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Fragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA.

TitleFragment-based exploration of binding site flexibility in Mycobacterium tuberculosis BioA.
Publication TypeJournal Article
Year of Publication2015
AuthorsDai R, Geders TW, Liu F, Park SWoong, Schnappinger D, Aldrich CC, Finzel BC
JournalJ Med Chem
Volume58
Issue13
Pagination5208-17
Date Published2015 Jul 09
ISSN1520-4804
KeywordsAnti-Bacterial Agents, Bacterial Proteins, Binding Sites, Calorimetry, Differential Scanning, Catalytic Domain, Crystallography, X-Ray, Models, Molecular, Molecular Conformation, Mycobacterium tuberculosis, Small Molecule Libraries, Thermodynamics, Transaminases, Tuberculosis
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.

DOI10.1021/acs.jmedchem.5b00092
Alternate JournalJ Med Chem
PubMed ID26068403
PubMed Central IDPMC4687966
Grant ListR01 AI091790 / AI / NIAID NIH HHS / United States
S10 OD017982 / OD / NIH HHS / United States
OD017982 / OD / NIH HHS / United States
R01AI091790 / AI / NIAID NIH HHS / United States

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