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Departamento de Estudios educativos

Semillero Maestros y contextos


Universidad de Caldas

Molecular dynamics of streptozotocin


inhibition of O-GlcNAcase

Juan David Marin Chiguachi


Universidad de Caldas

Chemistry and Biology degree`s

1 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 1/13


Departamento de Estudios educativos
Semillero Maestros y contextos

Contents in Brief
Universidad de Caldas

1. Structural composition of inhibitor


2. O-GlcNAcase or BtGH84
3. Molecular Docking
4. Complex ZTZ and BtGH84
5. Molecular Dynamic Simulation
6. Interactions between STZ and BtGH84
7. Superposition of the BtGH84 complex and STZ

2 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 2/13


Departamento de Estudios educativos
Semillero Maestros y contextos

Structural composition of inhibitor


Universidad de Caldas

Streptozotocin is a cytotoxic glucose analog that is preferentially internalized by


pancreatic β-cells [1]
STZ is currently used in the treatment of certain pancreatic cancers [2]
Streptozotocin is a glucosamine-nitrosourea compound.

A B

Figure 1. Structure of STZ Figure 2. Structure of A :nitrosourea and B: glucosamine

[1] Heinhib, Yuan & Martinez-Fleites, Carlos & Bubb, Abigail & Gloster, Tracey & Davies, Gideon. (2009). Structural insight into the
mechanism of streptozotocin ition of O-GlcNAcase. Carbohydrate research. 344. 627-31.
[2] Lenzen, S. (2008). The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51, 216–226.

3 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 3/13


Departamento de Estudios educativos
Semillero Maestros y contextos

O-GlcNAcase or BtGH84
Universidad de Caldas

Figure 3. Structure of BtGH84


Figure 4. In red the part of the conserved protein
corresponding to the active site, cofactor of Ca + 2

4 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 4/13


Departamento de Estudios educativos
Semillero Maestros y contextos
Universidad de Caldas
Molecular Docking

Figure 5. Box with ligand positioned at the active site of BtGH84

5 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 5/13


Departamento de Estudios educativos
Semillero Maestros y contextos
Universidad de Caldas
Complex ZTZ and BtGH84

Figure 6. STZ in complex with BtGH84

6 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 6/13


Departamento de Estudios educativos
Semillero Maestros y contextos
Universidad de Caldas
Molecular Dynamic

7 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 7/13


Departamento de Estudios educativos
Semillero Maestros y contextos
Universidad de Caldas

Figure 7. Graphs of temperature and density: 300 K and approximately 998 kg / m3 are reached

8 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 8/13


Departamento de Estudios educativos
Semillero Maestros y contextos
Universidad de Caldas

Figure 8. Enthalpy graph of the complex, it is a system that gives off heat

9 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 9/13


Departamento de Estudios educativos
Semillero Maestros y contextos

Interactions between STZ and BtGH84


Universidad de Caldas

Asparagine, lysine, glycine,


aspartate, cysteine and
tyrosine, are the amino acid
residues that present
interaction in the active site the
STZ inhibitor that they present
in the paper.

Figure 9. Schematic representation of the interactions between


STZ and BtGH84; hydrogen bonds are represented by dashed lines
together with their inter-atomic distances.
Heinhib, Yuan & Martinez-Fleites, Carlos & Bubb, Abigail & Gloster, Tracey & Davies, Gideon. (2009). Structural insight into the
mechanism of streptozotocin ition of O-GlcNAcase. Carbohydrate research. 344. 627-31.
10 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 10/13
Departamento de Estudios educativos
Semillero Maestros y contextos

Interactions between STZ and BtGH84


Universidad de Caldas

Figure 10. Comparison of the interaction of the ASP residue between experimental document and molecular
dynamics

Heinhib, Yuan & Martinez-Fleites, Carlos & Bubb, Abigail & Gloster, Tracey & Davies, Gideon. (2009). Structural insight into the
mechanism of streptozotocin ition of O-GlcNAcase. Carbohydrate research. 344. 627-31.
11 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 11/13
Departamento de Estudios educativos
Semillero Maestros y contextos

Interactions between STZ and BtGH84


Universidad de Caldas

Figure 11. Interactions between STZ and BtGH84 active site residues. Cyan His, Tyr Blue, Asp Yellow, Trp
Green, Asn Purple, Lyz Pink

12 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 12/13


Departamento de Estudios educativos
Semillero Maestros y contextos

Superposition of the BtGH84 complex and STZ


Universidad de Caldas

Figure 12. Representation of the structural superposition of the BtGH84 complex with STZ (blue) and native
BtGH84 (yellow).

13 Doctorado en “Sostenibilidad y Regeneración Urbana” 99/2011 13/13