Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.
Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors.
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DOI：
10.1021/acs.jmedchem.6b00007
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发表时间：
2016-04-14
影响因子：
7.3
通讯作者：
Abell C
中科院分区：
文献类型：
--
作者：
Kavanagh ME;Coyne AG;McLean KJ;James GG;Levy CW;Marino LB;de Carvalho LP;Chan DS;Hudson SA;Surade S;Leys D;Munro AW;Abell C
必需酶CYP 121是针对结核分枝杆菌抗生素耐药菌株的药物开发的靶点。使用级联生物物理测定法鉴定了三唑-1-基苯酚片段1与CYP 121结合。1的合成合并和优化使结合亲和力提高了100倍，产生了先导化合物2（KD = 15 μM）。将2解构成其组分逆转录片段允许评估结构基序的组效率，鉴定更多LE支架用于优化并突出结合亲和力热点。在LE逆转录片段支架上添加金属结合药效团的结构指导产生低纳摩尔（KD = 15 nM）CYP 121配体。将这些化合物与远端活性位点中的靶向结合热点结合，得到对人药物代谢P450具有优异选择性的化合物。使用X射线晶体学、紫外-可见光谱和天然质谱分析控制配体效力和选择性的因素为后续药物开发提供了见解。
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 (KD = 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 (KD = 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.