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Computational investigations of the binding mechanism of novel benzophenone imine inhibitors for the treatment of breast cancer

机译：新型二苯甲酮亚胺抑制剂与乳腺癌的结合机理的计算研究

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4-Hydroxytamoxifen ( 4-OHT ), the most common hormone used for the treatment of breast cancer, is a selective estrogen receptor modulator (SERM) inhibitor that acts as an antagonist in breast tissue and a partial agonist in the endometrium. However, the detailed molecular mechanism of 4-OHT structure modification has not been well investigated to date. Herein, molecular docking, molecular dynamics simulations and free energy calculations were performed to explore the mechanisms of the molecular interactions between newly designed benzophenone imines (BIs) and the three forms apo, antagonist and agonist of the human estrogen receptor hERα. The proposed inhibitors were designed by replacing the triarylethylene estrogenic scaffold found in 4-OHT with Schiff base triarylimine derivatives. The antiestrogen scaffold i.e. the O -alkyl side chain in 4-OHT was developed by incorporating an alanine amino acid side chain functionality into the triarylimine scaffold. Docking results reveal that the newly designed BIs bind to the hydrophobic open pocket of the apo and antagonist hERα conformations with higher affinity as compared to the natural and synthetic estrogen estradiol ( E2 ) and 4-OHT . The analysis of the molecular dynamics simulation results based on six different systems of the best docked BI ( 5c ) with hERα receptors demonstrates stable interactions, and the complex undergoes fewer conformational fluctuations in the open apo/antagonist hERα receptors as compared to the case of the closed agonist. In addition, the calculated binding free energies indicate that the main factor that contributes to the stabilization of the receptor–inhibitor complexes is hydrophobic interactions. This study suggests that the development of these Schiff base derivatives may be worth exploring for the preparation of new 4-OHT analogues.
机译：4-羟基他莫昔芬（4-OHT）是用于治疗乳腺癌的最常见激素，是一种选择性雌激素受体调节剂（SERM）抑制剂，可作为乳腺组织的拮抗剂和子宫内膜的部分激动剂。然而，迄今为止，尚未对4-OHT结构修饰的详细分子机理进行深入研究。本文中，进行了分子对接，分子动力学模拟和自由能计算，以探索新设计的二苯甲酮亚胺（BIs）与人类雌激素受体hERα的三种形式载脂蛋白，拮抗剂和激动剂之间的分子相互作用机理。拟议的抑制剂是通过用Schiff碱三芳嘌呤衍生物代替在4-OHT中发现的三芳基乙烯雌激素骨架而设计的。抗雌激素支架，即4-OHT中的O-烷基侧链是通过将丙氨酸氨基酸侧链官能团掺入到三芳嘌呤支架中而开发出来的。对接结果显示，与天然和合成雌激素雌二醇（E2）和4-OHT相比，新设计的BI与apo和拮抗hERα构象的疏水开放口袋结合具有更高的亲和力。分子动力学模拟结果的分析基于具有hERα受体的最佳对接BI（5c）的六个不同系统，显示了稳定的相互作用，并且与开环的apo /拮抗剂hERα受体相比，该复合物的构象波动较小。封闭激动剂。另外，计算的结合自由能表明，导致受体-抑制剂复合物稳定的主要因素是疏水相互作用。这项研究表明，这些席夫碱衍生物的开发可能值得探索新的4-OHT类似物的制备。

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