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Exploring pharmacophore of isoflavone derivatives for aromatase inhibition

机译：探索异黄酮衍生物的药效基团抑制芳香化酶

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The natural history of breast cancer suggests that many tumors are dependent upon estrogen for their development and continued growth. Aromatization of the steroidal 'A' ring is the rate limiting step for bioconversion of estrogen from androgen, and aromatase enzyme (CYP19) plays key role in the biosynthesis of estrogen. The enzyme possesses a prosthetic specific cytochrome P450 and a ubiquitous flavo-protein NADPH cytochrome P450 reductase. The key role of aromatase in estrogen biosynthesis has generated enormous interest in putative inhibitors of the enzyme and their use as therapy against endocrine responsive tumors. In view of such significance, 3D-QSAR studies have been explored to investigate the pharmacophore of isoflavone derivatives (Fig. 1) for inhibition of aromatase (CYP19) enzyme. The best model generated in classical QSAR study (^2=0.895, g2=0.726, i?2Ts =0.780) shows that substitutions by electron withdrawing group at atom Cu and electron rich groups at Oig are important for the activity. Further molecular ionization potential and steric factor also influence the inhibitory activity to CYP19. 3D QSAR study of Comparative Molecular Field Analysis (CoMFA, /?2=0.996, (7=0.841, #2ts=0.936) shows the importance of steric and electrostatic fields for the inhibitory activity. Similarly Comparative Molecular Similarity Analysis (CoMSIA, i?2=0.997, (7=0.802, i?2Ts=0.899) study signifies the importance of hydrogen bond acceptor and hydrophobic features in addition to steric and electrostatic force fields that play role in inhibiting the enzyme. Space modeling study (g2=0.859, Acost=105.597, 7?2Ts=0.912) adjudges the significance of hydrogen bond acceptor and hydrophobic features of the molecule and the critical distance among features are important for the inhibitor activity.
机译：乳腺癌的自然史表明，许多肿瘤的发展和持续生长都依赖于雌激素。甾体“ A”环的芳香化是雌激素从雄激素进行生物转化的限速步骤，芳香酶（CYP19）在雌激素的生物合成中起关键作用。该酶具有假体特异性细胞色素P450和泛黄素NADPH细胞色素P450还原酶。芳香化酶在雌激素生物合成中的关键作用引起了人们对该酶的抑制剂及其作为内分泌反应性肿瘤治疗的巨大兴趣。鉴于这种重要性，已经探索了3D-QSAR研究来研究异黄酮衍生物的药效基团（图1）用于抑制芳香化酶（CYP19）酶。在经典QSAR研究中生成的最佳模型（^ 2 = 0.895，g2 = 0.726，i？2Ts = 0.780）表明，原子Cu上的吸电子基团和Oig上的富电子基团的取代对于该活性很重要。进一步的分子电离势和空间位阻也影响对CYP19的抑制活性。比较分子场分析的3D QSAR研究（CoMFA，/?2=0.996，（7 = 0.841，＃2ts = 0.936））显示了空间和静电场对于抑制活性的重要性。 2 = 0.997，（7 = 0.802，i？2Ts = 0.899）研究表明，除了空间和静电力场在抑制酶方面发挥作用外，氢键受体和疏水特征也很重要。空间模型研究（g2 = 0.859， Acost ＝ 105.597，7≤2Ts ＝ 0.912）判断该分子的氢键受体和疏水特征的重要性，以及这些特征之间的临界距离对于抑制剂的活性很重要。

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