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Synthesis and Molecular Simulation Studies of Mandelic Acid Peptidomimetic Derivatives as Aminopeptidase N Inhibitors
Current Computer-Aided Drug Design ( IF 1.7 ) Pub Date : 2021-07-31 , DOI: 10.2174/1573409916666200703161039
Jiawei Chen 1 , Qiaoli Lv 2 , Guogang Tu 1
Affiliation  

Background: The aminopeptidase N (APN) over-expressed in tumor cells plays a critical role in angiogenesis which makes the development of APN inhibitors an attractive strategy for cancer research.

Aims and Objectives: It is clinically significant to develop potential APN inhibitors for cancer treatment. The design, synthesis, biological evaluation and molecular simulation of mandelic acid peptidomimetic derivatives as APN inhibitors are reported.

Materials and Methods: Analysis of the binding mode of bestatin to APN led to the design and synthesis of mandelic acid peptidomimetic derivatives. APN inhibitory activities in vitro were evaluated by the spectrophotometric method. The binding mode of the target compounds with the APN binding site was studied relying on docking studies, molecular dynamics simulation experiments and binding energies calculation.

Results: The structures of target compounds were confirmed by IR, 1H-NMR and MS. All compounds exhibited a different range of inhibitory ability with IC50 values lying in the micromolar level. The compound 9m was found to be most potent as compared to other target derivatives. The molecular simulation revealed that ligand coordinating with the catalytic zinc ion is very important for inhibitory activities.

Conclusion: The compound 9m might represent a promising scaffold for the further development of novel anti-cancer drugs.



中文翻译:

扁桃酸肽模拟物作为氨基肽酶 N 抑制剂的合成和分子模拟研究

背景:在肿瘤细胞中过表达的氨肽酶 N (APN) 在血管生成中起关键作用,这使得 APN 抑制剂的开发成为癌症研究的有吸引力的策略。

目的和目的:开发用于癌症治疗的潜在APN抑制剂具有临床意义。报道了扁桃酸拟肽衍生物作为 APN 抑制剂的设计、合成、生物学评价和分子模拟。

材料和方法:分析 bestatin 与 APN 的结合模式导致了扁桃酸拟肽衍生物的设计和合成。通过分光光度法评估体外 APN 抑制活性。通过对接研究、分子动力学模拟实验和结合能计算,研究了目标化合物与APN结合位点的结合方式。

结果:目标化合物的结构经IR、1H-NMR和MS确证。所有化合物都表现出不同范围的抑制能力,IC50 值在微摩尔水平。发现化合物 9m 与其他目标衍生物相比最有效。分子模拟表明,与催化锌离子配位的配体对于抑制活性非常重要。

结论:化合物9m可能代表一种有前途的支架,用于进一步开发新型抗癌药物。

更新日期:2021-07-31
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