 13C Resonans Magnetik Nuklear (RMN), Inframerah Transformasi Fourier (FTIR), spektrometri jisim (MS) dan analisis unsur CHN. Sebatian yang disintesis kemudiannya disimulasikan menerusi pengedokan molekul bagi mengkaji keafinan pengikatan mereka bersama struktur kristal homologi protein Wichapong, DENV-2 NS2B/NS3pro. Kajian in siliko menunjukkan bahawa sebatian 6b1-6b4, yang mengandungi kumpulan penukargantian tert-butil menunjukkan tenaga pengikatan yang tinggi dan interaksi yang baik dengan DENV-2 NS2B/NS3 serine protease. Ini mungkin disebabkan oleh kehadiran tert-butil dalam strukturnya, yang boleh berinteraksi dengan asid amino protein, dengan itu meningkatkan interaksi pengikatan antara ligan dan protein. Semakin rendah nilai FEB sebatian, semakin kuat ikatannya dengan enzim. Sebatian 6b2 menunjukkan nilai FEB terendah walaupun ia mempunyai kurang interaksi ikatan H-bond berbanding dengan sebatian 6b3, dan ini mungkin disebabkan oleh kehadiran interaksi non-kovalen yang banyak dan jarak ikatan yang berdekatan telah membantu meningkatkan kestabilan ikatannya.  Secara keseluruhannya, kajian ini menunjukkan bahawa sebatian asid sinamik berpotensi untuk pembangunan ubat-ubatan antiviral bagi merawat DENV.

 

Kata kunci: asid sinamik, sintesis, anti-denggi, pengedokan

 

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