Fragment-Based Exploration of Binding Site Flexibility in Mycobacterium tuberculosis BioA

The
PLP-dependent transaminase (BioA) of Mycobacterium
tuberculosis and other pathogens that catalyzes the
second step of biotin biosynthesis is a now well-validated target
for antibacterial development. Fragment screening by differential
scanning fluorimetry has been performed to discover new chemical scaffolds
and promote optimization of existing inhibitors. Calorimetry confirms
binding of six molecules with high ligand efficiency. Thermodynamic
data identifies which molecules bind with the enthalpy driven stabilization
preferred in compounds that represent attractive starting points for
future optimization. Crystallographic characterization of complexes
with these molecules reveals the dynamic nature of the BioA active
site. Different side chain conformational states are stabilized in
response to binding by different molecules. A detailed analysis of
conformational diversity in available BioA structures is presented,
resulting in the identification of two states that might be targeted
with molecular scaffolds incorporating well-defined conformational
attributes. This new structural data can be used as part of a scaffold
hopping strategy to further optimize existing inhibitors or create
new small molecules with improved therapeutic potential.