Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation.
Integration of multi-scale molecular modeling approaches with experiments for the in silico guided design and discovery of novel hERG-Neutral antihypertensive oxazalone and imidazolone derivatives and analysis of their potential restrictive effects on cell proliferation.
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DOI：
10.1016/j.ejmech.2017.12.021
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发表时间：
2018-02
影响因子：
6.7
通讯作者：
S. Durdağı;B. Aksoydan;I. Erol;I. Kantarcioglu;Y. Ergun;G. Bulut;M. Acar;Timucin Avşar;G. Liapakis;Vlasios Karageorgos;R. E. Salmas;Baris Sergi;S. Alkhatib;Gizem Turan;Berfu Nur Yigit;Kutay Cantasir;B. Kurt;T. KiliÇ
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文献类型：
--
作者：
S. Durdağı;B. Aksoydan;I. Erol;I. Kantarcioglu;Y. Ergun;G. Bulut;M. Acar;Timucin Avşar;G. Liapakis;Vlasios Karageorgos;R. E. Salmas;Baris Sergi;S. Alkhatib;Gizem Turan;Berfu Nur Yigit;Kutay Cantasir;B. Kurt;T. KiliÇ
AT1拮抗剂是最新的抗高血压药物，它们通过阻断血管紧张素II(A-II)对I型(AT1)A-II受体的有害影响来介导其作用。AT1拮抗剂的作用并不局限于心血管疾病。AT1受体阻滞剂可能被用作潜在的抗癌药物--由于抑制了A-II刺激的细胞增殖。因此，AT1受体和A-II生物合成机制是开发新的合成药物和治疗各种心血管疾病和其他疾病的靶点。在这项工作中，采用多尺度分子模拟方法，发现恶唑酮和咪唑酮衍生物在AT1受体的结合部位显示出与FDA批准的Sartan分子相似/更好的相互作用能量分布。然后在硅胶引导下合成设计的HIT分子，并使用[125I-Sar1-Ile8]Angii进行放射配基结合研究，测试它们与人AT1受体的结合亲和力。在所测试的化合物中，有19d9个分子以剂量反应的方式与受体结合，并且具有较高的亲和力。接下来，对这些HIT分子进行细胞毒性和伤口愈合试验。由于HIT分子19导致本研究中测试的所有三种细胞系(NIH3T3、A549和H358)的细胞运动减速，因此该分子将在进一步的测试中进行研究。在两种细胞系(HUVEC和MCF-7)中，19d以浓度依赖的方式诱导G2/M期细胞周期停滞。贴壁细胞从平板上脱落，并经历细胞死亡，可能是由于19d浓度的凋亡导致细胞周期停滞。
AT1 antagonists is the most recent drug class of molecules against hypertension and they mediate their actions through blocking detrimental effects of angiotensin II (A-II) when acts on type I (AT1) A-II receptor. The effects of AT1 antagonists are not limited to cardiovascular diseases. AT1 receptor blockers may be used as potential anti-cancer agents – due to the inhibition of cell proliferation stimulated by A-II. Therefore, AT1 receptors and the A-II biosynthesis mechanisms are targets for the development of new synthetic drugs and therapeutic treatment of various cardiovascular and other diseases. In this work, multi-scale molecular modeling approaches were performed and it is found that oxazolone and imidazolone derivatives reveal similar/better interaction energy profiles compared to the FDA approved sartan molecules at the binding site of the AT1 receptor.In silico-guided designed hit molecules were then synthesized and tested for their binding affinities to human AT1 receptor in radioligand binding studies, using [125I-Sar1-Ile8] AngII. Among the compounds tested,19dand9jmolecules bound to receptor in a dose response manner and with relatively high affinities. Next, cytotoxicity and wound healing assays were performed for these hit molecules. Since hit molecule19dled to deceleration of cell motility in all three cell lines (NIH3T3, A549, and H358) tested in this study, this molecule is investigated in further tests. In two cell lines (HUVEC and MCF-7) tested,19dinduced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at19dconcentrations that induced cell cycle arrest.