Asadi Parvin, Khodarahmi Ghadamali, Farrokhpour Hossein, Hassanzadeh Farshid, Saghaei Lotfollah
Department of Medicinal Chemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.
Department of Chemistry, Isfahan University of Technology, Isfahan, I.R. Iran.
Res Pharm Sci. 2017 Jun;12(3):233-240. doi: 10.4103/1735-5362.207204.
In an attempt to identify some new potential leads as anti-breast cancer agents, novel hybrid compounds were designed by molecular hybridization approach. These derivatives were structurally derived from hybrid benzofuran-imidazole and quinazolinone derivatives, which had shown good cytotoxicity against the breast cancer cell line (MCF-7). Since aromatase enzyme (CYP19) is highly expressed in the MCF-7 cell line, the binding of these novel hybrid compounds to aromatase was investigated using the docking method. In this study, due to the positive charge on the imidazole ring of the designed ligands and also, the presence of heme iron in the active site of the enzyme, it was decided to optimize the ligand inside the protein to obtain more realistic atomic charges for it. Quantum mechanical/molecular mechanical (QM/MM) method was used to obtain more accurate atomic charges of ligand for docking calculations by considering the polarization effects of CYP19 on ligands. It was observed that the refitted charge improved the binding energy of the docked compounds. Also, the results showed that these novel hybrid compounds were adopted properly within the aromatase binding site, thereby suggesting that they could be potential inhibitors of aromatase. The main binding modes in these complexes were through hydrophobic and H bond interactions showing agreement with the basic physicochemical features of known anti aromatase compounds. Finally, the complex structures obtained from the docking study were used for single point QM/MM calculations to obtain more accurate electronic interaction energy, considering the electronic polarization of the ligand by its protein environment.
为了确定一些新的潜在抗乳腺癌药物先导物，采用分子杂交方法设计了新型杂化化合物。这些衍生物在结构上源自杂化苯并呋喃 - 咪唑和喹唑啉酮衍生物，它们对乳腺癌细胞系（MCF - 7）显示出良好的细胞毒性。由于芳香化酶（CYP19）在MCF - 7细胞系中高度表达，使用对接方法研究了这些新型杂化化合物与芳香化酶的结合。在本研究中，由于设计配体的咪唑环上带正电荷，且酶的活性位点存在血红素铁，因此决定在蛋白质内部优化配体，以获得更符合实际的原子电荷。通过考虑CYP19对配体的极化效应，采用量子力学/分子力学（QM/MM）方法获得更准确的配体原子电荷用于对接计算。观察到重新拟合的电荷提高了对接化合物的结合能。此外，结果表明这些新型杂化化合物能够很好地适配于芳香化酶结合位点，从而表明它们可能是芳香化酶的潜在抑制剂。这些复合物中的主要结合模式是通过疏水和氢键相互作用，这与已知抗芳香化酶化合物的基本物理化学特征一致。最后，对接研究得到的复合物结构用于单点QM/MM计算，以考虑配体在其蛋白质环境中的电子极化，从而获得更准确的电子相互作用能。
