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Library Screening
The procedure finds the position of a small molecule in the active site
of a given protein with the minimum value of the free binding energy and
predicts the IC50 of the ligand. The
procedure finds the position of a small molecule in the active site of a given
protein with the minimum value of the free binding energy and predicts the IC50
of the ligand. Screens in silico a library of small molecules. Finds their
positions in the active site with the minimum value of the free binding energy and
predicts the IC50 values of these molecules.
BACKGROUND: Library Screening requires 3D structures of a protein and
compounds. The position of the active site of the protein should be known.
Protein structures can be downloaded from the Protein Data Bank, as well as
from some other sources of 3D biological macromolecular structure data. The
compounds should be formed in a library - a special feature of the program.
Create
and Open a Library
BACKGROUND: In order to work with a large number of compounds, particularly
to screen them against a protein, Quantum offers the opportunuty to organize
compounds in a library, which can be conveniently managed, e.g. add/remove new
compounds, view selected compounds, build models etc.
To create a library, select File New Library... in the Main Menu
(Figure 33) (a).
Figure 33 - New Library
This procedure will give you the opportunity to select compounds (Figure
34) (a) via the Add... button. You can also remove a molecule from the
selection (c).
Finally, you should define how this selection should be processed.
Figure 34 - Selecting Compounds
The window allows you the following options, which can be done with
selected compounds (b):
·
Add hydrogen atoms filling all
valences
·
Fix the protonation state, like
carboxil group deprotonization
·
Set the charges by a
quantum-mechanical method
All options are on by default.
Note: Switching on all options
guarantees that the program works properly. If molecules were already processed
by Quantum then options can be switched off. If compounds have the right number
of hydrogen atoms, for example, then the add hydrogens box can be OFF
etc.
To start processing the selection, you should press the Create...
button (d).
After finishing, you will see the following window (Figure 35):
Figure 35 - Library
There are several option for managing this library. You can:
·
Edit the compounds and switch on
some options that were off before.
·
Select molecules and visualize them
(b) as seen in (Figure 36) (a).
·
Save the library under another
name.
Figure 36 - Library Visualization
Building a Grid Box in the Active Site
See the same section in
the Ligand Docking
Selecting
Essential Metal Ions and Hetatoms in the Active Site
See the
same section in the Ligand Docking
Calculations and Results
The results of Library Screening can be seen in a window that will
appear instead of the information panel (Figure 37).
·
E bind, kJ/mol - free binding
energy
·
E es, kJ/mol - electrostatic and
solvation energy
·
E vdw, kJ/mol - short range
electrostatic and exchange and Van der Waals energies
· TdS, kJ/mol - entropy
contribution
·
E tor, kJ/mol - ligand internal
energy change
·
Charge, Mass, Flex.bonds - total
charge, mass and the number of flexible bonds of the ligand
·
RMSD, A - root mean square distance
between the initial and final positions.
Note: Free binding energy is equal to
the sum of all listed contributions (E es, E vdw, TdS and E tor). In our
calculations IC50 is 5.82 x (E bind).
Figure 37 - Results
·
sort columns by uinge the Sort
button;
·
visualize docked compounds by using
the View button, and
·
to save report in HTML format,
which is readable for most spreadsheet applications by using the save report
button.