AP 4. Drug Screening and Pharmacology

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Summary: AP4 This associate program of PMS-ICBG will test natural products identified in AP3 for their pharmaceutical potential in treating several important diseases. We have selected our disease targets by considering:1) unmet needs in human health; 2) health needs in the Philippines; 3) assays that have a strong tie to our eco-rationale and symbiosis studies in AP2; 4) that provide a mix of innovative and conservative approaches to drug discovery. Our assays target conditions that involve neuronal receptors, ion channels, and other proteins; pancreatic cancer; glioblastoma; pandrug-resistant "ESKAPE" infections; and apicomplexan parasite infections, with a focus on Crytosporidium and Toxoplasma. Further, we have formed interactions with appropriate entities that have further assays available and that are well suited to help us translate discoveries into products that will have a positive impact on human health. A particularly innovative focus of this AP is our use of the recently invented "constellation pharmacology" method, which provides a method for high-content screening against naturally differentiated mammalian cell types. Preliminary data show that this method is very promising in finding ligands for very challenging targets, and here we will take that further by screening natural products. This and other innovative methods proposed are reinforced with time-tested approaches to drug discovery to provide a relatively comprehensive screening of our library. Finally, we have developed strategies to validate hits and to determine their translational potential early on in studies. Promising candidates will be further investigated as part of this program. To achieve these goals, we plan to: 1) Screen priority extracts from AP3; 2) Employ constellation screening for neurological and cancer drug discovery; 3) Employ novel assays for antibiotic discovery; 4) Employ novel assays against parasites; 5) Identify molecular targets and further develop compounds.