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

Global Malaria Endemicity

Plasmodium falciparum

1-3 million people killed Infection via bite of infected mosquito Symptoms include:

- Fever- Headache- Vomiting

Current treatment:- artemisinin-based combination therapies

Venn Diagram

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

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

Search Criteria (3):Selectivity

- Look for genes that do not have orthologs in human hosts

Search Criteria (4): Stage Specificity Life Cycle of Plasmodium sp.

Search Criteria (4): Stage Specificity

- Look for genes that are highly upregulated in Blood (Intraerythrocytic) Stage

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

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

Assign Weights + Combine

- After searching, we could rank targets by assigning scores/ weights to each query

- And combine queries - (Union)

Ranked List of Targets

- After combination, targets fit more than one query will have scores added & ordered by descending score

5 Selected Drug Targets

5 drug targets were selected among top scoring ones Selected on the basis of:

- Essentiality- Druggability- Structure- Assayability- Validity

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

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