Team:Jiangsu High School/Model

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Target and signaling pathway
In our research, we obtained two compounds with autophagy agonistic activity, Paroxetine and Amitriptyline. To our surprise, both Paroxetine and Amitriptyline are antidepressants in a group of drugs called selective serotonin reuptake inhibitors (SSRIs), and it has been reported that several antidepressants could improve the symptoms of mental illness in AD patients, such as anxiety and depression. We also found both Paroxetine and Amitriptyline had high affinity to the 5-HT2A receptor. As a type of G protein-coupled receptor (GPCR), 5-HT2A receptor is involved in several cellular functions through regulating multiple intracellular signaling pathways. Paroxetine and Amitriptyline might regulate autophagy related pathway such as AMPK-ULK1/PI3K-AKT-mTOR through binding to 5-HT2A receptor.

We wanted to predict where these two compounds would bind to the target protein, so we used Maestro.
The selected protein was PDB: 6A93. And the compounds are Paroxetine and Amitriptyline.

Figure 1.
The structure of Paroxetine and Amitriptyline

Here is the process.

  1. Open the software Maestro
  2. Project-new-paroxetine1
  3. Protein preparation wizard
  4. import PDB No. (6A93), preprocess,


Figure 2.
The protein structure of 5-HT2A receptor (PDB: 6A93).

  1. review and modify, generate states
  1. optimize, force field opls 2005, minimize
  1. generate glide file

Application-glide-receptor grid generation
Job name: glide-grid_1-paroxetine
Receptor: select the similar molecule area

Figure 3.
The similar molecule ligand of 5-HT2A receptor (PDB: 6A93).


Figure 4.
The select area of protein 5-HT2A receptor (PDB: 6A93).

  1. ligprep

Ligprep-filename paroxetine
Force field: opls-2005
Job name: ligand 1

  1. molecular docking

glide-ligand docking
Receptor grid: upload previous file
Ligands: upload previous file
Setting-SP(standard precision), Ligand sampling: Flrxible


Figure 5.
The predicted binding area between Paroxetine and the protein5-HT2A receptor (PDB: 6A93).


Figure 6.
The predicted binding area between Amitriptyline and the protein5-HT2A receptor (PDB: 6A93).

Reference
1. Laursen AL, Mikkelsen PL, Rasmussen S, le Fèvre Honoré P. Paroxetine in the
treatment of depression--a randomized comparison with amitriptyline. Acta
Psychiatr Scand. 1985 Mar;71(3):249-55
2.Rasbach KA, Funk JA, Jayavelu T, Green PT, Schnellmann RG. 5-hydroxytryptamine
receptor stimulation of mitochondrial biogenesis. J Pharmacol Exp Ther. 2010
Feb;332(2):632-9. doi: 10.1124/jpet.109.159947. Epub 2009 Oct 29.
3. Maestro User Manual - Hom http://gohom.win/ManualHom/Schrodinger/Schrodinger_2015-2_docs/maestro/maestro_user_manual.pdf