Department of Chemical Technology, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India.
J Comput Chem. 2010 Sep;31(12):2342-53. doi: 10.1002/jcc.21528.
Aromatase is an enzyme that catalyzes the final step in the conversion of androgen to estrogen. It has become an attractive target for the treatment of estrogen responsive breast cancer. The study has been focused on designing aromatase inhibitors (AIs) that can be selected as probable drug candidate for the treatment of breast cancer. In the present study, long chain diarylalkyl-imidazole and -triazole scaffolds have been considered for exploring pharmacophores as potent AIs using QSAR (Quantitative SAR) and pharmacophore mapping studies. The model generated in linear free energy QSAR study (R(2) = 0.905, Q(2)= 0.885, R(2)(pred(ts)) = 0.763) showed the importance of hydrophobicity, size and shape of the molecule, van der Waals surface and hydrogen atom contribution influence the activity. 3D QSAR of comparative molecular field analysis (CoMFA, R(2)= 0.921, Q(2) = 0.741, R(2)(pred(ts))= 0.583) showed that steric and electrostatic features along with hydrophobicity and electronic charge contribution at C(4) (Fig. 1) influence on the inhibitory activity. Comparative molecular similarity analysis (CoMSIA, R(2) = 0.874, Q(2) = 0.716, R(2)(pred(ts)) = 0.591) study adjudged the presence of steric, electrostatic and hydrophobic fields together with hydrogen bond (HB) donor and acceptor play significant role in inhibitory activity to aromatase enzyme. Further pharmacophore mapping study (Q(2) = 0.947, Delta(cost) = 113.171, R(2)(pred(ts)) = 0.857) suggested that presence of HB acceptor, hydrophobicity with aromatic ring, and the importance of steric contribution influence on the activity. The critical distances among the features are also important for the inhibitor activity.
芳香酶是一种酶，可催化雄激素向雌激素转化的最后一步。它已成为治疗雌激素反应性乳腺癌的有吸引力的靶标。该研究一直专注于设计芳香酶抑制剂 (AIs)，可以作为治疗乳腺癌的候选药物。在本研究中，长链二芳基烷基咪唑和三唑支架已被考虑用于探索作为潜在 AI 的药效团，使用 QSAR（定量 SAR）和药效团映射研究。线性自由能 QSAR 研究中生成的模型（R(2) = 0.905，Q(2)= 0.885，R(2)(pred(ts)) = 0.763）表明，分子的疏水性、大小和形状、范德华表面和氢键供体和受体对活性有重要影响。比较分子场分析（CoMFA，R(2)= 0.921，Q(2) = 0.741，R(2)(pred(ts))= 0.583）的 3D-QSAR 表明，立体和静电特征以及 C(4)处的疏水性和电子电荷贡献（图 1）对抑制活性有影响。比较分子相似性分析（CoMSIA，R(2) = 0.874，Q(2) = 0.716，R(2)(pred(ts)) = 0.591）研究判断，立体、静电和疏水性场以及氢键供体和受体的存在对芳香酶酶的抑制活性起着重要作用。进一步的药效团映射研究（Q(2) = 0.947，Delta(cost) = 113.171，R(2)(pred(ts)) = 0.857）表明，氢键受体、芳香环的疏水性以及立体贡献的重要性对活性有影响。特征之间的临界距离对抑制剂活性也很重要。
