Frederickson, Martyn;
Selvam, Irwin R;
Evangelopoulos, Dimitrios;
McLean, Kirsty J;
Katariya, Mona M;
Tunnicliffe, Richard B;
Campbell, Bethany;
... Abell, Chris; + view all
(2022)
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).
European Journal of Medicinal Chemistry
, 230
, Article 114105. 10.1016/j.ejmech.2022.114105.
Preview |
Text
Evangelopoulos_1-s2.0-S022352342200006X-main.pdf Download (3MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | 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) |
| Location: | France |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ejmech.2022.114105 |
| Publisher version: | https://doi.org/10.1016/j.ejmech.2022.114105 |
| Language: | English |
| Additional information: | Copyright © 2022 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
| Keywords: | CYP121, Drug discovery, Mycobacterium tuberculosis, Tuberculosis, X-ray crystallography, Antitubercular Agents, Drug Design, Humans, Mycobacterium tuberculosis, Tuberculosis, X-Rays |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute > Microbial Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Eastman Dental Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10147986 |
Archive Staff Only
 |
View Item |
