3D-QSAR based computational screening of potent ligands against L-type calcium channel (LTCC) protein structure for iron overload in β-thalassemia.

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 (IC50 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.