Mustafa Nur Farhana, Cheng Kian-Kai, Razali Siti Aisyah, Wahab Habibah A, Salin Nurul Hanim, Zakaria Iffah Izzati, Nadri Muhammad Helmi
Faculty of Chemical and Energy Engineering, Universiti Teknologi Malaysia, 81310, Johor Bahru, Johor, Malaysia.
Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, Nerus, 21030, Kuala Terengganu, Terengganu, Malaysia.
Mol Divers. 2025 Apr;29(2):1175-1187. doi: 10.1007/s11030-024-10899-5. Epub 2025 Jan 22.
Dengue is one of the most prevalent viruses transmitted by the Aedes aegypti mosquitoes. Currently, no specific medication is available to treat dengue diseases. The NS2B-NS3 protease is vital during post-translational processing, which is a key target in this study. Due to methoxy group substitution, methoxyflavones are more bioavailable and metabolically stable than hydroxylated flavones. To date, research on the anti-dengue activity of methoxyflavones is limited. Hence, this work aims to determine the inhibitory activity of methoxyflavones against the dengue NS2B-NS3. Methoxyflavones derivatives were screened using molecular docking. The result showed a strong binding interaction of compound 1 and compound 2 with NS2B-NS3 protease. Both compounds exhibited comparable binding energy as the reference compound, quercetin, with values lower than - 8.1 kcal/mol. Molecular dynamics simulation using GROMACS revealed the stability and stiffness of the complexes over a 100 ns time scale. In addition, an in vitro assay for NS2B-NS3 protease inhibition revealed inhibitory effects of compounds 1 and 2 with IC values of 316.80 µM and 463.30 µM, respectively. The ADMET analyses showed favorable pharmacokinetics profiles that comply with Lipinski's Rule of Five. Collectively, our findings suggest that compounds 1 and 2 inhibit dengue NS2B-NS3 activity. These findings hold promise of methoxyflavones as starting compounds for potential dengue treatment, highlighting the need for further investigation.
登革热是由埃及伊蚊传播的最普遍的病毒之一。目前，尚无治疗登革热疾病的特效药物。NS2B-NS3蛋白酶在翻译后加工过程中至关重要，是本研究的关键靶点。由于甲氧基取代，甲氧基黄酮比羟基黄酮具有更高的生物利用度和代谢稳定性。迄今为止，关于甲氧基黄酮抗登革热活性的研究有限。因此，本研究旨在确定甲氧基黄酮对登革热NS2B-NS3的抑制活性。采用分子对接技术筛选甲氧基黄酮衍生物。结果表明化合物1和化合物2与NS2B-NS3蛋白酶有强烈的结合相互作用。这两种化合物与参考化合物槲皮素表现出相当的结合能，其值低于-8.1 kcal/mol。使用GROMACS进行的分子动力学模拟揭示了复合物在100 ns时间尺度上的稳定性和刚性。此外，NS2B-NS3蛋白酶抑制的体外试验表明化合物1和化合物2具有抑制作用，IC值分别为316.80 μM和463.30 μM。ADMET分析显示其药代动力学特征良好，符合Lipinski的五规则。总的来说，我们的研究结果表明化合物1和化合物2抑制登革热NS2B-NS3活性。这些发现表明甲氧基黄酮有望作为潜在登革热治疗的起始化合物，凸显了进一步研究的必要性。
