Fragment-Based Drug Design for Novel Inhibitors of Dengue Polymerase

This thesis explores the development of inhibitors for Dengue polymerase using fragment-based drug design. Fragment-based drug design often identifies very small molecules that bind weakly and require significant optimisation to develop them into higher affinity drug-like compounds. Assays were developed against Dengue polymerase serotypes 3 and 4. This enabled assessment of activity for 11 fragments and their 116 analogues, and prioritisation for development into higher affinity drug-like compounds. These were then elaborated by screening of unpurified reaction mixtures in order to triage vectors for elaboration. More than 700 compounds were tested to explore the development of high-affinity inhibitors of the dengue virus.