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

详细信息    查看全文

• 作者：Madeline E. Kavanagh ; Anthony G. Coyne ; Kirsty J. McLean ; Guy G. James ; Colin W. Levy ; Leonardo B. Marino ; Luiz Pedro S. de Carvalho ; Daniel S. H. Chan ; Sean A. Hudson ; Sachin Surade ; David Leys ; Andrew W. Munro ; Chris Abell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3272-3302
• 全文大小：1472K
• 年卷期：0
• ISSN：1520-4804

文摘

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 μM). 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.