Using a Fragment-Based Approach to Identify Alternative Chemical Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis

Autor(es):Mostrar menos -

Ribeiro, Joao A. ^{[1, 2]} ; Hammer, Alexander ^[3] ; Libreros-Zuniga, Gerardo A. ^{[2, 4, 5]} ; Chavez-Pacheco, Sair M. ^[2] ; Tyrakis, Petros ^[6] ; de Oliveira, Gabriel S. ^[2] ; Kirkman, Timothy ^[7] ; El Bakali, Jamal ^[3] ; Rocco, Silvana A. ^[8] ; Sforca, Mauricio L. ^[8] ; Parise-Filho, Roberto ^[9] ; Coyne, Anthony G. ^[3] ; Blundell, Tom L. ^[6] ; Abell, Chris ^[3] ; Dias, Marcio V. B. ^{[1, 6, 7, 2, 4]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Biol, BR-13083862 Campinas, SP - Brazil

^[2] Univ Sao Paulo, Dept Microbiol, Inst Biomed Sci, BR-05508000 Sao Paulo, SP - Brazil

^[3] Univ Cambridge, Dept Chem, Cambridge CB2 1EW - England

^[4] State Univ Sao Paulo, IBILCE, Dept Biol, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

^[5] Univ Valle, Dept Microbiol, Cali 760043 - Colombia

^[6] Univ Cambridge, Dept Biochem, Cambridge CB2 1GA - England

^[7] Univ Warwick, Dept Chem, Coventry CV4 7AL, W Midlands - England

^[8] Natl Lab Biosci, BR-13083100 Campinas, SP - Brazil

^[9] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, BR-05508000 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ACS INFECTIOUS DISEASES; v. 6, n. 8, p. 2192-2201, AUG 14 2020.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 10/15971-3 - Caracterização estrutural de enzimas envolvidas em vias de biossíntese de antibióticos com interesse biotecnológico
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 13/15906-5 - Aplicação da técnica "fragment based drug discovery" (FBDD) para duas enzimas da via de biossíntese de folato em Mycobacterium tuberculosis
• Beneficiário: João Augusto Ribeiro
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/25733-1 - Clonagem, expressão e purificação de enzimas envolvidas em biossíntese de antibióticos
• Beneficiário: Sair Maximo Chavez Pacheco
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 18/00351-1 - Biologia Estrutural aplicada às enzimas envolvidas na biossíntese de produtos naturais: aplicações biotecnológicas e entendimento molecular de reações enzimáticas pouco usuais
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular