Apr 1, 2020

Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis

BioRxiv : the Preprint Server for Biology
Luz Garcia-AlonsoMarcio Vinicius Bertacine Dias


Dihydrofolate reductase (DHFR), a key enzyme involved in folate metabolism, is a widely explored target in the treatment of cancer, immune diseases, bacteria and protozoa infections. Although several antifolates have proved successful in the treatment of infectious diseases, none have been developed to combat tuberculosis, despite the essentiality of M. tuberculosis DHFR (MtDHFR). Herein, we describe an integrated fragment-based drug discovery approach to target MtDHFR that has identified hits with scaffolds not yet explored in any previous drug design campaign for this enzyme. The application of a SAR by catalog strategy of an in house library for one of the identified fragments has led to a series of molecules that bind MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that differs from other DHFR antifolates, thus opening perspectives for the development of novel and relevant MtDHFR inhibitors.

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Mentioned in this Paper

Proton Pump Inhibitors
The Cancer Genome Atlas
Somatic Mutation
Cancer Gene Mutation
Protein-Protein Interaction
Genomic DNA
Malignant Neoplasms

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