Fragment-Merging Strategies with Known Pyrimidine Scaffolds Targeting Dihydrofolate Reductase from Mycobacterium tuberculosis

Autor(es)

Kirkman, Tim ; Fun Tan, Suk ; Chavez-Pacheco, Sair Maximo ; Hammer, Alexander ; Abell, Chris ; Tosin, Manuela ; Coyne, Anthony G. ; Dias, Marcio V. B.

• Tipo de documento: Artigo Científico
• Fonte: CHEMMEDCHEM; v. 18, n. 15, p. 9-pg., 2023-06-06.

Resumo

Dihydrofolate reductase (DHFR) is a key enzyme involved in the folate pathway that has been heavily targeted for the development of therapeutics against cancer and bacterial and protozoa infections amongst others. Despite being an essential enzyme for Mycobacterium tuberculosis (Mtb) viability, DHFR remains an underexploited target for tuberculosis (TB) treatment. Herein, we report the preparation and evaluation of a series of compounds against Mtb DHFR (MtbDHFR). The compounds have been designed using a merging strategy of traditional pyrimidine-based antifolates with a previously discovered unique fragment hit against MtbDHFR. In this series, four compounds displayed a high affinity against MtbDHFR, with sub-micromolar affinities. Additionally, we determined the binding mode of six of the best compounds using protein crystallography, which revealed occupation of an underutilised region of the active site. (AU)

• 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: 20/03850-9 - Parede celular micobacteriana: estudo estrutural e estratégias de inibição de enzimas relacionadas com sua biossíntese e regulação
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/09188-8 - Biossíntese de antibióticos poliéteres e aminoglicosídeos: investigação estrutural de enzimas não usuais ou com aplicabilidade em biologia sintética
• Beneficiário: Marcio Vinicius Bertacine Dias
• Modalidade de apoio: Auxílio à Pesquisa - Regular