Molecular docking and dynamics of potential inhibitors of NS5 protein methyltransferase domain of dengue virus serotype 3 derived from marine sponges

Dengue, a mosquito-borne disease predominantly transmitted by Aedes mosquitoes, is a significant public health concern, affecting nearly half of the global population. Unfortunately, the availability of specific treatment of dengue using antivirals has remained elusive. In this regard, bioactive compounds from marine organisms offer great potential for developing medicinal drugs due to their inherent diverse biological activities. In this study, the interactions of bioactive compounds derived from marine sponges with the methyltransferase (MTase) domain in non-structural 5 (NS5) protein were investigated using in silico approaches. A library composed of 50 compounds was docked to the guanosine triphosphate (GTP) pocket of NS5 Mtase which revealed that the top ten compounds had binding free energies (BFE) ranging from − 7.42 to − 8.75 kcal/mol. Through pharmacophore scoring, these ligands were found to exhibit non-covalent interactions with reported conserved residues of the GTP pocket. The drug-likeness of these compounds were also assessed through absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling. The interactions of top three compounds with the most negative BFE, aragusterol B (1), stelletin A (2), and alisiaquinone C (3), were validated using molecular dynamics (MD) simulations over 100 ns through root mean square deviation (RMSD), radius of gyration, principal component analysis (PCA), free energy landscape (FEL), and molecular mechanics Poisson-Boltzmann surface area (MMPBSA). MD simulations confirmed the favorable interactions between these three compounds and NS5 MTase, and although solubility remains a major drawback, these compounds can nonetheless serve as possible molecular scaffolds to design better analogs.