Molecular Modeling Study On Neuromedin B Receptor With Agonist And Antagonist And Using ArcGIS Analysis The Spatial Distribution Of Phenyketonuria

From 1990s,with the development of theoretical and computational methods as well as molecular modeling technology,drug design came into a brand-new era, which mainly involves the rational drug design.The core of the contents of rational drug design is discovery of the new selective drugs against certain targets such as enzyme,receptor,ion channel and nucleic acid,based on some endogenous ligands or characteristic of the chemical structures of some natural products.The kernel of the methodology focuses on the studies of the interactions between receptor and ligand. Rational drug design has become a hot research area.This thesis focuses on rat neuromedin B receptor and its ligand in theory study.The main contents include homology modeling,molecular docking,molecular dynamics simulation.Rat neuromedin B receptor(rNMBR)belongs to the family A of G-protein coupled receptor(GPCR).rNMBR is located through the central nervous system to alimentary tract,and has plenty of physiological function,such as causing growth of some tumor cells,thermoregulation,satiety and control of circadian rhythm and so on.The unique structure and important role in the signaling transduction of GPCR make them act as very useful for drug targets.So far,one third of approved small molecular drugs sold in market are the agonists or antagonists of GPCR.So understanding the regulation mechanisms of rNMBR by its agonists and antagonists at the atomic level is essential for reasonably designing NMBR antagonists as drug candidates for treating NMB-mediated diseases.In this study,a 3D model of rNMBR was constructed by homology modeling,and then molecular docking and molecular dynamics(MD) simulations were carried out.Based on the 3D structure,regulation mechanisms rNMBR by agonist and antagonists were investigated via three 10 ns MD simulations on the systems of apo-rNMBR,rNMBR-NMB and rNMBR-pd168368.It was found that the ligand was located among transmembrane regions 3,5,6,7(TM3,TM5,TM6, TM7)of rNMBR,NMB leading the receptor to its activated state.In contrast,binding of pd168368 to rNMBR locked rNMBR in its inactive state.Our simulation results not only provide a mechanistic interpretation of the effects of an agonist or antagonist regulating rNMBR at atomic level,but also give a general simulation strategy for understanding the regulation mechanisms of other GPCRs.This paper also presents the application of exploratory spatial data analysis(ESDA) and kriging from GIS(ArcGIS9.0)in disease mapping through the analysis of Phenylketonuria(PKU)in China.Firstly,we exert the semivariogram and trend surface analysis to analysis the autocorrelation and identify global trends of PKU morbidity rate.Then utilizing the fitted variogram function,we perform universal kriging on the PKU morbidity rates.In the end,we protract contour maps.The results make clear that the PKU morbidity rate displays spatial rules and it is higher in northwest of China than the southeast.The kriging method may be adapted to interpolate nonstationary spatial structure.The Kriging method can estimate the uncertainty of prediction while many deterministic methods cannot do so.We find that the morbidity rates of PKU were high in northwest region of China.