AP 4. Drug Screening and Pharmacology

摘要：AP 4 PMS-ICBG的这一联合项目将测试AP 3中确定的天然产品， 治疗多种重要疾病的潜力。我们在选择防治疾病目标时考虑到：1）未实现的目标 人类健康的需求; 2）菲律宾的健康需求; 3）与我们的生态理论有密切联系的测定 和共生研究在AP 2; 4），提供了一个创新和保守的药物治疗方法的组合 的发现我们的检测针对涉及神经元受体、离子通道和其他蛋白质的条件; 胰腺癌;胶质母细胞瘤;泛耐药“ESKAPE”感染;和顶复寄生虫 感染，重点是隐孢子虫和弓形虫。此外，我们还与 适当的实体，有进一步的分析，并非常适合帮助我们翻译发现 转化为对人类健康有积极影响的产品。 本AP的一个特别创新的焦点是我们使用了最近发明的“星座药理学” 方法，其提供了针对天然分化的哺乳动物细胞的高内容筛选方法 类型初步数据显示，这种方法在寻找非常具有挑战性的靶点的配体方面非常有前途， 在这里我们将通过筛选天然产物来进一步研究。这种方法和其他创新方法 通过经过时间考验的药物发现方法得到加强，以提供相对全面的筛选 我们的图书馆。 最后，我们已经制定了策略来验证命中并在早期确定其翻译潜力， 问题研究作为该计划的一部分，将对有前途的候选人进行进一步调查。 为了实现这些目标，我们计划： 1)从AP 3提取屏幕优先级; 2)采用星座筛选用于神经和癌症药物发现; 3)采用新的检测方法发现抗生素; 4)采用新的寄生虫检测方法; 5)确定分子靶点并进一步开发化合物。

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.