In silico studies of antiviral ligands derived from Ganoderma lucidum against dengue type 2 and zika viral proteins / Lim Wui Zhuan

Lim , Wui Zhuan (2024) In silico studies of antiviral ligands derived from Ganoderma lucidum against dengue type 2 and zika viral proteins / Lim Wui Zhuan. PhD thesis, Universiti Malaya.

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Abstract

Dengue and Zika infections are mainly transmitted through the bites of Aedes aegypti mosquitoes. Without potential cures or clinically approved antivirals for both infections, the Flaviviruses that cause these infectious diseases will continue to pose health risks, especially to the nations of Asia, Africa and South America. For dengue, it is a challenging process to find suitable treatment that can eradicate the infections successfully, as there are multiple serotypes circulating in tropical and subtropical regions around the world. In this study, the transcriptional changes caused by virus-host interactions were presented through the identification of differentially expressed genes (DEGs) and pathway analysis, to gain understanding of the pathogenicity of dengue virus (DENV) and Zika virus (ZIKV). Based on the enriched pathways in DAVID, KEGG and Reactome, the biological processes of DEGs in dengue and Zika patients were concentrated in cell division and DNA replication. DEGs such as MCM2, MCM4, MCM6 and PCNA can serve as potential biomarkers of dengue infections. Surprisingly, a few up-regulated DEGs in Zika datasets, namely OAS1, OAS2, OAS3 and DDX58, were associated with other diseases such as measles, Epstein-Barr virus infection, and hepatitis C. These antiviral interferon-stimulated genes suggested that ZIKA-infected patients responded to Zika infection primarily by suppressing viral RNA replication. Since cell cycle and genome replication were highlighted in the pathway analysis, the natural compounds derived from the antler-shaped fruiting body of Ganoderma lucidum were screened against the protease and envelope proteins of DENV and ZIKV, to find potential antivirals that can disrupt the above pathways. Docking results showed that hesperetin and naringenin were the best ligand candidates to bind at the catalytic site of NS2B-NS3 protease and the hydrophobic pocket of envelope protein, respectively. Their stable docking conformations and favourable binding free energy showed potential to prevent the viral replication and fusion processes. Naringenin was also able to target the same hydrophobic pocket of Zika virus envelope protein, however its binding free energy after 100 ns of simulation was less favourable than the reference ligand. A longer simulation time might be required to extend the convergence of the trajectories. This study can serve as a reference for molecular biological experiments in future to confirm the function of DEGs associated with dengue and Zika infections, as well as the roles of hesperetin and naringenin in combating the diseases.

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