Nagar Shuchi, Islam Md Ataul, Das Suvadra, Mukherjee Arup, Saha Achintya
Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata, 700009, India.
Mol Divers. 2008 Feb;12(1):65-76. doi: 10.1007/s11030-008-9077-9. Epub 2008 May 28.
Aromatase, which catalyses the final step in the steroidogenesis pathway of estrogen, has been target for the design of inhibitor in the treatment of hormone dependent breast cancer for postmenopausal women. The extensive SAR studies performed in the last 30 years to search for potent, selective and less toxic compounds, have led to the development of second and third generation of non-steroidal aromatase inhibitors (AI). Besides the development of synthetic compounds, several naturally occurring and synthetic flavonoids, which are ubiquitous natural phenolic compounds and mediate the host of biological activities, are found to demonstrate inhibitory effects on aromatase. The present study explores the pharmacophores, i.e., the structural requirements of flavones (Fig. 1) for inhibition of aromatase activity, using quantitative structure activity relationship (QSAR) and space modeling approaches. The classical QSAR studies generate the model (R (2) = 0.924, Q (2) = 0.895, s = 0.233) that shows the importance of aromatic rings A and C, along with substitutional requirements in meta and para positions of ring C for the activity. 3D QSAR of Comparative Molecular Field Analysis (CoMFA, R (2) = 0.996, R(2)(cv) = 0.791) and Comparative Molecular Similarity Analysis (CoMSIA, R (2) = 0.992, R(2)(cv) = 0.806) studies show contour maps of steric and hydrophobic properties and contribution of acceptor and donor of the molecule, suggesting the presence of steric hindrance due to ring C and R''-substituent, bulky hydrophobic substitution in ring A, along with acceptors at positions 11, and alpha and gamma of imidazole ring, and donor in ring C favor the inhibitory activity. Further space modeling (CATALYST) study (R = 0.941, Delta( cost ) = 96.96, rmsd = 0.876) adjudge the presence of hydrogen bond acceptor (keto functional group), hydrophobic (ring A) and aromatic rings (steric hindrance) along with critical distance among features are important for the inhibitory activity.
芳香化酶催化雌激素甾体生成途径的最后一步，一直是绝经后女性激素依赖性乳腺癌治疗中抑制剂设计的靶点。在过去30年中进行了广泛的构效关系研究，以寻找高效、选择性高且毒性较小的化合物，从而推动了第二代和第三代非甾体芳香化酶抑制剂（AI）的开发。除了合成化合物的开发外，人们还发现几种天然存在的和合成的黄酮类化合物（它们是普遍存在的天然酚类化合物，具有多种生物学活性）对芳香化酶具有抑制作用。本研究采用定量构效关系（QSAR）和空间建模方法，探索黄酮类化合物（图1）抑制芳香化酶活性的药效基团，即结构要求。经典的QSAR研究生成了模型（R (2) = 0.924，Q (2) = 0.895，s = 0.233），该模型表明芳香环A和C的重要性，以及环C间位和对位的取代要求对活性的影响。比较分子场分析（CoMFA，R (2) = 0.996，R(2)(cv) = 0.791）和比较分子相似性分析（CoMSIA，R (2) = 0.992，R(2)(cv) = 0.806）的三维QSAR研究显示了空间和疏水性质的等高线图以及分子中受体和供体的贡献，表明环C和R''-取代基存在空间位阻、环A上有庞大的疏水取代基，以及咪唑环11位、α位和γ位的受体和环C中的供体有利于抑制活性。进一步的空间建模（CATALYST）研究（R = 0.941，Delta( cost ) = 96.96，rmsd = 0.876）判定氢键受体（酮官能团）、疏水基团（环A）和芳香环（空间位阻）的存在以及各特征之间的临界距离对抑制活性很重要。
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