Gul Kainat, Zaman Naila, Azam Syed Sikander
Computational Biology Lab, National Centre for Bioinformatics (NCB), Quaid-i-Azam University, Islamabad, Pakistan.
J Mol Graph Model. 2023 May;120:108422. doi: 10.1016/j.jmgm.2023.108422. Epub 2023 Jan 21.
Roxadustat, a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase domain 2 (HIF-PHD2) has been recently overruled by the American Food and Drug Administration (FDA) in Phase 3 clinical trials. This study provides insights into the dynamics of Roxadustat with PHD2 and proposes two FDA-approved drugs; Pemetrexed and Valrubicin to treat chronic kidney disease (CKD). Role of chemical scaffolds such as synthetic pyrimidine-based antifolate is found critical for PHD2 inhibitory activity, which is concurrent with the experimental findings for stimulating Endogenous erythropoietin (EPO) gene expression. Furthermore, Fe and Mn in solution are essential for imparting structural stability to the screened carboxylic and non-carboxylic acid drugs. Comparative analysis of FDA-approved drugs namely, Roxadustat, two-hit carboxylic, and non-carboxylic-acid type compounds (Pemetrexed and Valrubicin), as well as the control ligands (KU1 and 4JR), unveil structural dynamics of Roxadustat and its failure. However, the proposed FDA compounds, Pemetrexed and Valrubicin, used to treat mesothelioma, non-small cell lung cancer, and bladder cancer should be subjected to in vitro analysis for renal anemia.
罗沙司他是一种缺氧诱导因子脯氨酰羟化酶结构域2（HIF-PHD2）的小分子抑制剂，最近在美国食品药品监督管理局（FDA）的3期临床试验中被否决。本研究深入探讨了罗沙司他与PHD2的相互作用动态，并提出了两种FDA批准的药物：培美曲塞和瓦鲁比星，用于治疗慢性肾脏病（CKD）。研究发现，合成嘧啶类抗叶酸等化学支架对PHD2抑制活性至关重要，这与刺激内源性促红细胞生成素（EPO）基因表达的实验结果一致。此外，溶液中的铁和锰对于赋予筛选出的羧酸类和非羧酸类药物结构稳定性至关重要。对FDA批准的药物罗沙司他、双靶点羧酸类和非羧酸类化合物（培美曲塞和瓦鲁比星）以及对照配体（KU1和4JR）的比较分析，揭示了罗沙司他的结构动态及其失败原因。然而，拟用于治疗间皮瘤、非小细胞肺癌和膀胱癌的FDA批准化合物培美曲塞和瓦鲁比星，应进行肾性贫血的体外分析。
