Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2.
Structure-Based Design of Inhibitors with Improved Selectivity for Steroidogenic Cytochrome P450 17A1 over Cytochrome P450 21A2.
复制标题
基于结构的抑制剂，具有在细胞色素P450 21a2上对类固醇生成细胞色素P450 17A1的选择性提高的抑制剂。
DOI：
10.1021/acs.jmedchem.8b00419
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发表时间：
2018-06-14
影响因子：
7.3
通讯作者：
Aubé J
中科院分区：
文献类型：
--
作者：
Fehl C;Vogt CD;Yadav R;Li K;Scott EE;Aubé J
抑制雄激素生物合成在临床上可有效治疗雄激素反应性前列腺癌。阿比特龙是雄激素生物合成所需的细胞色素 P450 17A1 (CYP17A1) 的临床一流抑制剂。然而，阿比特龙也会引起高血压、低钾血症和水肿，部分原因可能是由于另一种类固醇生成细胞色素 P450 CYP21A2 的脱靶抑制。阿比特龙类似物的设计基于结构证据，即 B 环取代基可能有利地与结合 CYP17A1 的极性残基相互作用，并与 CYP21A2 活性位点中的残基发生空间冲突。与阿比特龙的 6.6 倍相比，最好的类似物将 CYP17A1 抑制的选择性提高了 84 倍。与 CYP17A1 的共结晶验证了与 CYP17A1 活性位点残基的预期新接触。将这些类似物对接至 CYP21A2 中发现了空间冲突，这可能是结合减少和 CYP21A2 抑制的基础。总体而言，这些类似物可能以减少副作用的形式提供临床优势。
Inhibition of androgen biosynthesis is clinically effective for treating androgen-responsive prostate cancer. Abiraterone is a clinical first-in-class inhibitor of cytochrome P450 17A1 (CYP17A1) required for androgen biosynthesis. However, abiraterone also causes hypertension, hypokalemia, and edema, likely due in part to off-target inhibition of another steroidogenic cytochrome P450, CYP21A2. Abiraterone analogs were designed based on structural evidence that B-ring substituents may favorably interact with polar residues in binding CYP17A1 and sterically clash with residues in the CYP21A2 active site. The best analogs increased selectivity of CYP17A1 inhibition up to 84-fold compared with 6.6-fold for abiraterone. Cocrystallization with CYP17A1 validated the intended new contacts with CYP17A1 active site residues. Docking these analogs into CYP21A2 identified steric clashes that likely underlie decreased binding and CYP21A2 inhibition. Overall, these analogs may offer a clinical advantage in the form of reduced side effects.
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影响因子：
64.8
作者：
Li Z;Bishop AC;Alyamani M;Garcia JA;Dreicer R;Bunch D;Liu J;Upadhyay SK;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
3.4
作者：
Madhra, Mukesh Kumar;Sriram, Hari Mohan;Joseph, Sony
通讯作者：
Joseph, Sony
影响因子：
4.2
作者：
Huang, Audris;Jayaraman, Lata;Balog, Aaron
通讯作者：
Balog, Aaron
影响因子：
64.8
作者：
Li, Zhenfei;Alyamani, Mohammad;Li, Jianneng;Rogacki, Kevin;Abazeed, Mohamed;Upadhyay, Sunil K.;Balk, Steven P.;Taplin, Mary-Ellen;Auchus, Richard J.;Sharifi, Nima
通讯作者：
Sharifi, Nima
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH