abp final slides
TRANSCRIPT
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Aim: Prioritising 5 novel drug targets for P. falciparum
Clara Lin
Rohan Puri
Mushira Che Mokhtar
Joyna Chen
Eric
Kuek Li-eon
Billy Po
Colleen Chan
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Global Malaria Endemicity
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Plasmodium falciparum
1-3 million people killed Infection via bite of infected mosquito Symptoms include:
- Fever- Headache- Vomiting
Current treatment:- artemisinin-based combination therapies
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Venn Diagram
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Criteria for prioritizing drug targets
Essentiality The drug target has to be an essential gene in
Plasmodium falciparum (or other organism?) Essential genes required for fungal or bacterial
growth, plus viability Inhibition of essential enzymes kills parasite High priority
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Criteria for prioritizing drug targets
Druggability The ability to produce a drug against
drug target A measure of whether a particular
gene can be targeted by compounds that are efficient
Presence of proteins that favours interactions with drug-like chemical compounds
High priority In 1990s, many compounds were
terminated in clinical development, thus important to address this matter
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Search Criteria (3):Selectivity
- Look for genes that do not have orthologs in human hosts
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Search Criteria (4): Stage Specificity Life Cycle of Plasmodium sp.
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Search Criteria (4): Stage Specificity
- Look for genes that are highly upregulated in Blood (Intraerythrocytic) Stage
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Structure-based drug design
X-ray crystallography 21 protein with known
structures,13 of them have inhibitors.
Difficult to crystallize the protein and express and clone in E.coli
It is a method still in its infancy
But Structure-based strategy still can provides us high value of drug targets.
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Mehlin C. (2005) Comb. Chem&High Throughput screening
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Assayability
Refers to the feasibility of performing an assay for an enzyme based on the availability of protocols and reagents
Useful for targets validation Difficulties in producing soluble recombinant protein
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Assign Weights + Combine
- After searching, we could rank targets by assigning scores/ weights to each query
- And combine queries - (Union)
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Ranked List of Targets
- After combination, targets fit more than one query will have scores added & ordered by descending score
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5 Selected Drug Targets
5 drug targets were selected among top scoring ones Selected on the basis of:
- Essentiality- Druggability- Structure- Assayability- Validity
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Drug target example: adenosine deaminase
• Fulfills all previously mentioned criteria
• Has druggability of 1
• Involved in purine metabolism
• Has evidence of in vivo inhibition PDB sructure
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Conclusion
No proper vaccine available Drug targets What is bioinformatics? Use of bioinformatics in drug targeting
research TDR targets database (www.tdrtargets.com) Now that we’ve prioritised our 5 drugs
targets, what next? Limitations Conclusion: New & better drug targets