Structure activity relationship of anti thyroid drugs and breastfeeding

structure activity relationship of anti thyroid drugs and breastfeeding

Anti-Thyroid Drugs - Free download as Powerpoint Presentation .ppt /.pptx), PDF File .pdf), Text Antithyroid Drugs . Structure-activity relationships Therefore, formula feedings for infants are strongly recommended for nursing women. Treatment options for the hyperthyroid patient include anti-thyroid drugs to the structure–activity relationship, to detect antagonists of thyroid hormones, .. μg for adults, μg for pregnancy, and μg for lactation (Becker et al., ). Thyroid Peroxidase (TPO) is an active target of anti-thyroid drugs, that these drugs may be conducive in inhibiting the enzymatic activity of TPO The Xray crystallised structure of TPO was determined 16 years ago, but of low .. Taurog A () Porcine thyroid peroxidase: relationship between the native .

June 1, ; Accepted date: June 21, ; Published date: June 26, Citation: J Mol Imag Dynamic 7: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.

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 and both drugs. We found that both drugs interacted with the residues- Asp, His, Phe, Thr and His through hydrophobic interactions and formed stable hydrogen bonds with residue Arg of TPO Since both drugs engage residues- Asp, His and His which falls within the proximal heme binding site and catalytic site of TPO, we can conclude that these drugs may be conducive in inhibiting the enzymatic activity of TPO It is one of the major causes of hyperthyroidism in the geographical areas with Iodine abundance [ 2 ].

structure activity relationship of anti thyroid drugs and breastfeeding

The main ground cause of GD is the binding of circulating IgG antibodies to G-protein— coupled thyrotropin receptor TSHRresulting in the activation of Thyroglobulin gene which codes for thyroid hormonestriiodothyronine T3 and thyroxine T4 [ 45 ]. Since the activation of Thyroglobulin gene by the binding of TSIs to THSR is not natural, there is no feedback system leading to the excess production of thyroid hormones: This activation also triggers follicular hypertrophy and hyperplasia, thyroid enlargement [ 4 ].

The synthesis of triiodothyronine T3 and thyroxine T4 hormones from Thyroglobulin gene is catalyzed by Thyroid Peroxidase TPO upon the iodination and coupling of tyrosyl residue in Thyroglobulin [ 10 ] and is hence the target site of anti-thyroid drugs for the treatment of GD. TPO is a residues transmembrane homodimer [ 11 - 13 ], affixed to the apical membrane of thyroid follicle cells by its TMD region on its C-terminal end residues — [ 1415 ].

The Xray crystallised structure of TPO was determined 16 years ago, but of low resolution [ 1617 ]. Based on these homology studies, it was found that Asp, His, Glu, and His were important for proximal heme linkage.

The proximal histidine residues present in heme peroxidases are crucial in the redox properties of heme iron for catalysis [ 2021 ]. The homology modeling of TPO was done recently, reporting that its cis and trans conformations are involved equally in its antigenicity [ 22 ].

structure activity relationship of anti thyroid drugs and breastfeeding

Both ATDs obstructs the iodination of tyrosyl residues in Thyroglobulin catalyzed by Thyroid Peroxidase, thereby arresting the production of thyroid hormones [ 27 - 29 ]. MMZ is preferred to PTU, due to its better adherence and bioavailability [ 2330 - 32 ]; however, PTU is also recommended for pregnant women [ 3334 ]. Irradiation studies too have been done to treat hyperthyroidism [ 35 ].

Gln and His of the LPO too were involved in the enzyme inhibition [ 41 ].

structure activity relationship of anti thyroid drugs and breastfeeding

The protein structure of TPO was constructed first, and its stability was asserted. The complex structures of TPO with both the drugs were constructed using PatchDock server [ 4243 ] which gave the results based on the maximum surface area and minimum atomic contact energy. Since the residues- Asp, His and His belonging to the heme linkage region of the protein TPO were seen to be involved in the bond interaction with both drugs, these sites will now no longer be available for the iodination and coupling of tyrosyl residues by TPO for the synthesis of thyroid hormones.

R was also found to play crucial role in the drug-protein communication by forming hydrogen bond.

structure activity relationship of anti thyroid drugs and breastfeeding

The cat-SAR learning set consists of the chemical name, its structure as a MOL2 file, and its categorical designation e.

Typically, organic salts are included as the freebase and simple mixtures and technical grade preparations may be included as the major or active component, metals, metalo-organic compounds and polymers, and mixtures of unknown composition are not included. HQSAR allows the user to select attributes for fragment determination including atom counts i. Fragments can be linear, branched, or cyclic moieties.

For analysis of the developmental toxicity dataset the models developed contained fragments between three and seven atoms in size and considered atoms, bond types, and atomic connections. In the matrix, the rows are intact chemicals and columns are the molecular fragments.

Thus for each chemical, a tabulation of all its fragments is recorded across the table rows and for each fragment all chemicals that contain it are tabulated down the columns. Rather, the compound-fragment matrix is subsequently analyzed with the cat-SAR expert system in order to identify structural features associated with the categorized active and inactive compounds. The cat-SAR program, human developmental toxicity database, and the compound-fragments matrix are available through the corresponding author.

To ascertain an association between chemical descriptors i. The first selection rule the Number Rule is the number of chemicals identified in the learning set that possesses each particular fragment.

structure activity relationship of anti thyroid drugs and breastfeeding

The second selection rule the Proportion Rule is the proportion of active or inactive chemicals that then possesses the particular fragment.

Although previously published cat-SAR models required the user to select specific values for the Number and Proportion Rules, a new routine was implemented here to determine optimal values for the Number and Proportion rules.

For this exercise the values for the Number Rule were allowed to range between one and eight and the initial values for the Proportion Rule were allowed to range between 0. Predicting Activity The resulting list of important fragments can then be used for mechanistic analysis, or to predict the activity of an unknown compound.

In the latter circumstance, the model determines which, if any, fragments from the model's learning set the test compound contains. If none are present, no prediction of activity is made for the compound i. If one or more fragments are present, the number of active and inactive compounds containing each fragment is determined.

Here the fragment sum FragSum method calculates the average probability of the active and inactive fragments contained in a compound and is weighted to the number of active and inactive compounds that go into deriving each fragment. As described, a Cat-SAR prediction of activity or inactivity is based on two separate fragment sets i. Therefore, to classify compounds back to an active or inactive category i.

Depending on the application of the model, the cutoff point that separates active from inactive categorization, for example can be adjusted wherein a model with the best overall concordance can be selected i.

Thyroid hormone contains iodine that must be supplied by nutritional intake. The thyroid gland contains large stores of thyroid hormone in the form of thyroglobulin. These stores maintain systemic concentrations of thyroid hormone despite variations in iodine availability and nutritional intake. The thyroidal secretion is predominantly the prohormone thyroxine, which is converted in the liver and other tissues to the active form, triiodothyronine.

Local activation of thyroxine also occurs in target tissues e. Serum concentrations of thyroid hormones are precisely regulated by the pituitary hormone, thyrotropin TSHin a classic negative-feedback system. The predominant actions of thyroid hormone are mediated through binding to nuclear thyroid hormone receptors TRs and modulating transcription of specific genes.

Thyroid hormones share a common mechanism of action with steroid and steroid-like hormones, such as vitamin D and the retinoids, whose receptors are members of a superfamily of nuclear receptors Chapter 3.