RT Journal Article SR Electronic T1 Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.03.30.016204 DO 10.1101/2020.03.30.016204 A1 João Augusto Ribeiro A1 Alexander Hammer A1 Gerardo Andrés Libreros Zúñiga A1 Sair Maximo Chavez-Pacheco A1 Petros Tyrakis A1 Gabriel Stephani de Oliveira A1 Timothy Kirkman A1 Jamal El Bakali A1 Silvana Aparecida Rocco A1 Mauricio Luís Sforça A1 Roberto Parise-Filho A1 Anthony G. Coyne A1 Tom L Blundell A1 Chris Abell A1 Marcio Vinicius Bertacine Dias YR 2020 UL http://biorxiv.org/content/early/2020/04/01/2020.03.30.016204.abstract AB 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.