Comparative Study on the Binding Affinity of Methimazole and Propylthiouracil to Thyroid Peroxidase as an Anti-Thyroid Drug: An Insilico Approach

Abstract

Graves' disease (GD), an autoimmune disorder, scars majority of women worldwide, causing hyperthyroidism, Graves's ophthalmopathy and goitre. 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. 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. This makes the molecular interaction of TPO with the drugs crucial to understand. In this study, we used the molecular dynamics (MD) to study the molecular interaction differences between TPO 201-500 and both drugs. 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 TPO 201-500 , with Propylthiouracil having slightly higher binding energy than Methimazole. 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 TPO 201-500 . Since both drugs engage residues-Asp238, His239 and His494 which falls within the proximal heme binding site and catalytic site of TPO 201-500 , we can conclude that these drugs may be conducive in inhibiting the enzymatic activity of TPO 201-500 .

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

“…A study by Pradhan et al conducted molecular docking of methimazole and propylthiouracil with thyroid peroxidase. The results of this study predicted both drugs to bind in the same position, with the sulphur group forming a hydrogen bond with Arg491 of the thyroid peroxidase, resulting in inhibition of thyroid hormone production [11]. As these drugs show similar binding to the same target, it is reasonable to hypothesise that both drugs might also have a shared mechanism for the adverse drug reaction, going some way to explaining why multiple drugs have been associated with the same alleles.…”

“…Anti-thyroid drugs are used to treat hyperthyroidism as they normalise thyroid function through binding to the thyroid peroxidase enzyme [11]. These drugs are thioamides containing a thiocarbonyl group and a thiourea moiety within a heterocyclic structure.…”

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

“…A study by Pradhan et al conducted molecular docking of methimazole and propylthiouracil with thyroid peroxidase. The results of this study predicted both drugs to bind in the same position, with the sulphur group forming a hydrogen bond with Arg491 of the thyroid peroxidase, resulting in inhibition of thyroid hormone production (12). As these drugs show similar binding to the same target, it is reasonable to hypothesise that both drugs might also have a shared mechanism for the adverse drug reaction, going some way to explaining why multiple drugs have been associated with the same alleles.…”

“…Anti-thyroid drugs are used to treat hyperthyroidism as they normalise thyroid function through binding to the thyroid peroxidase enzyme (12). These drugs are thioamides containing a thiocarbonyl group and a thiourea moiety within a heterocyclic structure.…”