The discovery of novel antivirals for dengue, chikungunya, and SARS-CoV-2 by integrating structure-based design with rational hit-to-lead optimization, focusing on methyltransferase (MTase), Main Protease (Mpro), and other key enzyme targets. Using X-ray crystallography and molecular dynamics (MD) simulations, we elucidate essential protein–ligand interactions that guide the identification of promising scaffolds. These leads undergo systematic organic synthesis, with iterative structure–activity relationship (SAR) refinements to optimize potency, selectivity, and physicochemical properties. The resulting compounds are subjected to enzymatic and cell-based assays to confirm efficacy, alongside toxicity assessments to ensure safety. For the most promising candidates, pharmacokinetic (PK) studies provide insights into absorption and metabolism, enabling a streamlined progression from early target validation to clinically relevant lead compounds.