In-Silico Identification of Type II IMPDH Inhibitors for DENV Suppression

The Dengue virus (DENV) single-stranded positive-sense RNA virus that relies on the host’s guanine nucleotide pool for RNA synthesis, facilitated by the type II Inosine Monophosphate Dehydrogenase (IMPDH) enzyme. Inhibiting IMPDH disrupts this process. In this study, C2-Mycophenolic Acid (MYD), a known IMPDH inhibitor, was used as a template for generating alternative inhibitory compounds via NVIDIA’s AI molecule generation model, molmim, with a similarity constraint of 0.5. Molecular docking simulations were conducted using AutoDock Vina, and the generated ligands were analyzed for binding affinity and protein-ligand interactions. Three ligands, G11_1 (-9.441), G18_1 (-8.788), and G27_1 (-8.727) exhibited stronger docking scores than MYD (-8.439), demonstrating improved binding efficiency. These ligands contain critical structural features, including carbonyl groups, hydroxyl groups, and aromatic rings, facilitating hydrogen bonding, π-π stacking, and hydrophobic interactions with IMPDH residues. Upon further testing, this preliminary research offers a promising direction for discovering therapeutic approaches to tackle dengue.