The malate synthase project began in 2007. High throughput screening has been completed with a 1.4 million compound library and hits have been identified. Screening hits were validated and characterized with dose-response curves against the enzyme and Mtb whole cells. Interactions with the enzyme have been determined on atomic level through crystals structures of malate synthase-inhibitor complexes. From rounds of structure-based design, chemical synthesis and testing of analogs three chemically distinct series of inhibitors emerged. Each of them have potent enzyme inhibitors which also inhibit Mtb cell growth. Thorough characterization of leads activity in cells (proving that they are on target) and their pharmacological properties is ongoing.
Malate Synthase Inhibitors