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).

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ID: 275490
2022
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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 (MIC 6.25 μM), a novel hit compound suitable as a starting point for a more involved hit to lead candidate medicinal chemistry campaign.
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frederickson2022aeuropean Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Frederickson, Martyn;Selvam, Irwin R;Evangelopoulos, Dimitrios;McLean, Kirsty J;Katariya, Mona M;Tunnicliffe, Richard B;Campbell, Bethany;Kavanagh, Madeline E;Charoensutthivarakul, Sitthivut;Blankley, Richard T;Levy, Colin W;de Carvalho, Luiz Pedro S;Leys, David;Munro, Andrew W;Coyne, Anthony G;Abell, Chris;
Journal European journal of medicinal chemistry
Year 2022
DOI
S0223-5234(22)00006-X
URL
Keywords
X-ray crystallography Mycobacterium tuberculosis tuberculosis drug discovery cyp121

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