1. Structural Bioinformatics in Drug Discovery
By: Suhad Jihad
Msc. Software Engineering

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. 

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 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

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

7. Drug Discovery need time and money

8. Drug discovery Process :

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)

10. Drug discovery

11. Drug discovery

12. Drug discovery

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?

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. …
What is druggable gene,target,ligand & receptor ?

15. Drug discovery-Target
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

17. Drug discovery-Ligand
:It is a (usually small) molecule that binds to a biological macromolecule.
Ligand

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?

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
agonist?
It turn the switch ON

20. Drug discovery-Receptor
Example on agonist :
If a patient was being treated for congestive heart failure, meaning the patient’s heart could not pump enough blood to the rest of his body, we would need to increase his cardiac output …

21. Drug discovery-Receptor
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.

22. Drug discovery-Receptor
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
Antagonist?
The antagonist turns the cell’s light switch OFF

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…
Antagonist?

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

25. Drug discovery-Receptor

26. New Drug Discovery- Molecular Targeted Therepies

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.

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.

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.

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.

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.

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….
Molecular docking

33. Bioinformatics and drug discovery: Molecular docking

34. Bioinformatics and drug discovery: Molecular 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...

35. Bioinformatics and drug discovery: Molecular docking
Stages of High throughput docking for protein –ligand complex binding...

36. Bioinformatics and drug discovery: Molecular 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.

37. Molecular 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 : a large collection of GNU and Open Source tools which provide functionality similar to a Linux distribution on Windows.
Get that Linux feeling - on Windows .

38. Molecular docking-Step by Step
Download 1 HSG from RCSB protein database
1HSG saved as 3D structure:
By x-ray we get

39. Molecular 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

40. Molecular 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
Script-Select-Select Water Molecules
Save as 1hsg.pdb at MGLTool folder.

41. Molecular 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.

42. Molecular 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=

44. Molecular docking-Step by Step
Z-center=
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

45. Molecular 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 :
receptor=1hsg.pdbqt
ligand=ligand.pdbqt
out=out.pdbqt
center_x=16.072
center_y=
center_z=3.7748
size_x=26
size_y=26
size_z=26
exhaustiveness=8

46. Molecular docking-Step by Step
Save and close conf.
Run cmd prompt .
Change the directory to vina folder in my computer C:\Program Files\The Scripps Research Institute\vina
Write on this folder
Vina --config conf.txt--log log.txt
After the execution
Write vina-split- -input out.pdbqt

47. Molecular 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.

48. Glossary
Protease : an enzyme which breaks down proteins and peptides

49. Future Drug-personalised medicine
Pharmacogenomics
is the tailoring of drug treatments to people’s genetic makeup a form of personalized medicine.

50. References:-
Role of bioinformatics and pharmacogenomics in drug discovery and development process – Springer
project\Personalized 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

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

52. Recommendation DGIdb - Interaction Search Results