Baig Muhammad Waleed, Nasir Bakht, Waseem Durdana, Majid Muhammad, Khan Muhammad Zafar Irshad, Haq Ihsan-Ul
Department of Pharmacy, Quaid-i-Azam University, Islamabad 45320, Pakistan.
Department of Pharmacy, Capital University of Science and Technology, Islamabad, Pakistan.
Saudi Pharm J. 2020 Dec;28(12):1526-1537. doi: 10.1016/j.jsps.2020.09.021. Epub 2020 Oct 6.
Withanolides are natural medicinal agents whose safety and therapeutic profiles make them valuable to mankind. Among multiple withanolides, withametelin is underexplored. The present study was aimed to create a general biological profile of isolated withametelin from Mill. targeting different biological models. studies include drug-likeliness, pharmacokinetics, toxicity, molecular targets and cytotoxicity to cancer cell lines predictions. directed preliminary evaluation comprised of cancer/normal cell cytotoxicity, DPPH and protein kinase inhibition assays while bioactivities include antiinflammatory, analgesic, antidepressant and anticoagulant assays. Pharmacological findings were strengthened by molecular docking studies to check interactions with various proteins and to propose the future path of studies. Results indicated compliance with Lipinski drug-likeliness rule (score -0.55). ADMET prediction showed strong plasma protein binding, GI absorption (Caco-2 cells permeability = 46.74 nm/s), blood brain barrier penetration (Cbrain/Cblood = 0.31), efflux by P-glycoprotein, metabolism by CYP1A2, CYP2C19 and CYP3A4, medium hERG inhibition and non-carcinogenicity in rodents. Predicted molecular targets included mainly receptors (glucocorticoid, kappa opioid, delta opioid, adrenergic and dopamine), oxidoreductase (arachidonate 5-lipoxygenase and cyclooxygenase-2), enzymes (HMG-CoA reductase) and kinase (NFκb). Withametelin was more cytotoxic to cancer cells (DU145 IC 7.67 ± 0.54 µM) than normal lymphocytes (IC 33.55 ± 1.31 µM). It also showed good antioxidant and protein kinase inhibition potentials. Furthermore, withametelin (20 mg/kg) significantly reduced inflammatory paw edema (68.94 ± 5.55%), heat-induced pain (78.94 ± 6.87%) and immobility time (50%) in animals. Molecular docking showed hydrogen bonding interactions (binding energies: -11.3 to -7.8 kcal/mol) with arachidonate 5 lipoxygenase, NFκb and glucocorticoid receptor. Withametelin has potential for advance investigations for its cytotoxic, anti-inflammatory, analgesic and antidepressant activities.
睡茄内酯是天然药物，其安全性和治疗特性使其对人类具有重要价值。在多种睡茄内酯中，维胺酯的研究较少。本研究旨在针对不同生物模型，建立从 中分离出的维胺酯的一般生物学特征。研究包括药物相似性、药代动力学、毒性、分子靶点以及对癌细胞系的细胞毒性预测。定向初步评估包括癌症/正常细胞细胞毒性、DPPH 和蛋白激酶抑制试验，而生物活性包括抗炎、镇痛、抗抑郁和抗凝试验。通过分子对接研究来验证与各种蛋白质的相互作用并提出未来的研究方向，从而强化药理学研究结果。结果表明其符合 Lipinski 药物相似性规则（分数为 -0.55）。ADMET 预测显示其具有较强的血浆蛋白结合能力、胃肠道吸收能力（Caco-2 细胞通透性 = 46.74 nm/s）、血脑屏障穿透能力（Cbrain/Cblood = 0.31）、P-糖蛋白外排、经 CYP1A2、CYP2C19 和 CYP3A4 代谢、中等程度的 hERG 抑制以及在啮齿动物中无致癌性。预测的分子靶点主要包括受体（糖皮质激素、κ 阿片受体、δ 阿片受体、肾上腺素能受体和多巴胺受体）、氧化还原酶（花生四烯酸 5-脂氧合酶和环氧化酶-2）、酶（HMG-CoA 还原酶）和激酶（NFκb）。维胺酯对癌细胞（DU145，IC 7.67 ± 0.54 µM）的细胞毒性比对正常淋巴细胞（IC 33.55 ± 1.31 µM）更强。它还表现出良好的抗氧化和蛋白激酶抑制潜力。此外，维胺酯（20 mg/kg）可显著减轻动物的炎性爪肿胀（68.94 ± 5.55%）、热诱导疼痛（78.94 ± 6.87%）和不动时间（50%）。分子对接显示其与花生四烯酸 5-脂氧合酶、NFκb 和糖皮质激素受体存在氢键相互作用（结合能：-11.3 至 -7.8 kcal/mol）。维胺酯因其细胞毒性、抗炎、镇痛和抗抑郁活性具有进一步研究的潜力。
