Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis
Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis
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.
Abell Chris、Libreros Z¨2?iga Gerardo Andr¨|s、Chavez-Pacheco Sair Maximo、Kirkman Timothy、Coyne Anthony G.、Bertacine Dias Marcio Vinicius、Rocco Silvana Aparecida、Sfor?a Mauricio Lu¨as、de Oliveira Gabriel Stephani、Blundell Tom L、Ribeiro Jo?o Augusto、Parise-Filho Roberto、Hammer Alexander、Tyrakis Petros、Bakali Jamal El
Department of Chemistry, University of CambridgeInstitute of Biomedical Science, University of S?o Paulo||Department of Biology, IBILCE-State University of S?o Paulo||Department of Microbiology, University of ValleInstitute of Biomedical Science, University of S?o PauloLaboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, The University of S?o Paulo. S?o PauloDepartment of Chemistry, University of CambridgeInstitute of Biomedical Science, University of S?o Paulo||Institute of Biology, University of Campinas||Department of Biology, IBILCE-State University of S?o Paulo||Department of Biochemistry, University of Cambridge||Laboratory of Design and Synthesis of Bioactive Substances (LAPESSB), Department of Pharmacy, Faculty of Pharmaceutical Sciences, The University of S?o Paulo. S?o PauloNational Laboratory of BiosciencesNational Laboratory of BiosciencesInstitute of Biomedical Science, University of S?o PauloDepartment of Biochemistry, University of CambridgeInstitute of Biomedical Science, University of S?o Paulo||Institute of Biology, University of CampinasDepartment of Chemistry, University of WarwickDepartment of Chemistry, University of CambridgeDepartment of Biochemistry, University of CambridgeDepartment of Chemistry, University of Cambridge
药学生物科学研究方法、生物科学研究技术基础医学
Abell Chris,Libreros Z¨2?iga Gerardo Andr¨|s,Chavez-Pacheco Sair Maximo,Kirkman Timothy,Coyne Anthony G.,Bertacine Dias Marcio Vinicius,Rocco Silvana Aparecida,Sfor?a Mauricio Lu¨as,de Oliveira Gabriel Stephani,Blundell Tom L,Ribeiro Jo?o Augusto,Parise-Filho Roberto,Hammer Alexander,Tyrakis Petros,Bakali Jamal El.Using a fragment-based approach to identify novel chemical scaffolds targeting the dihydrofolate reductase (DHFR) from Mycobacterium tuberculosis[EB/OL].(2025-03-28)[2025-04-29].https://www.biorxiv.org/content/10.1101/2020.03.30.016204.点此复制
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