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)

DOI: 10.1016/j.ejmech.2022.114105

Authors: Martyn Frederickson (University of Cambridge) , Irwin R. Selvam (University of Manchester) , Dimitrios Evangelopoulos (Francis Crick Institute; University College Londo) , Kirsty J. Mclean (University of Manchester; University of Huddersfield) , Mona M. Katariya (University of Cambridge) , Richard B. Tunnicliffe (University of Manchester) , Bethany Campbell (University of Cambridge) , Madeline E. Kavanagh (University of Cambridge; The Scripps Research Institute) , Sitthivut Charoensutthivarakul (University of Cambridge; Mahidol University) , Richard T. Blankley (Agilent Technologies U.K. Ltd) , Colin W. Levy (University of Manchester) , Luiz Pedro S. De Carvalho (Francis Crick Institute) , David Leys (University of Manchester) , Andrew W. Munro (University of Manchester) , Anthony G. Coyne (University of Cambridge) , Chris Abell (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: European Journal Of Medicinal Chemistry , VOL 393

State: Published (Approved)
Published: January 2022
Diamond Proposal Number(s): 17773 , 24447

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 lead-to-clinical candidate medicinal chemistry campaign.

Journal Keywords: CYP121; Mycobacterium tuberculosis; X-ray crystallography; Drug discovery; Tuberculosis

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Added On: 12/01/2022 09:49

Discipline Tags:

Pathogens Antibiotic Resistance Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)