PDF(Pubmed)
Abstract：
BACKGROUND: Currently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and Aedes albopictus. The RdRp protease of dengue virus is a potential therapeutic target. This study focused on the in silico drug discovery of RdRp protease inhibitors.
METHODS: To assess the potential inhibitory activity of 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, a range of computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. The aim of these studies was to confirm the stability of the ligand-protein complex and the binding pose identified during the docking experiment.
RESULTS: Twenty-one compounds were found to have possible inhibitory activities against DENV according to the docking data, and they had a binding affinity of ≥-37.417 kcal/mol for DENV3- enzyme as compared to the reference compound panduratin A. Additionally, the drug-likeness investigation produced four hit compounds that were subjected to ADMET screening to obtain the lead compound, catechin. Based on ELUMO, EHOMO, and band energy gap, the DFT calculations showed strong electronegetivity, favouravle global softness and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups for catechin. The MD simulation result also demonstrated favourable RMSD, RMSF, SASA and H-bonds in at the binding pocket of DENV3-NS5 RdRp for catechin as compared to panduratin A.
CONCLUSIONS: According to the present findings, catechin showed high binding affinity and sufficient drug-like properties with the appropriate ADMET profiles. Moreover, DFT and MD studies further supported the drug-like action of catechin as a potential therapeutic candidate. Therefore, further in vitro and in vivo research on cocoa and its phytochemical catechin should be taken into consideration to develop as a potential DENV inhibitor.
METHODS: To assess the potential inhibitory activity of 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, a range of computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. The aim of these studies was to confirm the stability of the ligand-protein complex and the binding pose identified during the docking experiment.
RESULTS: Twenty-one compounds were found to have possible inhibitory activities against DENV according to the docking data, and they had a binding affinity of ≥-37.417 kcal/mol for DENV3- enzyme as compared to the reference compound panduratin A. Additionally, the drug-likeness investigation produced four hit compounds that were subjected to ADMET screening to obtain the lead compound, catechin. Based on ELUMO, EHOMO, and band energy gap, the DFT calculations showed strong electronegetivity, favouravle global softness and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups for catechin. The MD simulation result also demonstrated favourable RMSD, RMSF, SASA and H-bonds in at the binding pocket of DENV3-NS5 RdRp for catechin as compared to panduratin A.
CONCLUSIONS: According to the present findings, catechin showed high binding affinity and sufficient drug-like properties with the appropriate ADMET profiles. Moreover, DFT and MD studies further supported the drug-like action of catechin as a potential therapeutic candidate. Therefore, further in vitro and in vivo research on cocoa and its phytochemical catechin should be taken into consideration to develop as a potential DENV inhibitor.
摘要：
背景：目前，没有治疗登革热的抗病毒药物,一种由两种蚊子传播的潜在致命的热带传染病，埃及伊蚊和白纹伊蚊。登革病毒的RdRp蛋白酶是潜在的治疗靶标。本研究集中于RdRp蛋白酶抑制剂的计算机药物发现。
方法：为了评估来自可可可可L.的29种酚酸对DENV3-NS5RdRp的潜在抑制活性，采用了一系列的计算方法。这些包括对接，药物相似性分析，ADMET预测，密度泛函理论(DFT)计算，和分子动力学(MD)模拟。这些研究的目的是确认配体-蛋白质复合物的稳定性和在对接实验期间鉴定的结合姿态。
结果：根据对接数据，发现21种化合物对DENV具有可能的抑制活性，与参考化合物panduratinA相比，它们对DENV3-酶的结合亲和力≥-37.417kcal/mol。此外，药物相似性调查产生了四个命中化合物，这些化合物经过ADMET筛选以获得前导化合物，儿茶素.根据ELUMO,EHOMO,和能带能隙，DFT计算显示出强电负性，有利于整体柔软性和化学反应性，在儿茶素的电子供体到电子受体基团之间具有相当大的分子内电荷转移。MD模拟结果也证明了有利的RMSD，RMSF,与panduratinA相比，在DENV3-NS5RdRp的结合袋中的SASA和H键。
结论：根据目前的发现，儿茶素在适当的ADMET谱下显示出高结合亲和力和足够的药物样特性。此外，DFT和MD研究进一步支持儿茶素作为潜在治疗候选物的药物样作用。因此,应考虑对可可及其植物化学儿茶素进行进一步的体外和体内研究，以开发作为潜在的DENV抑制剂。
方法：为了评估来自可可可可L.的29种酚酸对DENV3-NS5RdRp的潜在抑制活性，采用了一系列的计算方法。这些包括对接，药物相似性分析，ADMET预测，密度泛函理论(DFT)计算，和分子动力学(MD)模拟。这些研究的目的是确认配体-蛋白质复合物的稳定性和在对接实验期间鉴定的结合姿态。
结果：根据对接数据，发现21种化合物对DENV具有可能的抑制活性，与参考化合物panduratinA相比，它们对DENV3-酶的结合亲和力≥-37.417kcal/mol。此外，药物相似性调查产生了四个命中化合物，这些化合物经过ADMET筛选以获得前导化合物，儿茶素.根据ELUMO,EHOMO,和能带能隙，DFT计算显示出强电负性，有利于整体柔软性和化学反应性，在儿茶素的电子供体到电子受体基团之间具有相当大的分子内电荷转移。MD模拟结果也证明了有利的RMSD，RMSF,与panduratinA相比，在DENV3-NS5RdRp的结合袋中的SASA和H键。
结论：根据目前的发现，儿茶素在适当的ADMET谱下显示出高结合亲和力和足够的药物样特性。此外，DFT和MD研究进一步支持儿茶素作为潜在治疗候选物的药物样作用。因此,应考虑对可可及其植物化学儿茶素进行进一步的体外和体内研究，以开发作为潜在的DENV抑制剂。
