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Rational Drug Design
This tool is aimed at designing a ligand - a potential drug candidate
-which will interact specifically with a selected molecular target.
BACKGROUND: There are two main ways to discover drugs by in-silico
methods. One is screening of large series
of synthetic and natural compounds. Another is constructing a potential drug in
the active site of a given protein. The last approach has been enhanced
recently through use of combinatorial chemistry.
Quantum's Algorithm
Quantum's rational drug design algorithm proceeds in the following
steps:
·
more then 2000 scaffolds (some of
scaffolds are as shown (Figure 53)) are screened against a given protein;
·
the scaffolds with minimum free
binding energies are selected;
·
for each such scaffold, a special
prosedure constructs a sub_library from the scaffold and its so called R-groups
(see the Figure below);
·
screen the compounds from
sub_library against the active site.
Figure 53 - Scaffolds
The advantages of the algorithm:
·
more then 1 million compounds can
be quckly analysed ;
·
all molecules can be chemically
synthesized.
Note: The procedure
takes the same time as full screening of an equivalent library of 30,000
compounds.
Now let us procced with Rational Drug Design procedure step by step:
Shoose Tools->Rational Drug Design.
Select
a Protein
Make sure that the protein is displayed.
Choose the protein by clicking on a structure.
After selecting the protein the viewer zooms in and shows the molecule
in sticks.
Building
a Grid Box in the Active Site
BACKGROUND: Whenever the ligand position inside the active site is not
known, the program uses optimization to minimize the binding free energy using
Quantum's advanced energy evaluation algorithm. The recommended way to speedup
the calculation is to employ precalculated potentials stored in the grids. A
grid is a 3D box (gridbox) characterized by three orthogonal directions and its
size.
In order to construct a grid box, the following requirements should be
met:
·
All active site atoms should be covered
by a grid box, or at least all important chemical groups of the active site
should lie inside of the grid box.
·
Do not make a grid box too large. A
larger grid makes the grid calculation last longer and it takes more memory to
store the grid values in the computer's RAM. The time of the grids'
calculations is proportional to the grid box volume.
Note: If you make each side of the grid
box two times longer, then the calculation time increases 8 (2x2x2) times. The
same is true for the volume of the memory required for using grids.
·
We recommend that the gid box
volume does not exceed 20x20x20 A3. For instance, it can be 40x20x10 A3 or
5x40x40 A3 and so on.
First, select the center of the grid box by selecting any atom that lies
approximately in the middle of the active site.
After clicking a cube with dimensions 20x20x20 A3 will appear.
Now you have to adjust the box position and size.
·
The grid box has axes OX, OY and
OZ, which are displayed on the screen.
·
If you decide to change the size of
one of the axes, you should use Grid box Wizard.
·
Just click on the size button
and choose the size. The grid box will automatically be changed.
Note: The default size is 20A. The
following options are available: 5A, 10A, 15A, 20A ( default) and 25A.
Selecting Essential Metal Ions and
Hetatoms in the Active Site
BACKGROUND: The small molecule can interact with metal ions and hetatoms
in the active site. Correct energy calculation should involve all of the
important structures within the active site. After the grid box is defined, all
structures within it will be renamed and shown.
Note: We recommend that you do not
include water molecules in modeling since Quantum has its own model of water.
You can remove any structure from the list.
Increase the grid box size to add a structure if necessary.
Adding hydrogen atoms to the protein and to the
hetatoms
·
Go to the next step - "Dock
the Molecule"- if you think the protein and all other structures in the active
site have the right number of hydrogen atoms.
· Use the Build Model option from the Wizard to set the protonation
state and add hydrogens by using Quantum's algorithms. We recommend this option.
·
Use Builder to manually set bond
types and add/remove hydrogen atoms.
Press the Apply button to start modeling.
Calculations and Results
All stages of the process are displayed on the Progress Bar and in the
Information Panel.
When the calculation is complete you can see the results in a window
that will appear instead of the information panel.
This window contains compounds constructed from the scaffolds and their
R-groups. They are sorted by the IC50 values: the best ones are on the top.
·
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 number of flexible bonds of the ligand
·
RMSD, A - root mean square distance
between the initial and final positions
·
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).