Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors

Autor(es):Mostrar menos -

Kavanagh, Madeline E. ^[1] ; Coyne, Anthony G. ^[1] ; McLean, Kirsty J. ^[2] ; James, Guy G. ^[1] ; Levy, Colin W. ^[2] ; Marino, Leonardo B. ^{[3, 4]} ; de Carvalho, Luiz Pedro S. ^[3] ; Chan, Daniel S. H. ^[1] ; Hudson, Sean A. ^{[1, 5]} ; Surade, Sachin ^[6] ; Leys, David ^[2] ; Munro, Andrew W. ^[2] ; Abell, Chris ^[1]

Afiliação do(s) autor(es)

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

^[2] Univ Manchester, Ctr Synthet Biol Fine & Specialty Chem SYNBIOCHEM, Manchester Inst Biotechnol, Fac Life Sci, 131 Princess St, Manchester M1 7DN, Lancs - England

^[3] Francis Crick Inst, Mill Hill Lab, Lab Mycobacterial Metab & Antibiot Res, London NW7 1AA - England

^[4] Sao Paulo State Univ UNESP, Sch Pharmaceut Sci, BR-4801902 Araraquara, SP - Brazil

^[5] Australian Natl Univ, Res Sch Chem, Coll Phys & Math Sci, Bldg 137, Sullivans Creek Rd, Canberra, ACT 0200 - Australia

^[6] Univ Cambridge, Dept Biochem, 80 Tennis Court Rd, Cambridge CB2 1GA - England

• Tipo de documento: Artigo Científico
• Fonte: Journal of Medicinal Chemistry; v. 59, n. 7, p. 3272-3302, APR 14 2016.
• Citações Web of Science: 23

Resumo

The essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (K-D = 15 mu M). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (K-D = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development. (AU)

• Processo FAPESP: 11/21232-1 - Avaliação do envolvimento de eIF5A na via secretória em Saccharomyces cerevisiae
• Beneficiário: Leonardo Biancolino Marino
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto