The main ground cause of GD is the binding of circulating IgG antibodies to G-protein– coupled thyrotropin receptor (TSHR), resulting in the activation of Thyroglobulin gene which codes for thyroid hormonestriiodothyronine (T3) and thyroxine (T4). GD has reported a frequency of 20-30 cases per 100,000 individuals each year, with the possibility 3% of women and 0.5% of men acquiring GD during their lifetime. It is one of the major causes of hyperthyroidism in the geographical areas with Iodine abundance. Graves' disease (GD) is an autoimmune Thyroid disorder (AITD), typically characterized by the presence of thyrotoxicosis, goiter, and ophthalmopathy (Grave’s ophthalmopathy). Graves’ disease Thyroid peroxidase Methimazole Propylthiouracil Molecular dynamics MM-PBSA/GBSA Introduction Since both drugs engage residues- Asp238, His239 and His494 which falls within the proximal heme binding site and catalytic site of TPO201-500, we can conclude that these drugs may be conducive in inhibiting the enzymatic activity of TPO201-500. We found that both drugs interacted with the residues- Asp238, His239, Phe243, Thr487 and His494 through hydrophobic interactions and formed stable hydrogen bonds with residue Arg491 of TPO201-500. The binding free energy calculation done using Molecular Mechanics Poisson–Boltzmann (MM-PBSA) and generalized Born and surface area continuum solvation (GBSA) results indicated that both drugs bind strongly to TPO201-500, with Propylthiouracil having slightly higher binding energy than Methimazole. In this study, we used the molecular dynamics (MD) to study the molecular interaction differences between TPO201-500 and both drugs.
This makes the molecular interaction of TPO with the drugs crucial to understand. Most of the protein-drug interaction studies so far have been focussed mainly at in vivo level, or by using Myeloperoxidase and Lactose peroxidases as TPO surrogates for the same. Thyroid Peroxidase (TPO) is an active target of anti-thyroid drugs, Methimazole and Propylthiouracil, which inhibit the enzyme function of catalysing the thyroid hormones synthesis. Graves’ disease (GD), an autoimmune disorder, scars majority of women worldwide, causing hyperthyroidism, Graves’s ophthalmopathy and goitre.
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