Hariono, Maywan
(2015)
Rational Design And Synthesis Of Inhibitors For H1n1 Neuraminidase And Dengue Protease Enzymes.
PhD thesis, Universiti Sains Malaysia.
Abstract
Influenza dan denggi adalah dua daripada penyakit berjangkit yang disebabkan oleh virus. Rintangan virus terhadap ubat influenza komersial dan ketiadaan ubat untuk merencat virus denggi menggalakkan usaha untuk mencari perencat virus yang berpotensi. Setakat ini, enzim neuraminidase H1N1 ialah satu daripada sasaran utama dalam pencarian perencat influenza A manakala enzim protease NS2B-NS3 DENV2 pula merupakan sasaran utama dalam penemuan ubat denggi. Kajian sebelum ini mendapati bahawa asid ferulik yang dipencilkan daripada kulit buah manggis dapat merencat aktiviti neuraminidase H1N1 dengan nilai IC50 = 200 M. Struktur aromatiknya yang sederhana menarik perhatian untuk dikembangkan sebagai perencat neuraminidase H1N1. Sebanyak 20 terbitan asid ferulik telah pun direkabentuk dan disintesis. Kajian asai atas sebatian tersebut menunjukkan nilai IC50 daripada 50 sehingga > 1000 M. Rekabentuk hubungan kuantitatif struktur dan aktiviti menggunakan kaedah Multiple Linear Regression dilaksanakan untuk menghasilkan model yang menentukan hubungan positif daripada penderma dan penerima ikatan hidrogen dengan keputusan statistik yang baik (r2 = 0.758; r2 (adj) = 1.185; Least-squared error = 0.189).
Influenza and dengue are two of infectious diseases which caused by viruses. The viral resistances towards commercial anti-influenza as well as no drug available to combat dengue infection have prompted the search for potential inhibitors. Currently, H1N1 neuraminidase is one of the major targets in searching for inhibitor of influenza A as well as DENV2 NS2B-NS3 protease in dengue drug discovery. In a previous study, ferulic acid from G. mangostana pericarps has been isolated and showed an inhibition against H1N1 neuraminidase in vitro with IC50 = 200 M. Its simple aromatic structure was attractive to be developed as H1N1 neuraminidase inhibitor. Twenty ferulic acid derivatives were designed in silico and synthesised, respectively. The in vitro assay showed the inhibitory activity with IC50 from 50 to >1000 M. The Quantitative Structure-Activity Relationship (QSAR) modelling using Multiple Linear Regression was then carried out to produce the model defining a positive correlation of number of hydrogen bond donor as well as hydrogen bond acceptor with a good statistical results (r2 = 0.758; r2 (adj) = 1.185; Least-squared error = 0.189).
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