Fragment‐Merging Strategies with Known Pyrimidine Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis

Author:

Kirkman Tim1ORCID,Fun Tan Suk2,Chavez‐Pacheco Sair Maximo3,Hammer Alexander2,Abell Chris2,Tosin Manuela1,Coyne Anthony G.2,Dias Marcio V. B.13

Affiliation:

1. Department of Chemistry University of Warwick Gibbet Hill Coventry CV4 7AL UK

2. Yusuf Hamied Department of Chemistry University of Cambridge Lensfield Road Cambridge CB2 1EW UK

3. Department of Microbiology Institute of Biomedical Science University of São Paulo Av. Prof. Lineu Prestes 1374 CEP 05508–000 São Paulo Brazil

Abstract

AbstractDihydrofolate 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.

Funder

Cambridge Trust

Fundação de Amparo à Pesquisa do Estado de São Paulo

University of Warwick

Publisher

Wiley

Subject

Organic Chemistry,General Pharmacology, Toxicology and Pharmaceutics,Molecular Medicine,Drug Discovery,Biochemistry,Pharmacology

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