systems pharmacology 1: drug re-positioning prediction

Drug repositioning& Drug combination

PredictionSystems Pharmacology

NGS in Systems Biology workshop

By: Ali Kishk

Drug repositioning• Drug repositioning is the application of

known drugs and compounds to new indications.

Method1-Getting the expression levels of a Drug / small molecule effect “e.g. : Salbutamol” on a specific cell line “e.g. : A495”.

2-Using the down expression levels for Enrichment for diseases.

So What is Enrichment ?& How we will get the expression level of a drug / small molecule??

LINCS database

LINCs L1000 database

• Provide gene expression profiles induced by over 10 000 compounds, shRNAs, and kinase inhibitors using the L1000 platform.

• aka The Connectivity Map

Enrichment Analysis• Searching a list of genes to label• To classify them by Pathways, Diseases, Transcription factor.

• Here we will use Enrichr.

web-based software application that facilitates querying,browsing and interrogating many of the currently available LINCS L1000 data

•

LINCS Canvas Browser

How to predict a new use of a drug “e.g. : salbutamol” ?? Steps :1- Get the LINCS L1000 gene list of the drug using LINCS Canvas Browser2-Search for Enrichment for diseases using Enrichr with the Down regulated genes.

1-Getting the LINCS L1000 gene list of the drug using LINCS Canvas BrowserSteps :• 1- Open LINCs Canvas browser.• 2- In the search menu, Type * to indicate whatever you type.• 3-continue after * by typing the drug name, the autocomplete feature

will show a list of candidate experiment.• 4-select your desired related cell line from the list “ you can search

L1000CDS2 cell line to see related tissues: L1000CDS2 CCLE signature• http://amp.pharm.mssm.edu/L1000CDS2/#/index”

1-Getting the LINCS L1000 gene list of the drug using LINCS Canvas BrowserContinueSteps :• 5-Wait until the downloading is finished.• 6-On the down right, You will see “Down regulated genes”, right click

on it then select “Inspect”• 7-Click CTRL+ F then search “dnGenes”, You will find a list that

resembles down regulated genes. Copy this list to a notepad then rename it “Down genes”

• 8-repeat 6&7 to the up regulated genes.

Demo 1

Then save the gene list as down genes.txt

LINCS Canvas Browser Continue : If your desired drug doesn’t appear in LINCs Canvas Browser: 1- open m.ncbi.nlm.nih.gov/compound/ .2- Search the PubChems for your drug / small molecule.3- Copy the CID number.4- Edit this API with your PubChem ID.api.lincscloud.org/a2/pertinfo?q={"pubchem_cid":"45375808"}&user_key=lincsdemo5-copy and paste it in your browser then search for “alt_iname” by CTRL+F, then use this name in the LINCS canvas browser.

If your desired drug doesn’t appear in LINCs Canvas Browser:• NB :

• If Step 5 return wit no result on your browser, Then there is any pertubagen is done yet by your drug / small molecule.

• Try many CID in the API if your search on PubChem ID return with many result “eg: many salt or ester forms of the drug”

2-Enrichment Analysis for

diseases using Enrichr with the Down

regulated genes.

Goal :2- What are the top diseases Enriched ? And what genes are involved ?

Enrichr:An integrative web-based and mobile software application that includes new gene-set libraries, an alternative approach to rank enriched terms, and various interactive visualization approaches to display enrichment results 

Enrichr Steps for diseases :• 1- Open Enrichr site : amp.pharm.mssm.edu/Enrichr/• 2- enter the gene list “down-regulated”• 3- Click Disease/Pheotype tab• 4- Choose dbgap.

Enrichr output• The top results is list of diseases has the most enriched gene list with

our gene list.

• Bar Graph : can be changed by clicking to any bar due to changing the statistical test.

• Table : can be exported to excel file

Try it out with our gene list

Open the exported file as an Excel sheet

The shared genes between your gene-list & each disease.

Thank You Ph.ali.kishk@gmail.com

linked-in : https://eg.linkedin.com/in/ali-kishk-997423a9