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

Ran Dai, Todd W. Geders, Feng Liu, Sae Woong Park, Dirk Schnappinger, Courtney C. Aldrich, Barry C. Finzel

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5208-5217
Number of pages10
JournalJournal of medicinal chemistry
Volume58
Issue number13
DOIs
StatePublished - Jul 9 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

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