Khalid Hira, Sattar Farah, Ahmad Iqra, Junior Valdir Ferreira de Paula, Nishan Umar, Ullah Riaz, Dib Hanna, Omari Khaled W, Shah Mohibullah
Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan.
Postgraduate Program in Veterinary Sciences, Faculty of Veterinary Medicine, State University of Ceara, Fortaleza, Brazil.
Front Pharmacol. 2025 Jan 9;15:1512864. doi: 10.3389/fphar.2024.1512864. eCollection 2024.
Platelet-derived growth factor alpha (PDGFRA) plays a significant role in various malignant tumors. PDGFRA expression boosts thyroid cancer cell proliferation and metastasis. Radiorefractory thyroid cancer is poorly differentiated, very aggressive, and resistant to radioiodine therapy. Thus, novel anticancer drugs that inhibit its metastasis are urgently required. In this context, we proposed the PDGFRA inhibitors by an optimized structure-based drug design approach. We performed a virtual screening of metabolites derived from anticancer medicinal plants (Swertia chirayita, Myristica fragrans, and Datura metel) and successfully identified seven hits, namely cis-Grossamide K, Daturafoliside O, N-cis-feruloyltyramine, Maceneolignan H, Erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4, 5-trimethoxyphenyl) propan-1, 3-diol, Myrifralignan C, and stigmasteryl-3-O-β-glucoside as potential PDGFRA inhibitors. Not only the top 7 hits exhibited higher docking scores in docking simulation but also optimal drug-likeness and non-toxic profiles in pharmacokinetics analysis among 119 compounds. Our top hits are non-mutagenic, can cross the blood-brain barrier, and inhibit p-glycoprotein, while the N-cis-feruloyltyramine has the potential to become a lead compound. The protein-ligand stability of the top 3 hits, namely cis-Grossamide K, Daturafoliside O, and N-cis-feruloyltyramine, and their interactions at the potential binding site of target protein were confirmed through molecular dynamic simulations. We also analyzed pharmacophoric features for stable binding in the PDGFRA active site. These drug candidates were further characterized to predict their biological activity spectra in the human body and medicinal characteristics to know their extensive behavior in laboratory testing. This study necessitates the and studies to confirm the potential of our hits for the discovery of novel therapeutics against the thyroid cancer.
血小板衍生生长因子α（PDGFRA）在各种恶性肿瘤中发挥着重要作用。PDGFRA表达促进甲状腺癌细胞的增殖和转移。放射性难治性甲状腺癌分化不良、侵袭性强且对放射性碘治疗耐药。因此，迫切需要能够抑制其转移的新型抗癌药物。在此背景下，我们通过优化的基于结构的药物设计方法提出了PDGFRA抑制剂。我们对源自抗癌药用植物（獐牙菜、肉豆蔻和曼陀罗）的代谢产物进行了虚拟筛选，并成功鉴定出七个命中化合物，即顺式-格罗酰胺K、曼陀罗苷O、N-顺式阿魏酰酪胺、马塞新木脂素H、赤式-2-(4-烯丙基-2,6-二甲氧基苯氧基)-1-(3,4,5-三甲氧基苯基)丙烷-1,3-二醇、肉豆蔻新木脂素C和豆甾醇-3-O-β-葡萄糖苷作为潜在的PDGFRA抑制剂。在119种化合物中，不仅前七个命中化合物在对接模拟中表现出更高的对接分数，而且在药代动力学分析中具有最佳的类药性质和无毒特征。我们的顶级命中化合物无致突变性，可穿过血脑屏障并抑制P-糖蛋白，而N-顺式阿魏酰酪胺有潜力成为先导化合物。通过分子动力学模拟证实了前三个命中化合物，即顺式-格罗酰胺K、曼陀罗苷O和N-顺式阿魏酰酪胺的蛋白质-配体稳定性及其在靶蛋白潜在结合位点的相互作用。我们还分析了在PDGFRA活性位点稳定结合的药效团特征。对这些候选药物进行了进一步表征，以预测它们在人体中的生物活性谱和药用特性，从而了解它们在实验室测试中的广泛行为。这项研究需要进行 和 研究，以证实我们的命中化合物在发现针对甲状腺癌的新型疗法方面的潜力。
