Inhibition of human CYP1 enzymes by a classical inhibitor α-naphthoflavone and a novel inhibitor N-(3, 5-dichlorophenyl)cyclopropanecarboxamide: An in vitro and in silico study.,Chemical Biology & Drug Design

当前位置： X-MOL 学术 › Chem. Bio. Drug Des. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Inhibition of human CYP1 enzymes by a classical inhibitor α-naphthoflavone and a novel inhibitor N-(3, 5-dichlorophenyl)cyclopropanecarboxamide: An in vitro and in silico study.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-03-09 , DOI: 10.1111/cbdd.13669
Risto Olavi Juvonen ₁ , Elmeri Matias Jokinen ₂ , Adeel Javaid ₁ , Marko Lehtonen _{1,

3} , Hannu Raunio ₁ , Olli Taneli Pentikäinen ₂

Affiliation

Enzymes in the cytochrome P450 family 1 (CYP1) catalyze metabolic activation of procarcinogens and deactivation of certain anticancer drugs. Inhibition of these enzymes is a potential approach for cancer chemoprevention and treatment of CYP1-mediated drug resistance. We characterized inhibition of human CYP1A1, CYP1A2, and CYP1B1 enzymes by the novel inhibitor N-(3,5-dichlorophenyl)cyclopropanecarboxamide (DCPCC) and α-naphthoflavone (ANF). Depending on substrate, IC50 values of DCPCC for CYP1A1 or CYP1B1 were 10-95 times higher than for CYP1A2. IC50 of DCPCC for CYP1A2 was 100-fold lower than for enzymes in CYP2 and CYP3 families. DCPCC IC50 values were 10-680 times higher than the ones of ANF. DCPCC was a mixed-type inhibitor of CYP1A2. ANF was a competitive tight-binding inhibitor of CYP1A1, CYP1A2, and CYP1B1. CYP1A1 oxidized DCPCC more rapidly than CYP1A2 or CYP1B1 to the same metabolite. Molecular dynamics simulations and binding free energy calculations explained the differences of binding of DCPCC and ANF to the active sites of all three CYP1 enzymes. We conclude that DCPCC is a more selective inhibitor for CYP1A2 than ANF. DCPCC is a candidate structure to modulate CYP1A2-mediated metabolism of procarcinogens and anticancer drugs.

中文翻译：

经典抑制剂α-萘黄酮和新型抑制剂N-（3,5-二氯苯基）环丙烷甲酰胺对人CYP1酶的抑制作用：一项体外和计算机模拟研究。

细胞色素P450家族1（CYP1）中的酶催化致癌物的代谢活化和某些抗癌药的失活。抑制这些酶是癌症化学预防和CYP1介导的耐药性治疗的潜在方法。我们表征了新型抑制剂N-（3,5-二氯苯基）环丙烷甲酰胺（DCPCC）和α-萘黄酮（ANF）对人CYP1A1，CYP1A2和CYP1B1酶的抑制作用。取决于底物，CYP1A1或CYP1B1的DCPCC的IC50值比CYP1A2高10-95倍。CYP1A2的DCPCC的IC50比CYP2和CYP3家族的酶的IC50低100倍。DCPCC IC50值是ANF的10-680倍。DCPCC是CYP1A2的混合型抑制剂。ANF是CYP1A1，CYP1A2和CYP1B1的竞争性紧密结合抑制剂。CYP1A1氧化DCPCC比CYP1A2或CYP1B1更快地氧化为同一代谢物。分子动力学模拟和结合自由能计算解释了DCPCC和ANF与所有三种CYP1酶的活性位点结合的差异。我们得出结论，DCPCC比ANF对CYP1A2更具选择性。DCPCC是调节CYP1A2介导的致癌物和抗癌药代谢的候选结构。

更新日期：2020-03-09

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11