We use structure-based approach in which X-ray structures of therapeutically important protein drug targets are used to define a template for the design of novel small molecule ligands which provide the starting point for the design of novel drugs. The main therapeutic areas of interest are in the fields of cancer, parasitic infection and HIV. We have designed and written a database-mining program called LIDAEUS (LIgand Discovery At Edinburgh UniverSity). 3D databases of available molecules are searched to select potential ligands for protein binding pockets. A number of novel ligands that bind with micromolar dissociation constants have been discovered. As a general strategy we select ligands suitable for combinatorial chemistry and in collaboration with Professor Nick Turner we have synthesised a number of combinatorial families of tightly binding ligands specific for different target proteins. In the field of cancer we have a collaboration with the company Cyclacel and have used the LIDAEUS approach to discover a new family of tight binding CDK inhibitors. We are also looking at the interactions between large immunophilins and Hsp90 and the structures of cyclophilin-40 have been determined. The same approach has been used to develop libraries of cyclophilin inhibitors which could be therapeutically valuable in HIV therapy. Antiparasitic drug targets in Lieshmania, Trypanosomes and Plasmodium include a a number of enzymes in the parasite glycolytic pathway including phosphofructokinase, pyruvate kinase and phosphoglycerate mutase and weak lead compounds are available for each of these new X-ray structures. We also collaborate with Prof Yongyuth Yuthavong on plasmodial targets including DHFR-TS