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Conserved water mediated H-bonding dynamics of Ser117 and Thr119 residues in human transthyretin-thyroxin

Avik Banerjee1, Hridoy R Bairagya, Bishnu P Mukhopadhyay

  • 1Department of Chemistry, National Institute of Technology-Durgapur, Durgapur, West Bengal 713209, India.

Journal of Molecular Graphics & Modelling
|June 5, 2013
PubMed

Transthyretin (TTR) is a protein whose aggregation and deposition causes amyloid diseases in human beings. Amyloid fibril formation is prevented by binding of thyroxin (T4) or its analogs to TTR. The MD simulation study of several solvated X-ray structures of apo and holo TTR has indicated the role of a conserved water molecule and its interaction with T4 binding residues Ser117 and Thr119. Geometrical and electronic consequences of those interactions have been exploited to design a series of thyroxin analogs (Mod1-4) by modifying 5' or 3' or both the iodine atoms of thyroxin. Binding energy of the designed ligands has been calculated by docking the molecules in tetrameric structure of the protein. Theoretically investigated pharmacological parameters along with the binding energy data indicate the potentiality of 3',5'-diacetyl-3,5-dichloro-l-thyronine (Mod4) to act as a better inhibitor for TTR-related amyloid diseases.

Keywords:
AmyloidCSFDockingFACFAPHBPHuman transthyretinKKelvinLigand modelingMDModMolecular dynamics simulationRBPSSAT4TPSAcerebrospinal fluidfamilial amyloid cardiomyopathyfamilial amyloidotic polyneuropathyfemto-secondfshTTRhalogen binding pockethuman transthyretinmodifiedmolecular dynamicsnano-secondnspico-secondpsretinol-binding proteinsenile systemic amyloidosisthyroxintotal polar surface area

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