How to use bioinformatics tools like Auto-dock Vina in Drug Discovery

1. Structural Bioinformatics
in Drug Discovery
By: Suhad Jihad
Msc. Software Engineering
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3. Structural bioinformatics
Bioinformatics is the discipline that has
grown up with the task of panning the
streams of sequence data for
pharmaceutical gold dust.
It is an art in which the best results have
been achieved by seasoned experts who
know when and how to deploy
ultrasensitive data-mining tools.
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5. How is bioinformatics work?
The preceding figure illustrates the different phases in
sequence analysis :
Here sequence data have been collated and analyzed in
advance using Genome Threader
http://www.genomethreader.org/ and other techniques to
create a specialized facility for target discovery.
data collation(collect and combined) many range of
databases provides information on primary gene and
protein sequences, 3-D protein structure, and the results of
basic sequence analysis
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6. bioinformatics in drug discovery
 History of Drug Development :
Plants or natural products are source for
medical substance.
For example: Foxgloves used to treat
heart failure
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7. Drug Discovery need time and money
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8. Drug discovery Process :
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9. Bioinformatics in drug discovery
The Improved Method :
• Drug discovery process begins
with a disease (rather than a treatment)
Use disease model to pinpoint
relevant genetic/biological
components (i.e. possible drug targets)
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10. Drug discovery
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11. Drug discovery
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12. Drug discovery
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13. Drug discovery-Drug work
How does a drug act anyway?
How does Aspirin relieve headaches?
 Why do β-blockers lower blood pressure?
 Where does a calcium channel blocker
act?
How does cocaine work?
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14. Drug discovery-Drug work
 An active substance must bind to a very special target
molecule in the body to exert its pharmacological action.
Usually this is a protein, but nucleic acids in the form of
RNA and DNA can also be target structures for active
molecules. An important prerequisite for the binding is
that the active substance has the correct size and shape
to fit into a cavity on the surface of the protein, a binding
pocket, as well as possible. Furthermore, it is also
necessary that the surface properties of ligand and
protein fit together so that the specific interactions can
form. …
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15. Drug discovery-Target
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• Target-based drug discovery starts with a
thorough understanding of the disease
mechanisms and the role of enzymes,
receptors or proteins within the disease
pathology.

16. Drug discovery-Druggable genome
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17. Drug discovery-Ligand
 :It is a (usually small) molecule
that binds to a biological macromolecule.
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18. Drug discovery-Receptor
• Receptor is any functional macromolecule
in a cell which a drug binds to produce its
effect.
….So what exactly dose this mean?
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19. Drug discovery-Receptor
A receptor is like a light switch…
It has two functions : ON and OFF
What is an
In pharmacology, an agonist is a drug
that stimulates a cell receptor that would
normally be stimulated by naturally
occurring substances in a person’s body
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20. Drug discovery-Receptor
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21. In order to increase the patient’s cardiac
output …We would give the patient
Dobutamine, a drug that directly mirrors
the effects of norepinephrine , a chemical
made by the body.
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Drug discovery-Receptor

22. • What is an In pharmacology,
an antagonist is a drug that interferes with
the physiological action of another
substance, especially by combining with
and blocking its receptor
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Drug discovery-Receptor

23. Drug discovery-Receptor
• Example on If a patient arrived
in the Emergency Room with an opioid
overdose of hydrocodone, we would need
to prevent the medication from taking
effect…
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24. Drug discovery-Receptor
To prevent the Hydrocodone from taking
effect…
We would give him Naloxone to block the
receptors in the body, thereby preventing
the Hydrocodone from binding and
causing an overdose
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25. Drug discovery-Receptor
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26. New Drug Discovery- Molecular Targeted
Therepies
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27. Bioinformatics and drug discovery:
By bioinformatics companies can
generate more and more drugs in a short
period of time with low risk.
Drugs are usually only developed when
the particular drug target for those drugs’
actions have been identified and studied.
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28. Bioinformatics and drug discovery:
Insilico Methods in Drug Discovery
 In silico methods can help in identifying drug
targets via bioinformatics tools.
 Analyze the target structures for possible
binding/active sites.
 Generate candidate molecules, check for their
drug likeness.
 Dock these molecules with the target, rank them
according to their binding affinities, further
optimize the molecules to improve binding
characteristics.
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29. Bioinformatics and drug discovery:
Insilico Methods in Drug Discovery
 The use of computers and computational
methods permeates all aspects of drug
discovery today and forms the core of structure-
based drug design.
 High-performance computing, data
management software and internet are
facilitating the access of huge amount of data
generated and transforming the massive
complex biological data into workable knowledge
in modern day drug discovery process.
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30. Bioinformatics and drug discovery:
Insilico Methods in Drug Discovery
 The use of complementary experimental
and informatics techniques increases the
chance of success in many stages of the
discovery process, from the identification
of novel targets and elucidation of their
functions to the discovery and
development of lead compounds with
desired properties.
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31. Bioinformatics and drug discovery:
Insilico Methods in Drug Discovery
Computational tools offer the advantage of
delivering new drug candidates more
quickly and at a lower cost.
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32. Bioinformatics and drug discovery:
Insilico Methods in Drug Discovery
 There are five Insilico methods in drug
discovery.
In my presentation I use this one:-
Starting with an Image to clarify the idea….
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Bioinformatics and drug discovery:
Molecular dockingMolecular docking

34. Bioinformatics and drug discovery:
Molecular dockingMolecular docking
 Docking is the computational
determination of binding affinity between
molecules (protein structure and ligand).
Given a protein and a ligand find out the
binding free energy of the complex formed
by docking them. Following figure shows
the stages of High throughput docking for
protein –ligand complex binding...
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35. Bioinformatics and drug discovery:
Molecular dockingMolecular docking
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Stages of High throughput docking for
protein –ligand complex binding...

