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

João Augusto Ribeiro, Alexander Hammer, Gerardo Andrés Libreros Zúñiga, Sair Maximo Chavez-Pacheco, Petros Tyrakis, Gabriel Stephani de Oliveira, Timothy Kirkman, Jamal El Bakali, Silvana Aparecida Rocco, Mauricio Luís Sforça, View ORCID ProfileRoberto Parise-Filho, View ORCID ProfileAnthony G. Coyne, Tom L Blundell, Chris Abell, View ORCID ProfileMarcio Vinicius Bertacine Dias
doi: https://doi.org/10.1101/2020.03.30.016204
João Augusto Ribeiro
1Institute of Biomedical Science, University of São Paulo, Brazil
2Institute of Biology, University of Campinas, Brazil
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Alexander Hammer
3Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
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Gerardo Andrés Libreros Zúñiga
1Institute of Biomedical Science, University of São Paulo, Brazil
4Department of Biology, IBILCE-State University of São Paulo, Brazil
5Department of Microbiology, University of Valle, Cali, Colombia
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Sair Maximo Chavez-Pacheco
1Institute of Biomedical Science, University of São Paulo, Brazil
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Petros Tyrakis
6Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK
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Gabriel Stephani de Oliveira
1Institute of Biomedical Science, University of São Paulo, Brazil
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Timothy Kirkman
7Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, The University of São Paulo. São Paulo. Brazil
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Jamal El Bakali
3Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
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Silvana Aparecida Rocco
8National Laboratory of Biosciences, Campinas, Brazil
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Mauricio Luís Sforça
8National Laboratory of Biosciences, Campinas, Brazil
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Roberto Parise-Filho
9Department of Chemistry, University of Warwick, UK
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  • ORCID record for Roberto Parise-Filho
Anthony G. Coyne
3Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
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Tom L Blundell
6Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK
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Chris Abell
3Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
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Marcio Vinicius Bertacine Dias
1Institute of Biomedical Science, University of São Paulo, Brazil
2Institute of Biology, University of Campinas, Brazil
4Department of Biology, IBILCE-State University of São Paulo, Brazil
6Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK
7Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, The University of São Paulo. São Paulo. Brazil
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  • ORCID record for Marcio Vinicius Bertacine Dias
  • For correspondence: mvbdias@usp.br
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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, 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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Posted April 01, 2020.
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Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis
João Augusto Ribeiro, Alexander Hammer, Gerardo Andrés Libreros Zúñiga, Sair Maximo Chavez-Pacheco, Petros Tyrakis, Gabriel Stephani de Oliveira, Timothy Kirkman, Jamal El Bakali, Silvana Aparecida Rocco, Mauricio Luís Sforça, Roberto Parise-Filho, Anthony G. Coyne, Tom L Blundell, Chris Abell, Marcio Vinicius Bertacine Dias
bioRxiv 2020.03.30.016204; doi: https://doi.org/10.1101/2020.03.30.016204
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Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis
João Augusto Ribeiro, Alexander Hammer, Gerardo Andrés Libreros Zúñiga, Sair Maximo Chavez-Pacheco, Petros Tyrakis, Gabriel Stephani de Oliveira, Timothy Kirkman, Jamal El Bakali, Silvana Aparecida Rocco, Mauricio Luís Sforça, Roberto Parise-Filho, Anthony G. Coyne, Tom L Blundell, Chris Abell, Marcio Vinicius Bertacine Dias
bioRxiv 2020.03.30.016204; doi: https://doi.org/10.1101/2020.03.30.016204

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