ABP FINAL SLIDES

Aim: Prioritising 5 novel drug targets for P. falciparum : 

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 : 

Global Malaria Endemicity

Plasmodium falciparum : 

Plasmodium falciparum 1-3 million people killed Infection via bite of infected mosquito Symptoms include: Fever Headache Vomiting Current treatment: - artemisinin-based combination therapies

Slide 5: 

Venn Diagram

Criteria for prioritizing drug targets : 

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 : 

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 : 

Search Criteria (3):Selectivity Look for genes that do not have orthologs in human hosts

Search Criteria (4): Stage Specificity : 

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

Search Criteria (4): Stage Specificity : 

Search Criteria (4): Stage Specificity - Look for genes that are highly upregulated in Blood (Intraerythrocytic) Stage

Structure-based drug design : 

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. Mehlin C. (2005) Comb. Chem&High Throughput screening

Assayability : 

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 : 

Assign Weights + Combine After searching, we could rank targets by assigning scores/ weights to each query And combine queries (Union)

Ranked List of Targets : 

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 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 : 

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 : 

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