36. Bioinformatics and drug discovery:
Molecular dockingMolecular docking
• Docking or Computer aided drug
designing: can be broadly classified as
“Receptor based methods” which make
use of the structure of the target protein
and “Ligand based methods” which is
based on the known inhibitors.
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37. Molecular docking-Step by StepMolecular docking-Step by Step
What program installation you need to
start docking?
• Discovery Studio 4.1 Client
• AutoDockTools Vina
• AutoDockTools-1.5.6
• Python 3.4
• PyMol Molecular graphic system.
• Cygwin Terminal https://www.cygwin.com/ : a
large collection of GNU and Open Source tools
which provide functionality similar to a
Linux distribution on Windows. 37

38. Molecular docking-Step by StepMolecular docking-Step by Step
 Download 1 HSG from RCSB protein database
http://www.rcsb.org/pdb/home/home.do
 1HSG saved as 3D structure:
By x-ray we get
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39. Molecular docking-Step by StepMolecular docking-Step by Step
Open this file from Discovery Studio 4.1
View protein-ligand interaction.
Separate crystalized ligand from protein.
Go to Scripts-Ligand Interaction-Show
ligand Binding SiteAtoms to show lablel
residues.
Scripts-Selection-Select Water Molecules
Edit-Delete.
 Scripts-Selection-Select protein chains
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40. Molecular docking-Step by StepMolecular docking-Step by Step
Edit-delete.
Then save the ligand as ligand.pdb in the
folder for MGL tools.
Then open 1hsg again go to Script –
Selection-Ligand
Edit-delete.
Script-Select-Select Water Molecules
Edit-delete.
Save as 1hsg.pdb at MGLTool folder.
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41. Molecular docking-Step by StepMolecular docking-Step by Step
Exit Discovery Studio.
Now run MGLTool from autodock but you
must ensure the two files are inside
MGLTool and run autodock from adt batch
file only.
Then open read molecule and read 1hsg
file Edit-Add-hydrogens-only polar.
Grid-macromolecule-choose-1hsg-select
molecule.
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42. Molecular docking-Step by StepMolecular docking-Step by Step
• Then the molecule will initialized save it as
1hsg.pdbqt
• Grid-gridbox-then set the values as
• No. of points in x-direction=26
• No. of point in y-direction=26
• No. of points in z-direction=26
• Spacing =1.000
• X-center=16.072
• Y-center=26.5007
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44. Molecular docking-Step by StepMolecular docking-Step by Step
• Z-center= 3.7748
• File close current saving.
• Then hide this molecule and open ligand
• Ligand –input- open and choose your
ligand file.
• Ligand – TorsionTree –Set Number of
Torsions.
• Put No. 6 and press dismiss
• Ligand-Output-Save as .pdbqt
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45. Molecular docking-Step by StepMolecular docking-Step by Step
• File –Exit
• Go to MGLTool folder and
copy(1hsg.pdbqt & ligand.pdbqt) and
paste them in Vina folder in your
computer.
• In vina folder create text document name it
as conf. and write in it :
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receptor=1hsg.pdbqt
ligand=ligand.pdbqt
out=out.pdbqt
center_x=16.072
center_y=26.5007
center_z=3.7748
size_x=26
size_y=26
size_z=26
exhaustiveness=8

46. Molecular docking-Step by StepMolecular docking-Step by Step
• Save and close conf.
• Run cmd prompt .
• Change the directory to vina folder in my
computer C:Program FilesThe Scripps
Research Institutevina
• Write on this folder
• Vina --config conf.txt--log log.txt
• After the execution
• Write vina-split- -input out.pdbqt
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47. Molecular docking-Step by StepMolecular docking-Step by Step
• Open vina folder and see the nine
out_ligand file.
• You can check each of them.
• Now open Pymol and open 1hsg that you
download from RCSB and ligand that
produced to check the best docking
parameters.
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48. GlossaryGlossary
Protease : an enzyme which breaks down
proteins and peptides
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49. Future Drug-personalised medicine
• is the tailoring of
drug treatments to people’s genetic
makeup a form of personalized medicine.
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50. References:-
Role of bioinformatics and
pharmacogenomics in drug discovery and
development process – Springer
projectPersonalized Medicine - NIH News
in Health, December 2013.html
Target discovery using bioinformatics.html
Identifying targets for drug discovery using
bioinformatics. - PubMed - NCBI.html
Drug and target protein structures in the
PDB.html
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51. References:-
• AutoDock4.2.6_UserGuide.pdf
• How to prepare the environment to run
Autodock in Windows Operating
System.pdf
• Turning Docking and Virtual Screening as
simple as it can get....html
• drug discovery.pdf
• drug dock.pdf
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52. Recommendation
DGIdb - Interaction Search Results
http://www.drugbank.ca/
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