3 research outputs found
A new strategy for hit generation: Novel in cellulo active inhibitors of CYP121A1 from Mycobacterium tuberculosis via a combined X-ray crystallographic and phenotypic screening approach (XP screen)
There is a pressing need for new drugs against tuberculosis (TB) to combat the growing resistance
to current antituberculars. Herein a novel strategy is described for hit generation against promising
TB targets involving X-ray crystallographic screening in combination with phenotypic screening.
This combined approach (XP Screen) affords both a validation of target engagement as well as
determination of in cellulo activity. The utility of this method is illustrated by way of an XP Screen
against CYP121A1, a cytochrome P450 enzyme from Mycobacterium tuberculosis (Mtb)
championed as a validated drug discovery target. A focused screening set was synthesized and
tested by such means, with several members of the set showing promising activity against Mtb
strain H37Rv. One compound was observed as an X-ray hit against CYP121A1 and showed
improved activity against Mtb strain H37Rv under multiple assay conditions (pan-assay activity).
Data obtained during X-ray crystallographic screening were utilized in a structure-based campaign
to design a limited number of analogues (less than twenty), many of which also showed pan-assay
activity against Mtb strain H37Rv. These included the benzo[b][1,4]oxazine derivative (MIC90 6.25
µM), a novel hit compound suitable as a starting point for a more involved lead-to-clinical candidate
medicinal chemistry campaign