UCSF-CDD Community Meeting. Panel Introduction One example: Applying Open Collaborative Drug Discovery to Malaria Drug Resistance

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1 UCSF-CDD Community Meeting Panel Introduction One example: Applying Open Collaborative Drug Discovery to Malaria Drug Resistance

2 Acknowledgements Chibale Group, University of Cape Town Rosenthal Group, UCSF McKerrow Group, UCSF Dr. Christopher Lipinski FDA and Orphan Approved Drug Database

3 F e ( I I I ) Drug Resistance in Malaria: The Case of Chloroquine PARASITIZED RED BLOOD CELL Red blood cell Malaria parasite Food vacuole Haemozoin (malaria pigment) Proteases PARASITE FOOD VACUOLE (ph ~ 5.5) Peptides Autoxidation OH Detoxification Host haemoglobin haematin O OH HO O β-haematin (haemozoin) REACTIO IHIBITED BY CHLOROQUIE Cl OH Fe(III) Formation of stacked π-π complex O OH HO O

4 Chemosensitizers: a strategy to overcome resistance Compound that alone does not necessarily have intrinsic activity Compound that acts synergistically In this case to overcome chloroquine resistance

5 Three Sources of Chemosensitizers 1. atural products Chemosensitizers or resistance reversal agents 2. Synthetic libraries Pharmacophore combination or hybridization e.g. Reversed Chloroquine with Ar(C) 4 Me substructure 3. CDD community researcher database Scaffold-jumping and approved drugs

6 1-Aryl, 4-amino Unit and Synthetic Chemosensitizers C MeO Me MeO MeO OMe Verapamil Me Me Cl S Me H Chloropromazine Desipramine Cl HO CF 3 Me Amitriptyline Me Me Cyproheptadine F F Penfluridol

7 Chemosensitizer

8 s t n u o c M P C 3 H-CQ Accumulation in PfCRT-transformed and Untransformed Dictyostelium discoideum OMe OMe ontro l 0 C µ + 80 verapamil V PL M µ + 50 OMe OMe P 14 M µ + 50 MeO MeO P 32 M P14 P32 acts similar to that of VPL, which reverses CQ resistance potentially by hydrophobic binding to PfCRT thereby replacing the loss charge P14 appears to acts via a different mechanism Fe AX2 DD2 HB3 = Wild Type = mutant PfCRT carrying key charge loss mutation K76T = mutant PfCRT carrying T76K mutation MeO MeO O P32

9 Collaborative Approach to Identify Chemosensitizers Mine SAR in CDD-Chibale Group Database Identify a conserved chemosensitizer pharmacophore: Ar-(C) 4 --C Compare internal results with community databases: 1. McKerrow-CDD Database: Open-Content SAR 2. Lipinski-CDD Database: FDA & Orphan Drugs 3. Future Community Collaborations

10 CDD Community Open Access Data 1. Prof. McKerrow (UCSF) Open-Content drug discovery T. Brucei, T. Cruzi, S. Mansoni, Leishmania, P. falciparum 2. Dr. Christopher Lipinski (ex-pfizer) Chemoinformatics data on FDA and Orphan approved drugs 3. Prof. Roos (U. Penn) Modern Malaria literature data linked to genes 4. Prof. Gelb (UW) Modern Malaria literature data linked to assays 5. Prof. Guy (St. Jude CRH) >13,000 Army Malaria screening data dating back to WW-II after escrow period

11 McKerrow Group 237 Compounds with Ar(C) 4 C Pharmacophores

12 Lipinski-CDD Database of Approved Drugs with Ar(C) 4 C Pharmacophores

13 CDD Collaborative Road-Map

14 Viral Community Growth Flickr MySpace YouTube Keys to success community content, community recruiting: More diverse scientists contributing, the better Research recognition without duplicating efforts For Global Health

15 Collaborative Drug Discovery Panel Introductions Case Study Special Acknowledgement: Chibale Group University of Cape Town