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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >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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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

机译：多尺度分子建模方法与实验中的多尺度分子建模方法在硅引导设计和发现的新细胞中性抗高血压恶唑酮和咪唑酮衍生物的分析及其潜在限制对细胞增殖的影响分析

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Abstract 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 [ 125 I-Sar 1 -Ile 8 ] AngII. Among the compounds tested, 19d and 9j molecules 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 molecule 19d led 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, 19d induced G2/M cell cycle arrest in a concentration dependent manner. Adherent cells detached from the plates and underwent cell death possibly due to apoptosis at 19d concentrations that induced cell cycle arrest. Graphical abstract Display Omitted Highlights ? It is found that oxazolone and imidazolone derivatives show high affinity to AT1 receptor. ? In Silico -guided designed hit molecules were synthesized. ? Synthesized molecules were tested for their affinities to human AT1 receptor in radioligand binding studies. ? Cytotoxicity, wound healing assays and cell cycle analysis were performed for these hit molecules. ? In two cell lines tested, 19d induced G2/M cell cycle arrest in a concentration dependent manner.
机译：摘要AT1拮抗剂是最新药物类别的针对高血压的分子，它们通过阻断II（A-II）对I型（AT1）A-II受体的影响而介导其作用。 AT1拮抗剂的效果不限于心血管疾病。 AT1受体阻滞剂可用作潜在的抗癌剂 - 由于A-II刺激的细胞增殖抑制。因此，AT1受体和A-II生物合成机制是开发新的合成药物和各种心血管和其他疾病的治疗治疗的目标。在这项工作中，进行多尺度分子建模方法，并发现恶唑酮和咪唑酮衍生物揭示与AT1受体的结合位点的FDA批准的Sartan分子相比类似/更好的相互作用能谱。然后在硅导设计的击中分子中合成并测试其在放射性配体结合研究中对人AT1受体的结合亲和力，使用[125 I-SAR1 -1-8] Angii。在测试的化合物中，19D和9J分子以剂量反应方式和相对高的亲和力结合受体。接下来，对这些击中分子进行细胞毒性和伤口愈合测定。由于在本研究中测试的所有三种细胞系（NIH3T3，A549和H358）中的所有三种细胞系（NIH3T3，A549和H358）导致了细胞运动的减速，因此在进一步测试中研究了该分子。在两条细胞系（HUVEC和MCF-7）中测试，19D诱导浓度依赖性方式的G2 / M细胞周期停滞。由于19D浓度诱导细胞周期停滞的19D浓度，可能是由于凋亡的粘附细胞和接受细胞死亡。图形抽象显示省略了亮点？发现恶唑酮和咪唑酮衍生物对AT1受体具有高亲和力。还是在Silico -guideDive设计的命中分子中合成。还是在放射性配体结合研究中测试合成分子对人AT1受体的亲和力。还是对这些击中分子进行细胞毒性，伤口愈合测定和细胞循环分析。还是在两条测试中，19D诱导浓度依赖性方式诱导G2 / M细胞循环捕获。

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