Molecular docking of thiamine reveals similarity in binding properties between the prion protein and other thiamine-binding proteins

Journal of Molecular Modeling
Nataraj S PagadalaDavid S Wishart

Abstract

Prion-induced diseases are a global health concern. The lack of effective therapy and 100% mortality rates for such diseases have made the prion protein an important target for drug discovery. Previous NMR experimental work revealed that thiamine and its derivatives bind the prion protein in a pocket near the N-terminal loop of helix 1, and conserved intermolecular interactions were noted between thiamine and other thiamine-binding proteins. Furthermore, water-mediated interactions were observed in all of the X-ray crystallographic structures of thiamine-binding proteins, but were not observed in the thiamine-prion NMR study. To better understand the potential role of water in thiamine-prion binding, a docking study was employed using structural X-ray solvent. Before energy minimization, docked thiamine assumed a "V" shape similar to some of the known thiamine-dependent proteins. Following minimization with NMR-derived restraints, the "F" conformation was observed. Our findings confirmed that water is involved in ligand stabilization and phosphate group interaction. The resulting refined structure of thiamine bound to the prion protein allowed the 4-aminopyrimidine ring of thiamine to π-stack with Tyr150, and facilitated hydrog...Continue Reading

References

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Citations

Jan 26, 2017·Expert Opinion on Drug Discovery·Nataraj S PagadalaRakesh Bhat
Sep 17, 2019·Biochemistry. Biokhimii︠a︡·V A AleshinV I Bunik

Related Concepts

Thiamine-binding protein
4-aminopyrimidine
Carrier Proteins
Hydrogen Bonding
Prions
Plasma Protein Binding Capacity
Protein Conformation
Pyrimidines
Thiamine Mononitrate
Protein Conformation, beta-Strand

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