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Fragment merging strategies with known pyrimidine scaffolds targeting dihydrofolate reductase from Mycobacterium tuberculosis
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Kirkman, Tim, Tan, Suk Fun, Pacheco, Sair Maximo Chavez, Hammer, Alexander, Tosin, Manuela, Coyne, Anthony and Dias, Marcio (2023) Fragment merging strategies with known pyrimidine scaffolds targeting dihydrofolate reductase from Mycobacterium tuberculosis. ChemMedChem, 18 (15). e202300240. doi:10.1002/cmdc.202300240 ISSN 1860-7179.
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WRAP-fragment-merging-strategies-known-pyrimidine-scaffolds-targeting-dihydrofolate-reductasefrom-Mycobacterium-tuberculosis-2023.pdf - Accepted Version Embargoed item. Restricted access to Repository staff only - Requires a PDF viewer. Download (1466Kb) |
Official URL: http://dx.doi.org/10.1002/cmdc.202300240
Abstract
Dihydrofolate reductase (DHFR) is a key enzyme involved in the folate pathway that has been heavily targeted for the development of therapeutics against cancer and bacterial and protozoa infections amongst others. Despite being an essential enzyme for Mycobacterium tuberculosis (Mtb) viability, DHFR remains an underexploited target for tuberculosis (TB) treatment. Herein, we report the preparation and evaluation of a series of compounds against Mtb DHFR (MtbDHFR). The compounds have been designed using a merging strategy of traditional pyrimidine-based antifolates with a previously discovered unique fragment hit against MtbDHFR. In this series, four compounds displayed a high affinity against MtbDHFR, with sub-micromolar affinities. Additionally, we determined the binding mode of six of the best compounds using protein crystallography, which revealed occupation of an underutilised region of the active site.
Item Type: | Journal Article | ||||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
Journal or Publication Title: | ChemMedChem | ||||||||
Publisher: | Wiley | ||||||||
ISSN: | 1860-7179 | ||||||||
Official Date: | 1 August 2023 | ||||||||
Dates: |
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Volume: | 18 | ||||||||
Number: | 15 | ||||||||
Article Number: | e202300240 | ||||||||
DOI: | 10.1002/cmdc.202300240 | ||||||||
Status: | Peer Reviewed | ||||||||
Publication Status: | Published | ||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||
Date of first compliant deposit: | 25 May 2023 | ||||||||
Date of first compliant Open Access: | 8 June 2023 |
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