CHEMICAL SCREENING AND OPTIMIZATION FACILITY- HIGH THROUGHPUT SCREENING

点击翻译按钮获取中文摘要

Background: The Contraception Research Branch (CRB) within the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) supports research to develop compounds that can disrupt oogenesis, spermatogenesis, normal ovulation, sperm maturation and/or function affording safe and effective contraceptives that can be implemented for men and/or women. The Chemical Screening and Optimization Facility (CSOF) is designed to fulfill a unique role by identifying, optimizing, and conducting small scale production of molecular agents that achieve a contraceptive effect. The CSOF provides overall project management and the capabilities to support these objectives pursuant to development of new contraceptive methods: these include but are not limited to, the generation of recombinant peptides and proteins, assay development high throughput screening (HTS), x-ray crystallography, computational chemistry, medicinal chemistry, and pharmacology. Compounds identified and optimized by the CSOF will be prepared under non-Good Manufacturing Practices (non-GMP) for further preclinical evaluation. The CSOF plays a critical role in the drug development mission of the CRB. Scope and Objectives: One approach to achieve this goal includes high throughput screening studies for the purpose of identifying hit compounds. The research directed by this task order will utilize either in-house methods or appropriate subcontract facilities capable of high throughput screening, confirm a tory assays (as needed) or in silico methods (as needed) or will be done in conjunction with a successful service request applicant who would assume responsibility for all biochemical and/or biological assays. Specifically, this Task Order is for the identification of small molecule(s) hits that engages a validated target either for inhibition or activation of a process with the net outcome being male and/or female contraception. It is expected that for a given service request up to 100 new chemical entities will be identified with biological properties consistent with conventional bioavailability design parameters (e.g. Lipinski’s Rule of 5) over a period of up to twelve months. At the conclusion of which, the identified hit compound/small molecule(s) will have a significant improvement over established positive controls for ligand affinity (e.g., IC50 < 1 uM, up to 100fold improvement compared to positive control) as demonstrated using identified biochemical assays, false positive considerations, safety considerations (PAINs compliant), and isoforms electivity (>25 fold, if applicable).