不可溶性磷酸二酯酶1 (PPA1) 在细胞代谢中起着重要作用，它促进了各种代谢过程的副产物 PPi-a 的水解，影响细胞生长和分化。PPA1酶的过度表达与患者存活率下降相关，并且被证明对肿瘤细胞动态产生影响，因此被视为治疗多种癌症的潜在治疗靶点，包括结直肠癌、弥漫性大B细胞淋巴瘤和肺腺癌。尽管有这种治疗前景，到目前为止还没有已知的PPA1抑制剂。在本研究中，我们使用具有临床试验和/或美国食品药品监督管理局批准历史的30,470种化合物进行了潜在的PPA1抑制剂的分子对接筛选。我们特别针对与已知催化结构域重合的活性口袋进行了筛选。我们筛选出了有希望的结果，并进一步对这些结果进行了吸收、分布、代谢、排泄和毒性 (ADMET) 过滤。接下来，我们对通过所有过滤的三种物质（devazepide，quinotolast和tarazepide）进行了分子动力学 (MD) 分析。MD分析加强了蛋白质-配体复合物的稳定性，并通过我们的均方根偏差、旋转半径和蛋白质二级结构分析证实了配体的结合。此外，MD后的分子力学泊松-玻尔兹曼表面积计算将devazepide和quinotolast作为具有较高结合亲和力的物质，得到主成分分析、自由能量景观和动态交叉相关矩阵结果的支持。总体而言，我们的研究揭示了devazepide和quinotolast作为潜在的PPA1抑制剂候选物，在需要进一步实验验证的复用研究中可予考虑。这些结果不仅揭示了PPA1抑制的潜在临床复用前景，而且为开发针对关键的PPA1酶的未来化合物提供了宝贵的见解。© 2023 The Authors. 由Wiley Periodicals LLC出版的Journal of Cellular Biochemistry.

Inorganic pyrophosphatase 1 (PPA1) is pivotal to cellular metabolism as it facilitates the hydrolysis of PPi-a by-product of various metabolic processes that influence cell growth and differentiation. Overexpression of PPA1 enzyme has been linked to diminished patient survival and was shown to influence tumor cell dynamics, thereby positioning it as a potential therapy target for a variety of cancers including colorectal cancer, diffuse large B-cell lymphoma, and lung adenocarcinoma. Despite this therapeutic promise, there are no known inhibitors of PPA1 as of today. In this study, we searched for potential PPA1 inhibitors using a molecular docking screen of 30 470 compounds with a history of clinical trials and/or US Food and Drug Administration approval. We specifically targeted the active pocket that coincides with the established catalytic domain. Our screen identified promising hits, which we further subjected to ADMET (absorption, distribution, metabolism, excretion, and toxicity) filtering. Subsequent molecular dynamics (MD) analyses were conducted on devazepide, quinotolast, and tarazepide-the three substances that successfully navigated all filters. MD analyses reinforced the stability of the protein-ligand complexes and confirmed ligand binding, as substantiated by our root mean square deviation, radius of gyration and secondary structures of proteins analyses. Furthermore, Molecular Mechanics Poisson-Boltzmann Surface Area calculations post-MD identified devazepide and quinotolast as showing higher binding affinities; being supported by principal component analysis, free energy landscape, and dynamic cross-correlation matrix results. Overall, our study reveals devazepide and quinotolast as potential candidates for PPA1 inhibition which could be considered for repurposing studies that need further experimental validation. These results not only reveal a potential for clinical repurposing for PPA1 inhibition but they also offer valuable insights into the development of future compounds for targeting the crucial PPA1 enzyme.© 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.