Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors.
Substrate Fragmentation for the Design of M. tuberculosis CYP121 Inhibitors.
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DOI：
10.1002/cmdc.201600248
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发表时间：
2016-09-06
期刊：
影响因子：
3.4
通讯作者：
Abell, Chris
中科院分区：
文献类型：
--
作者：
Kavanagh, Madeline E.;Gray, Janine L.;Gilbert, Sophie H.;Coyne, Anthony G.;McLean, Kirsty J.;Davis, Holly J.;Munro, Andrew W.;Abell, Chris
将必需的结核分枝杆菌（Mtb）酶CYP 121的环二肽底物解构为其组分片段，并针对该酶进行筛选。 鉴定了许多命中，其中一个表现出非预期的抑制剂样结合模式。通过对CYP 121底物结构的指导，阐明了抑制药效团，并通过合成阐述快速提高了片段结合亲和力。所得抑制剂具有低微摩尔亲和力，良好的预测理化性质和对CYP 121的选择性超过其他Mtb P450。抑制剂结合模式的光谱表征提供了对弱氮供体配体对P450血红素的影响的深入了解，提高了对控制CYP 121-配体识别的因素的理解，并推测了该酶对Mtb的生物学作用。
The cyclo‐dipeptide substrates of the essential M. tuberculosis (Mtb) enzyme CYP121 were deconstructed into their component fragments and screened against the enzyme. A number of hits were identified, one of which exhibited an unexpected inhibitor‐like binding mode. The inhibitory pharmacophore was elucidated, and fragment binding affinity was rapidly improved by synthetic elaboration guided by the structures of CYP121 substrates. The resulting inhibitors have low micromolar affinity, good predicted physicochemical properties and selectivity for CYP121 over other Mtb P450s. Spectroscopic characterisation of the inhibitors′ binding mode provides insight into the effect of weak nitrogen‐donor ligands on the P450 heme, an improved understanding of factors governing CYP121–ligand recognition and speculation into the biological role of the enzyme for Mtb.
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影响因子：
15
作者：
Barelier S;Cummings JA;Rauwerdink AM;Hitchcock DS;Farelli JD;Almo SC;Raushel FM;Allen KN;Shoichet BK
通讯作者：
Shoichet BK
影响因子：
2.9
作者：
Conner, Kip P.;Cruce, Alex A.;Krzyaniak, Matthew D.;Schimpf, Alina M.;Frank, Daniel J.;de Montellano, Paul Ortiz;Atkins, William M.;Bowman, Michael K.
通讯作者：
Bowman, Michael K.
影响因子：
16.6
作者：
Hudson, Sean A.;McLean, Kirsty J.;Abell, Chris
通讯作者：
Abell, Chris
影响因子：
14.8
作者：
Gondry, Muriel;Sauguet, Ludovic;Pernodet, Jean-Luc
通讯作者：
Pernodet, Jean-Luc
影响因子：
120.1
作者：
Hann, Michael M.;Keserue, Gyoergy M.
通讯作者：
Keserue, Gyoergy M.