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Using a fragment-based approach to identify alternative chemical scaffolds targeting dihydrofolate reductase from mycobacterium tuberculosis

DOI: 10.1021/acsinfecdis.0c00263 DOI Help

Authors: João A. Ribeiro (University of Saõ Paulo) , Alexander Hammer (University of Cambridge) , Gerardo A. Libreros-Zúñiga (University of Saõ Paulo; University of Valle) , Sair M. Chavez-Pacheco (University of Saõ Paulo) , Petros Tyrakis (University of Cambridge) , Gabriel S. De Oliveira (University of Saõ Paulo) , Timothy Kirkman (University of Warwick) , Jamal El Bakali (University of Cambridge) , Silvana A. Rocco (National Laboratory of Biosciences, Brazil) , Mauricio L. Sforça (National Laboratory of Biosciences, Brazil) , Roberto Parise-Filho (UniversityofSaõ Paulo) , Anthony G. Coyne (University of Cambridge) , Tom L. Blundell (University of Cambridge) , Chris Abell (University of Cambridge) , Marcio V. B. Dias (University of Saõ Paulo; University of Campinas; University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: July 2020

Abstract: 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, they have been underexplored 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 to MtDHFR with low micromolar affinities. Crystal structures of MtDHFR in complex with compounds of this series demonstrated a novel binding mode that considerably differs from other DHFR antifolates, thus opening perspectives for the development of relevant MtDHFR inhibitors.

Journal Keywords: fragment-based drug discovery; Mycobacterium tuberculosis; dihydrofolate reductase

Diamond Keywords: Tuberculosis (TB); Bacteria; Enzymes

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 15/07/2020 09:09

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)