Fortuitous in vitro compound degradation produces a tractable hit against Mycobacterium tuberculosis dethiobiotin synthetase: a cautionary tale of what goes in, does not always come out

Abstract

A molecule flagged in an in silico docking screen against MtDTBS, was inadvertently hydrolysed in the crystal conditions used for hit validation. The resulting fragment-sized molecule bound to the DAPA substrate binding pocket of the target enzyme (MtDTBS) with millimolar affinity, as measured by surface plasmon resonance, but was later modified to a highly potent (nanomolar) ligand and promising lead for the development of novel tuberculosis treatments.