Targeting the dengue virus NS5-Methyltransferase SAM binding site with limonoids: Molecular docking, dynamics simulation, DFT and ADMET analysis

Abstract

Dengue virus (DENV) infects over 100 million people annually, yet no approved antiviral therapies are available. The DENV genome is a positive-sense single-stranded RNA (+) ssRNA) encoding ten proteins: three structural (capsid, membrane, and envelope) and seven non-structural (NS1–NS5). Among these, the NS5 methyltransferase (NS5-MTase) is essential for viral replication and is a promising drug target due to the absence of approved inhibitors. NS5-MTase has two binding sites: one for S-adenosyl-L-methionine (SAM) and another for RNA. The RNA-binding site is shallow and solvent-exposed, making the SAM-binding site a more suitable target for small-molecule inhibitors. Phytocompounds, particularly limonoids—a class of tetraterpenoids with known pharmacological activities are promising candidates in antiviral drug discovery. In this study, 500 limonoids were screened through molecular docking against the SAM-binding site of DENV NS5-MTase. This is the first large-scale in silico virtual screening of limonoids targeting this site. Three top compounds were identified: 7-deacetyl-21-hydroxyneotrichilenonelide (DHC), demethyl-3-detigloyl-iso-swietenine (DDIS), and demethyl-iso-swietenolide (DIS). The docking scores of the three compounds were −9.4, −9.5, and −9.9 kcal/mol, respectively. These three compounds were further evaluated using molecular dynamics (MD) simulations to assess the stability and interaction profiles of the protein-ligand complexes. DIS exhibited the most stable binding conformation (forming 3-4 H-bond/ns and maintaining a RMSD below 0.15 nm) and a more favorable interaction profile compared to the other compounds during MD simulations. Additionally, binding free energy (MM-PBSA), in silico ADMET analysis, and DFT calculations, also indicate that DIS is the most promising candidate against DENV.