title: Fragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA.
abstract: 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.
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 8-101 Weaver-Densford, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Ran
authors.initials: R
authors.lastname: Dai
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 8-101 Weaver-Densford, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Geders
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 8-101 Weaver-Densford, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.affiliation: ‡Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States.
authors.forename: Sae Woong
authors.initials: SW
authors.lastname: Park
authors.affiliation: ‡Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, United States.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schnappinger
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 8-101 Weaver-Densford, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Courtney C
authors.initials: CC
authors.lastname: Aldrich
authors.affiliation: †Department of Medicinal Chemistry, University of Minnesota, 8-101 Weaver-Densford, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
authors.forename: Barry C
authors.initials: BC
authors.lastname: Finzel
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D002152:Calorimetry, Differential Scanning; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013816:Thermodynamics; D000637:Transaminases / Q000737:chemistry* / Q000378:metabolism*; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D000637:Transaminases; C102100:BioA protein, bacteria