Aim: Prioritising 5 novel drug targets for  P. falciparum Clara Lin Rohan Puri Mushira Che Mokhtar Joyna Chen Eric Kuek Li...
Global Malaria Endemicity
Plasmodium falciparum <ul><li>1-3 million people killed </li></ul><ul><li>Infection via bite of infected mosquito </li></u...
 
Venn Diagram
Criteria for prioritizing drug targets <ul><li>Essentiality </li></ul><ul><ul><li>The drug target has to be an essential g...
Criteria for prioritizing drug targets <ul><li>Druggability </li></ul><ul><ul><li>The ability to produce a drug against dr...
Search Criteria (3):Selectivity <ul><li>Look for genes that do not have orthologs in human hosts </li></ul>
Search Criteria (4): Stage Specificity Life Cycle of  Plasmodium sp.
Search Criteria (4): Stage Specificity <ul><li>-  Look for genes that are highly upregulated in Blood (Intraerythrocytic) ...
Structure-based drug design <ul><li>X-ray crystallography </li></ul><ul><li>21 protein with known structures,13 of them ha...
Assayability <ul><li>Refers to the feasibility of performing an assay for an enzyme based on the availability of protocols...
Assign Weights + Combine <ul><li>After searching, we could rank targets by assigning </li></ul><ul><ul><ul><li>scores/ wei...
Ranked List of Targets <ul><li>-  After combination, targets fit more than one query will have scores added & ordered by d...
5 Selected Drug   Targets <ul><li>5 drug targets were selected among top scoring ones </li></ul><ul><li>Selected on the ba...
Drug target example: adenosine    deaminase <ul><li>Fulfills all previously mentioned criteria </li></ul><ul><li>Has drugg...
Conclusion <ul><li>No proper vaccine available    Drug targets </li></ul><ul><li>What is bioinformatics? </li></ul><ul><l...
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  • Abp Final Slides

    1. 1. 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
    2. 2. Global Malaria Endemicity
    3. 3. Plasmodium falciparum <ul><li>1-3 million people killed </li></ul><ul><li>Infection via bite of infected mosquito </li></ul><ul><li>Symptoms include: </li></ul><ul><ul><li>Fever </li></ul></ul><ul><ul><li>Headache </li></ul></ul><ul><ul><li>Vomiting </li></ul></ul><ul><li>Current treatment: </li></ul><ul><li>- artemisinin-based combination therapies </li></ul>
    4. 5. Venn Diagram
    5. 6. Criteria for prioritizing drug targets <ul><li>Essentiality </li></ul><ul><ul><li>The drug target has to be an essential gene in Plasmodium falciparum (or other organism?) </li></ul></ul><ul><ul><li>Essential genes required for fungal or bacterial growth, plus viability </li></ul></ul><ul><ul><li>Inhibition of essential enzymes kills parasite </li></ul></ul><ul><ul><li>High priority </li></ul></ul>
    6. 7. Criteria for prioritizing drug targets <ul><li>Druggability </li></ul><ul><ul><li>The ability to produce a drug against drug target </li></ul></ul><ul><ul><li>A measure of whether a particular gene can be targeted by compounds that are efficient </li></ul></ul><ul><ul><li>Presence of proteins that favours interactions with drug-like chemical compounds </li></ul></ul><ul><ul><li>High priority </li></ul></ul><ul><ul><li>In 1990s, many compounds were terminated in clinical development, thus important to address this matter </li></ul></ul>
    7. 8. Search Criteria (3):Selectivity <ul><li>Look for genes that do not have orthologs in human hosts </li></ul>
    8. 9. Search Criteria (4): Stage Specificity Life Cycle of Plasmodium sp.
    9. 10. Search Criteria (4): Stage Specificity <ul><li>- Look for genes that are highly upregulated in Blood (Intraerythrocytic) Stage </li></ul>
    10. 11. Structure-based drug design <ul><li>X-ray crystallography </li></ul><ul><li>21 protein with known structures,13 of them have inhibitors. </li></ul><ul><li>Difficult to crystallize the protein and express and clone in E.coli </li></ul><ul><li>It is a method still in its infancy </li></ul><ul><li>But Structure-based strategy still can provides us high value of drug targets. </li></ul>Mehlin C. (2005) Comb. Chem&High Throughput screening
    11. 12. Assayability <ul><li>Refers to the feasibility of performing an assay for an enzyme based on the availability of protocols and reagents </li></ul><ul><li>Useful for targets validation </li></ul><ul><li>Difficulties in producing soluble recombinant protein </li></ul>
    12. 13. Assign Weights + Combine <ul><li>After searching, we could rank targets by assigning </li></ul><ul><ul><ul><li>scores/ weights to each query </li></ul></ul></ul><ul><li>And combine queries </li></ul><ul><li>(Union) </li></ul>
    13. 14. Ranked List of Targets <ul><li>- After combination, targets fit more than one query will have scores added & ordered by descending score </li></ul>
    14. 15. 5 Selected Drug Targets <ul><li>5 drug targets were selected among top scoring ones </li></ul><ul><li>Selected on the basis of: </li></ul><ul><li>Essentiality </li></ul><ul><li>Druggability </li></ul><ul><li>Structure </li></ul><ul><li>Assayability </li></ul><ul><li>Validity </li></ul>
    15. 16. Drug target example: adenosine deaminase <ul><li>Fulfills all previously mentioned criteria </li></ul><ul><li>Has druggability of 1 </li></ul><ul><li>Involved in purine metabolism </li></ul><ul><li>Has evidence of in vivo inhibition </li></ul>PDB sructure
    16. 17. Conclusion <ul><li>No proper vaccine available  Drug targets </li></ul><ul><li>What is bioinformatics? </li></ul><ul><li>Use of bioinformatics in drug targeting research </li></ul><ul><li>TDR targets database ( www.tdrtargets.com ) </li></ul><ul><li>Now that we’ve prioritised our 5 drugs targets, what next? </li></ul><ul><li>Limitations </li></ul><ul><li>Conclusion: New & better drug targets </li></ul>
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