title: Conserved water mediated H-bonding dynamics of Ser117 and Thr119 residues in human transthyretin-thyroxin complexation: inhibitor modeling study through docking and molecular dynamics simulation.
abstract: 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.
authors.affiliation: Department of Chemistry, National Institute of Technology-Durgapur, Durgapur, West Bengal 713209, India.
authors.forename: Avik
authors.initials: A
authors.lastname: Banerjee
authors.forename: Hridoy R
authors.initials: HR
authors.lastname: Bairagya
authors.forename: Bishnu P
authors.initials: BP
authors.lastname: Mukhopadhyay
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Nandi
authors.forename: Deepak K
authors.initials: DK
authors.lastname: Mishra
mesh_terms: D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000737:chemistry*; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D012694:Serine / Q000737:chemistry; D013912:Threonine / Q000737:chemistry; D013974:Thyroxine / Q000737:chemistry* / Q000378:metabolism; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D046912:Multiprotein Complexes; D011228:Prealbumin; D014867:Water; D013912:Threonine; D012694:Serine; D013974:Thyroxine
keywords: Amyloid; CSF; Docking; FAC; FAP; HBP; Human transthyretin; K; Kelvin; Ligand modeling; MD; Mod; Molecular dynamics simulation; RBP; SSA; T4; TPSA; cerebrospinal fluid; familial amyloid cardiomyopathy; familial amyloidotic polyneuropathy; femto-second; fs; hTTR; halogen binding pocket; human transthyretin; modified; molecular dynamics; nano-second; ns; pico-second; ps; retinol-binding protein; senile systemic amyloidosis; thyroxin; total polar surface area