Site-specific basicities regulate molecular recognition in receptor binding

In silico docking of thyroid hormones

Gergo Tóth, Ferenc Baska, András Schretner, Ákos Rácz, B. Noszál

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Interactions between thyroid hormone α and β receptors and the eight protonation microspecies of each of the main thyroid hormones (thyroxine, liothyronine, and reverse liothyronine) were investigated and quantitated by molecular modeling. Flexible docking of the various protonation forms of thyroid hormones and high-affinity thyromimetics to the two thyroid receptors was carried out. In this method the role of the ionization state of each basic site could be studied in the composite process of molecular recognition. Our results quantitate at the molecular level how the ionization state and the charge distribution influence the protein binding. The anionic form of the carboxyl group (i.e., carboxylate site) is essential for protein binding, whereas the protonated form of amino group worsens the binding. The protonation state of the phenolate plays a less important role in the receptor affinity; its protonation, however, alters the electron density and the concomitant stacking propensity of the aromatic rings, resulting in a different binding score. The combined results of docking and microspeciation studies show that microspecies with the highest concentration at the pH of blood are not the strongest binding ones. The calculated binding free energy values can be well interpreted in terms of the interactions between the actual sites of the microspecies and the receptor amino acids. Our docking results were validated and compared with biological data from the literature. Since the thyroid hormone receptors influence several physiologic functions, such as metabolic rate, cholesterol and triglyceride levels, and heart frequency, our binding results provide a molecular basis for drug design and development in related therapeutic indications.

Original languageEnglish
Pages (from-to)721-730
Number of pages10
JournalEuropean Biophysics Journal
Volume42
Issue number9
DOIs
Publication statusPublished - Sep 2013

Fingerprint

Thyroid Hormone Receptors
Triiodothyronine
Thyroid Hormones
Protein Binding
Computer Simulation
Amino Acid Receptors
Drug Design
Thyroxine
Thyroid Gland
Triglycerides
Cholesterol
Electrons
Therapeutics

Keywords

  • Microspeciation
  • Molecular modeling
  • Protein binding
  • Receptor binding
  • Thyroid
  • Thyroxine

ASJC Scopus subject areas

  • Biophysics

Cite this

Site-specific basicities regulate molecular recognition in receptor binding : In silico docking of thyroid hormones. / Tóth, Gergo; Baska, Ferenc; Schretner, András; Rácz, Ákos; Noszál, B.

In: European Biophysics Journal, Vol. 42, No. 9, 09.2013, p. 721-730.

Research output: Contribution to journalArticle

Tóth, Gergo ; Baska, Ferenc ; Schretner, András ; Rácz, Ákos ; Noszál, B. / Site-specific basicities regulate molecular recognition in receptor binding : In silico docking of thyroid hormones. In: European Biophysics Journal. 2013 ; Vol. 42, No. 9. pp. 721-730.
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