drug discovery using bioinformatic

Structural Bioinformatics in Drug Discovery

By: Suhad Jihad Msc. Software Engineering

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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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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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http://www.genomethreader.org/

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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Drug Discovery need time and money

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Drug discovery Process :

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Bioinformatics in drug discoveryThe 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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Drug discovery

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Drug discovery

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Drug discovery

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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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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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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.

Drug discovery-Druggable genome

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Drug discovery-Ligand

:It is a (usually small) molecule that binds to a biological macromolecule.

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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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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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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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• 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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• 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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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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New Drug Discovery- Molecular Targeted Therepies

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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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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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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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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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Bioinformatics and drug discovery:Insilico Methods in Drug DiscoveryComputational tools offer the advantage of

delivering new drug candidates more quickly and at a lower cost.

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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 docking 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...

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Stages of High throughput docking for protein –ligand complex binding...

Bioinformatics and drug discovery:Molecular docking 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.

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Molecular docking-Step by StepMolecular docking-Step by StepWhat 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.

Get that Linux feeling - on Windows .

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http://en.wikipedia.org/wiki/Linux_distribution

http://linux.org/

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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Molecular docking-Step by StepMolecular docking-Step by StepOpen this file from Discovery Studio 4.1View 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 MoleculesEdit-Delete. Scripts-Selection-Select protein chains

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Molecular docking-Step by StepMolecular docking-Step by StepEdit-delete.Then save the ligand as ligand.pdb in the

folder for MGL tools.Then open 1hsg again go to Script –

Selection-LigandEdit-delete.Script-Select-Select Water MoleculesEdit-delete.Save as 1hsg.pdb at MGLTool folder.

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Molecular docking-Step by StepMolecular docking-Step by StepExit 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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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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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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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.pdbqtligand=ligand.pdbqt

out=out.pdbqt

center_x=16.072center_y=26.5007center_z=3.7748

size_x=26size_y=26size_z=26

exhaustiveness=8

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 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

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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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GlossaryGlossaryProtease : an enzyme which breaks down proteins and peptides

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Future Drug-personalised medicine• is the tailoring of

drug treatments to people’s genetic makeup a form of personalized medicine.

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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.htmlIdentifying targets for drug discovery using

bioinformatics. - PubMed - NCBI.htmlDrug and target protein structures in the

PDB.html50

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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RecommendationDGIdb - Interaction Search Resultshttp://www.drugbank.ca/

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