Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach

Gupta, Manish Kumar; Misra, Krishna

doi:10.1007/s13721-013-0023-0

Cited by 17 publications

(15 citation statements)

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“…The software has already been proven to be useful in diverse applications. Examples include synthetic biology [ 59 ], mechanistic modeling of methicillin-resistance in bacteria [ 60 ], explaining dynamic damage response in human fibroblasts after exposing them to γ radiation [ 61 ], drug discovery [ 62 ] and drug effect modeling [ 63 , 64 ], and modeling complex signaling cascades [ 65 ]. Endeavors such as the path2models project [ 66 ] have additionally demonstrated the usefulness of automated rate law assignment.…”

Section: Discussionmentioning

confidence: 99%

SBMLsqueezer 2: context-sensitive creation of kinetic equations in biochemical networks

et al. 2015

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BackgroundThe size and complexity of published biochemical network reconstructions are steadily increasing, expanding the potential scale of derived computational models. However, the construction of large biochemical network models is a laborious and error-prone task. Automated methods have simplified the network reconstruction process, but building kinetic models for these systems is still a manually intensive task. Appropriate kinetic equations, based upon reaction rate laws, must be constructed and parameterized for each reaction. The complex test-and-evaluation cycles that can be involved during kinetic model construction would thus benefit from automated methods for rate law assignment.ResultsWe present a high-throughput algorithm to automatically suggest and create suitable rate laws based upon reaction type according to several criteria. The criteria for choices made by the algorithm can be influenced in order to assign the desired type of rate law to each reaction. This algorithm is implemented in the software package SBMLsqueezer 2. In addition, this program contains an integrated connection to the kinetics database SABIO-RK to obtain experimentally-derived rate laws when desired.ConclusionsThe described approach fills a heretofore absent niche in workflows for large-scale biochemical kinetic model construction. In several applications the algorithm has already been demonstrated to be useful and scalable. SBMLsqueezer is platform independent and can be used as a stand-alone package, as an integrated plugin, or through a web interface, enabling flexible solutions and use-case scenarios.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-015-0212-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

SBMLsqueezer 2: context-sensitive creation of kinetic equations in biochemical networks

et al. 2015

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“…A density functional theory method was opted by Tappa and his group [85] to evaluate the inhibitory effect of the MMZ tautomers-1-methyl-1H-imidazole-2 (3H)-thione (M1) and 1-methyl-1H-imidazole-2-thiol (M2) where the effect of M1 was superior to M2 tautomer. Gupta and Kumar [86] did metabolic modelliing and tested the drug activity of PTU against TPO, TSHR and sodium iodide symporter (NIS) using systems biology approach and deduced that PTU is effective on TPO. They also observed TSHR to be potent target for therapeutic study.…”

Section: Calculations Of Binding Free Energiesmentioning

confidence: 99%

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

Pradhan¹,

Sarma²,

Bharadwaz³

et al. 2017

J Mol Imaging Dynam

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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 .

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“…In our previous study, only a specific pathway in thyroid cell and its simulation effect with quantitative data was analyzed, and effects of varying amounts of PTU drug on specific targets were considered (Gupta et al, 2012;Gupta and Misra, 2013). A deeper analysis of normal and abnormal behavior of thyroid pathways could allow us understanding of the underlying complexity of thyroid pathway.…”

Section: Study Aimsmentioning

confidence: 99%

A Comprehensive Metabolic Modeling of Thyroid Pathway in Relation to Thyroid Pathophysiology and Therapeutics

Gupta

Singh

Shukla

et al. 2013

OMICS: A Journal of Integrative Biology

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The thyroid pathway represents a complex interaction of different glands for thyroid hormone synthesis. Thyrotropin releasing hormone is synthesized in the hypothalamus and regulates thyrotropin stimulating hormone gene expression in the pituitary gland. In order to understand the complexity of the thyroid pathways, and using experimental data retrieved from the biomedical literature (e.g., NCBI, HuGE Navigator, Protein Data Bank, and KEGG), we constructed a metabolic map of the thyroid hormone pathway at a molecular level and analyzed it topologically. A total of five hub nodes were predicted in regards to the transcription thyroid receptor (TR), cAMP response element-binding protein (CREB), signal transducer and activator of transcription 3 (STAT 3), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), and activator protein 1 (AP-1) as being potentially important in study of thyroid disorders and as novel putative therapeutic drug targets. Notably, the thyroid receptor is a highly connected hub node and currently used as a therapeutic target in hypothyroidism. Our analysis represents the first comprehensive description of the thyroid pathway, which pertains to understanding the function of the protein and gene interaction networks. The findings from this study are therefore informative for pathophysiology and rational therapeutics of thyroid disorders.

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Modeling and simulation analysis of propyl-thiouracil (PTU), an anti-thyroid drug on thyroid peroxidase (TPO), thyroid stimulating hormone receptor (TSHR), and sodium iodide (NIS) symporter based on systems biology approach

Cited by 17 publications

References 59 publications

SBMLsqueezer 2: context-sensitive creation of kinetic equations in biochemical networks

SBMLsqueezer 2: context-sensitive creation of kinetic equations in biochemical networks

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

A Comprehensive Metabolic Modeling of Thyroid Pathway in Relation to Thyroid Pathophysiology and Therapeutics

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