MD Simulation And Docking On Inhibitors Binding With TTR

Transthyretin(TTR)is an important transporter of thyroxine both in plasm and cerebrospinal fluid(CSF).Thyroxine and its analogues could bind with TTR at two equivalent binding sites located in the central binding channel.TTR could dissociate into monomers and then misfold partly disrupted intermediates followed by amyloidoses.It is an effective therapeutic strategy to design a series of ligands binding with TTR to prevent it from disassembling.In this paper,DOCK and molecular dynamics(MD) simulations are performed to study on inhibitors binding to TTR.This research give far-reaching informations for different inhibitors binding with transthyretin.The main work in this study is as follows:1,MD simulations are performed to study the differences of binding channel shapes of TTR with two kinds of inhibitors,flufenamic acid(FLU) and N-phenyl phenoxazine(BPD).A possible binding mechanism accounting for NC and IC is proposed:for NC of FLU,the expanding of the second binding site weaken the interaction between TTR and FLU,for IC of BPD,the same size of second binding site as WT-TTR has similar binding affinity with BPD like the first one.2,In this paper,collecting the sample of MD simulations and calculcate the free binding energy by MM/PBSA and MM/GBSA methods to inspect the binding mode of transthyretin with inhibitors.From the relations of free binding energy,it can give reasonable explanation why FLU adopts negative cooperativity and BPD adopts independent cooperativity.This research give far-reaching informations for the free energy of the different inhibitors binding with transthyretin.3,The binding modes of inhibitors with TTR were studied using docking and molecular dynamic simulations.The binding free energies were also calculated using MMPBSA and MMGBSA methods.The results indicate that the inhibitors are in multiple binding modes and could effectively prevent TTR from dissociation,which are consistent with experimental data.