Yadav Piyush Kumar, Ojha Krishna Kumar, Kumar Anil, Singh Ajay Kumar
Department of Bioinformatics, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, India.
Department of Bioinformatics, Central University of South Bihar, Gaya, Bihar, India.
Comput Biol Med. 2025 Aug;194:110551. doi: 10.1016/j.compbiomed.2025.110551. Epub 2025 Jun 11.
Excessive body iron, also known as iron overload, occurs in thalassaemia patients who require blood transfusions. Iron overload causes iron accumulation in a variety of tissues, particularly in the liver, brain, heart, and endocrine tissues. Arrhythmias, dilated cardiomyopathy, and diastolic failure are caused by elevated cardiac iron levels. The removal of iron using an iron-chelating agent is the primary strategy for the treatment of iron overload. Deferasirox has been used in humans for half a century; however, it is less favoured by patients owing to intravenous administration and adverse effects. L-type calcium channel (LTCC) blockers have been shown to reduce excess iron in cardiomyocytes, liver cells, and nerve cells. The uptake of non-transferrin-bound iron (NTBI) in rat ventricular myocytes has been demonstrated to be mediated by the LTCC. In iron-overloaded animal models, the LTCC blocker nifedipine suppressed iron overload-mediated hepatocyte apoptosis and increased urine iron excretion. LTCC inhibitors also play a role in the regulation of renal iron transport. This in silico study utilized the bioactivity value (IC value) of known inhibitors for the 3D QSAR pharmacophore model was prepared. The selected model (Hypo1) was used to screen the library and was validated using a test set of compounds. The best-hit molecules were further investigated using virtual screening and molecular docking analysis. Top-ranked candidates were tested for toxicity, and their inhibitory activity and iron chelation efficacy were predicted. Finally, most chemical compounds were obtained with optimised docking scores, low estimated values, acceptable toxicity, and ADMET profiles. Through lead optimization, the Hit_1 compound was selected to design the novel inhibitor. The compound was screened using the pharmacophore derivative, and docking studies show an improved estimate of the novel compound's activity.
体内铁过量，也称为铁过载，发生在需要输血的地中海贫血患者中。铁过载会导致铁在多种组织中蓄积，尤其是在肝脏、大脑、心脏和内分泌组织中。心脏铁水平升高会导致心律失常、扩张型心肌病和舒张功能衰竭。使用铁螯合剂去除铁是治疗铁过载的主要策略。地拉罗司已在人类中使用了半个世纪；然而，由于静脉给药和不良反应，它不太受患者青睐。L型钙通道（LTCC）阻滞剂已被证明可减少心肌细胞、肝细胞和神经细胞中的过量铁。已证明大鼠心室肌细胞中非转铁蛋白结合铁（NTBI）的摄取是由LTCC介导的。在铁过载动物模型中，LTCC阻滞剂硝苯地平可抑制铁过载介导的肝细胞凋亡并增加尿铁排泄。LTCC抑制剂在肾脏铁转运的调节中也起作用。这项计算机模拟研究利用已知抑制剂的生物活性值（IC值）制备了3D QSAR药效团模型。使用所选模型（Hypo1）对文库进行筛选，并使用一组化合物进行验证。使用虚拟筛选和分子对接分析对最佳命中分子进行进一步研究。对排名靠前的候选物进行毒性测试，并预测其抑制活性和铁螯合功效。最后，获得了大多数具有优化对接分数、低估计值、可接受毒性和ADMET特性的化合物。通过先导优化，选择Hit_1化合物设计新型抑制剂。使用药效团衍生物对该化合物进行筛选，对接研究显示对新型化合物活性的估计有所改善。
