Shill Dipok Kumer, Jahan Shafina, Alam Mohammad Mamun, Limon Md Belayet Hasan, Alam Muntasir, Rahman Mohammed Ziaur, Rahman Mustafizur
Virology Laboratory, Infectious Diseases Division, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh.
Bioinform Biol Insights. 2023 Feb 27;17:11779322231158249. doi: 10.1177/11779322231158249. eCollection 2023.
Dengue outbreak is one of the concerning issues in Bangladesh due to the annual outbreak with the alarming number of death and infection. However, there is no effective antiviral drug available to treat dengue-infected patients. This study evaluated and screened antiviral drug candidates against dengue virus serotype 3 (DENV-3) through viroinformatics-based analyses. Since 2017, DENV-3 has been the predominant serotype in Bangladesh. We selected 3 non-structural proteins of DENV-3, named NS3, NS4A, and NS5, as antiviral targets. Protein modeling and validation were performed with VERIFY-3D, Ramachandran plotting, MolProbity, and PROCHECK. We found 4 drug-like compounds from DRUGBANK that can interact with these non-structural proteins of DENV-3. Then, the ADMET profile of these compounds was determined by admetSAR2, and molecular docking was performed with AutoDock, SWISSDOCK, PatchDock, and FireDock. Furthermore, they were subjected to molecular dynamics (MD) simulation study using the DESMOND module of MAESTRO academic version 2021-4 (force field OPLS_2005) to determine their solution's stability in a predefined body environment. Two drug-like compounds named Guanosine-5'-Triphosphate (DB04137) and -adenosyl-l-homocysteine (DB01752) were found to have an effective binding with these 3 proteins (binding energy > 33.47 KJ/mole). We found NS5 protein was stable and equilibrated in a 100 ns simulation run along with a negligible (<3Å) root-mean-square fluctuation value. The root-mean-square deviation value of the -adenosyl-l-homocysteine-NS5 complex was less than 3Å, indicating stable binding between them. The global binding energy of -adenosyl-l-homocysteine with NS5 was -40.52 KJ/mole as ∆G. Moreover, these 2 compounds mentioned above are non-carcinogenic according to their ADMET (chemical absorption, distribution, metabolism, excretion, and toxicity) profile (in silico). These outcomes suggest the suitability of -adenosyl-l-homocysteine as a potential drug candidate for dengue drug discovery research.
由于每年都会爆发登革热疫情，且死亡和感染人数惊人，登革热疫情是孟加拉国令人担忧的问题之一。然而，目前尚无有效的抗病毒药物可用于治疗登革热感染患者。本研究通过基于病毒信息学的分析，评估和筛选了针对登革热病毒3型（DENV-3）的抗病毒药物候选物。自2017年以来，DENV-3一直是孟加拉国的主要血清型。我们选择了DENV-3的3种非结构蛋白，即NS3、NS4A和NS5，作为抗病毒靶点。使用VERIFY-3D、拉氏图、MolProbity和PROCHECK进行蛋白质建模和验证。我们从DRUGBANK中发现了4种类药物化合物，它们可以与DENV-3的这些非结构蛋白相互作用。然后，通过admetSAR2确定这些化合物的ADMET特征，并使用AutoDock、SWISSDOCK、PatchDock和FireDock进行分子对接。此外，使用MAESTRO学术版2021-4的DESMOND模块（力场OPLS_2005）对它们进行分子动力学（MD）模拟研究，以确定它们在预定义身体环境中的溶液稳定性。发现两种类药物化合物，即鸟苷-5'-三磷酸（DB04137）和S-腺苷-L-高半胱氨酸（DB01752）与这3种蛋白质有有效结合（结合能>33.47 KJ/摩尔）。我们发现NS5蛋白在100纳秒的模拟运行中是稳定的且达到了平衡，同时均方根波动值可忽略不计（<3Å）。S-腺苷-L-高半胱氨酸-NS5复合物的均方根偏差值小于3Å，表明它们之间结合稳定。S-腺苷-L-高半胱氨酸与NS5的全局结合能为-40.52 KJ/摩尔（∆G）。此外，根据它们的ADMET（化学吸收、分布、代谢、排泄和毒性）特征（计算机模拟），上述这2种化合物无致癌性。这些结果表明S-腺苷-L-高半胱氨酸作为登革热药物发现研究的潜在药物候选物具有适用性。
