Baptista Luiz Phillippe R, Sinatti Vanessa Vc, Da Silva Joao Hm, Dardenne Laurent Emmanuel, Guimarães Ana Carolina
Laboratory for Functional Genomics and Bioinformatics, Fiocruz, Oswaldo Cruz Institute, Rio de Janeiro, RJ, Brazil.
Group for Computational Modelling, Fiocruz, Oswaldo Cruz Foundation, Eusébio, CE, Brazil.
Adv Appl Bioinform Chem. 2019 Aug 7;12:15-32. doi: 10.2147/AABC.S197119. eCollection 2019.
Lung cancer is the leading cause of cancer-related death worldwide. Among its subtypes, non-small cell lung cancer (NSCLC) is the most common. Recently, the mitochondrial isoform of the enzyme phosphoenolpyruvate carboxykinase (HsPEPCK-M) was identified as responsible for the metabolic adaptation in the NSCLC allowing tumor growth even under conditions of glucose deficiency. This adaptation is possible due to the role of HsPEPCK-M in gluconeogenesis, converting the oxaloacetate to phosphoenolpyruvate in the presence of GTP, which plays an important role in the energetic support of these tumors. In this context, it was shown that the inhibition or knockdown of this enzyme was able to induce apoptosis in NSCLC under low glucose conditions.
In this study, novel putative inhibitors were proposed for the human PEPCK-M (HsPEPCK-M) based on a computer-aided approach.
Comparative modeling was used to generate 3D models for HsPEPCK-M. Subsequently, the set of natural compounds of the ZINC database was screened against HsPEPCK-M models using structure-based pharmacophore modeling and molecular docking approaches. The selected compounds were evaluated according to its chemical diversity and clustered based on chemical similarity.
The pharmacophore hypotheses, generated based on known PEPCK inhibitors, were able to select 7,124 candidate compounds. These compounds were submitted to molecular docking studies using three conformations of HsPEPCK-M generated by comparative modeling. The aim was to select compounds with high predicted binding affinity for at least one of the conformations of HsPEPCK-M. After molecular docking, 612 molecules were selected as potential inhibitors of HsPEPCK-M. These compounds were clustered according to their structural similarity. Chemical profiling and binding mode analyses of these compounds allowed the proposal of four promising compounds: ZINC01656421, ZINC895296, ZINC00895535 and ZINC02571340.
These compounds may be considered as potential candidates for HsPEPCK-M inhibitors and may also be used as lead compounds for the development of novel HsPEPCK-M inhibitors.
肺癌是全球癌症相关死亡的主要原因。在其亚型中，非小细胞肺癌（NSCLC）最为常见。最近，磷酸烯醇丙酮酸羧激酶的线粒体同工型（HsPEPCK-M）被确定为NSCLC代谢适应的原因，即使在葡萄糖缺乏的情况下也能使肿瘤生长。这种适应是可能的，因为HsPEPCK-M在糖异生中发挥作用，在GTP存在的情况下将草酰乙酸转化为磷酸烯醇丙酮酸，这在这些肿瘤的能量支持中起重要作用。在这种情况下，研究表明该酶的抑制或敲低能够在低葡萄糖条件下诱导NSCLC细胞凋亡。
在本研究中，基于计算机辅助方法提出了针对人PEPCK-M（HsPEPCK-M）的新型假定抑制剂。
使用比较建模生成HsPEPCK-M的三维模型。随后，使用基于结构的药效团建模和分子对接方法，针对HsPEPCK-M模型筛选ZINC数据库中的天然化合物集。根据所选化合物的化学多样性进行评估，并基于化学相似性进行聚类。
基于已知的PEPCK抑制剂生成的药效团假说能够选择7124种候选化合物。使用通过比较建模生成的HsPEPCK-M的三种构象对这些化合物进行分子对接研究。目的是选择对HsPEPCK-M的至少一种构象具有高预测结合亲和力的化合物。分子对接后，612个分子被选为HsPEPCK-M的潜在抑制剂。这些化合物根据其结构相似性进行聚类。对这些化合物的化学分析和结合模式分析提出了四种有前景的化合物：ZINC01656421、ZINC895296、ZINC00895535和ZINC02571340。
这些化合物可被视为HsPEPCK-M抑制剂的潜在候选物，也可作为开发新型HsPEPCK-M抑制剂的先导化合物。
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