S-Adenosyl-l-Homocysteine Exhibits Potential Antiviral Activity Against Dengue Virus Serotype-3 (DENV-3) in Bangladesh: A Viroinformatics-Based Approach

Abstract

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 S-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 S-adenosyl-l-homocysteine-NS5 complex was less than 3Å, indicating stable binding between them. The global binding energy of S-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 S-adenosyl-l-homocysteine as a potential drug candidate for dengue drug discovery research.

The endoplasmic reticulum (ER): a crucial cellular hub in flavivirus infection and potential target site for antiviral interventions

“…Compound 3A, which is supposed to deplete the pyrimidine pools, is an interesting small molecule because of its broad-spectrum antiviral activity (positive and negative strand RNA viruses, DNA viruses and retroviruses) in combination with low cytotoxicity 148 . Compound 2 and 3 in the study of Ye et al inhibited S-adenosylhomocysteine hydrolase, an enzyme involved in the synthesis of adenosine 149 . Other potential targets of host directed antivirals are cellular kinases used by viruses throughout their life cycle, as DENV NS5 was shown to be phosphorylated by host kinases.…”

Identification and Molecular Characterization of NS1 and NS2 Genes of Dengue Virus from two mini outbreaks (2022-2023) in Pakistan

“…One of the most popular methods for creating precise structural models of proteins and for explaining experimental ndings is homology modeling [36][37][38]. It is frequently employed in the investigation of inter-individual variations in drug metabolism as well as structure-based drug design.…”

“…For protein sequence and structure analysis, we used ExPASy and Robetta tool [36,37]. The Robetta server offers automated tools for analyzing and predicting protein structure.…”

Molecular Characterization and Expression Analysis of NS3 and NS4 Genes of Dengue Virus Serotype-2 from Pakistani Isolates

“…The Robetta server provides automated tools to analyze and predict the structure of proteins. It takes input sequences, identi es potential domains, and generates structural models using either de novo structure prediction or comparative modeling techniques [36,37]. 3D Models predicted through ExPASy and Robetta tools were visualized using molecular visualization system PyMOL (https://pymol.org/2/) [37,38].…”