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)

Martyn Frederickson, Irwin Selvam, Dimitrios Evangelopoulos, Kirsty McLean, Mona M. Katariya, Richard B. Tunnicliffe, Bethany Campbell, Madeline E. Kavanagh, Sitthivut Charoensutthivarakul, Richard T. Blankley, Colin W. Levy, Luiz Pedro S. de Carvalho, David Leys, Andrew W. Munro, Anthony Coyne, Chris Abell

Research output: Contribution to journalArticlepeer-review

Abstract

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 hit to lead candidate medicinal chemistry campaign.
Original languageEnglish
Article number114105
Number of pages23
JournalEuropean Journal of Medicinal Chemistry
Volume230
Early online date19 Jan 2022
DOIs
Publication statusPublished - 15 Feb 2022
Externally publishedYes

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