Using a Fragment-based approach to identify new hits to drugs against Mycobacterium tuberculosis Pantothenate Kinase

The increasing recurrence of Mycobacterium tuberculosis strains resistant to available therapies motivates researchers to seek new alternatives to combat tuberculosis. In this sense, Pantothenate Kinase (PanK), which is involved in Coenzyme A biosynthesis, was validated as a potential therapeutic target for the development of new antitubercular drugs. Thus, the aim of this work was to validate small molecules (fragments) as hits for new drug development by the Fragment-Based Drug Discovery (FBDD) strategy. Through Thermal Shift screening, 86 hits were selected, of which 29 stabilized and 57 destabilized the enzyme. Then, by 1D 1H NMR, 55 out of these initial hits demonstrated to interact with PanK. Most of the selected compounds have one or two aromatic rings of 6 or 5 carbons or both. We are currently working on the determination of the binding mode of such molecules by crystallography and obtaining the Kd value by Isothermal titration calorimetry (ITC).