Dengue caused by the dengue virus (DENV) is a severe health problem in tropical regions such as Southeast Asia, especially Indonesia. Indonesian have used rhizome as traditional medicine for 1300 years. This study investigated the compounds from Kaempferia galanga, Curcuma longa, Zingiber officinale, Curcuma aeruginosa, Curcuma zanthorrhiza, Alpinia galanga, and Allium sativum as antivirals agents, explicitly targeting the DENV envelope protein to inhibit viral fusion. This study involved 121 bioactive compounds and DENV2's prefusion envelope protein. The virtual screening and molecular docking were done through occupied the Lipinski rule of five checker (http://www.scfbio-iitd.res.in/software/drugdesign/lipinski.jsp) and AutoDock Vina (https://pyrx.sourceforge.io/) respectively. The top nine compounds with the strongest binding affinity were galangin, kampferide, demetoxy curcumin, bisdemethoxycurcumin, β-selinene, 6-(hydroxymethyl)-1,4,4-trimethylbicyclo[3.1.0]hexan-2-ol, piperine, estra-1,3, 5(10)-trien-17β-ol, and curcumin. These compounds' affinity values were significantly lower, around 45-62%, than chloroquine. Most of them interact with the kl hairpin and hydrophobic pocket formed by residues Val130, Leu135, Phe193, Leu198, and Phe279of critical domains that can interfere with the conformational change and rearrangement of protein dimer in the post-fusion stage. This study suggested that the galangin, demethoxycurcumin, and bisdemethoxycurcumin are considered the most potential compounds to be developed as anti-prefusion E DENV2 low-affinity and intense interaction with those. Keywords: DENV2, envelope protein, in silico, viral fusion, viral infection

Dengue is a severe health problem, especially in under-developing countries like Indonesia. The government and the community have made various efforts. However, the current programs are focusing on controlling disease vector. Medical treatment so far only treats the symptoms. On the other hand, the development of antiviral compounds has been dominated by synthetic compounds which may have serious side effects. The potential of natural compounds in Asia is still largely unexplored. Dengue virus nonstructural protein 5 (NS5) is highly conserved in all serotypes. This study aims to screen several potential natural compounds to be developed as specific antiviral compounds targeting DENV NS5. This research conducted by using in silico approaches including data mining, molecular docking, and 2D-3D visualization. About 170 compounds from 88 organisms analyzed to get the top nine compounds with the highest affinity against NS5 protein. The top nine compounds are from the halichondramide, trigocherriolide, quinadoline, tryptoquivaline, and zingiberene groups. The docking results showed that these potential compounds have an affinity of about 67-100% higher than ribavirin. The visualization results show that these compounds are grouped into three different binding sites. They are RdRP, MTase, and the junction. Compounds that bind in RdRP are thought to interfere with the process of RNA viral synthesis, compounds that bind to MTase are thought to disrupt the viral RNA capping process, while compounds that bind between the two domains are thought to interfere NS5 structural integrity. The compound with the highest affinity is halishigamide A. Halishigamide A is known to have antimicrobial properties, but the action mechanism is still unknown. Compared to the control drug, the halishigamide A tends to have more dynamic movement and interaction to the target protein’s binding site due to its residues’ chemicals motive. Together, these results showed the potency of natural products as specific antiviral compounds targeting DENV NS5.

The E5 protein is the smallest known oncoprotein linked to HPV 16 cancer development. In this study, we determined the potential of asarinin and thiazolo as an inhibitor of the E5 protein through molecular dynamics. The results showed that the binding site is unstable because of its hydrophobic nature and small size, causing considerable changes in the binding site for each of the 3 drugs examined. Except for asarinin, which still interacts with the first hydrophobic domain, they preserved their capacity to prevent endosomal acidification, hyper amplification of the EGFR pathway and contact with BAP31. It may inhibit E5-MHC I interaction. Thiazolo[3,2-a]benzymidazole-3(2H)-one,2-(2-fluorobenzylideno)-7,8-dimethyl (thiazolo) is expected to form more stable protein-ligand complexes than the other 2. However, the SASA, hydrogen bond and DCCM plots show that both compounds are equivalent to HPV 16 E5 protein. HIGHLIGHTS The smallest known oncoprotein associated with cancer development as a result of HPV 16 infection is the E5 protein The SASA, hydrogen bond, and DCCM plots, on the other hand, show that asarinin and thiazolo are equivalent to the HPV 16 E5 protein Thiazolo is predicted to produce more stable protein-ligand complexes than the others because of its unique molecular dynamic properties GRAPHICAL ABSTRACT

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