CHEMICAL SCREENING AND OPTIMIZATION FACILITY- HIGH THROUGHPUT SCREENING

化学筛选和优化设施 - 高通量筛选

• 批准号: 10421851
• 负责人: LEYI GONG
• 金额: $ 88.97万
• 依托单位: SRI INTERNATIONAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-28 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10421851
• 关键词: Affinity; Biochemical; Biological; Biological Assay; Biological Availability; Chemicals; Contraceptive Agents; Contraceptive methods; Development; Female Contraceptive Agents; Generations; Goals; Ligands; Male Contraceptive Agents; Methods; Mission; Molecular; National Institute of Child Health and Human Development; Oogenesis; Outcome; Ovulation; Pharmaceutical Chemistry; Pharmacology; Play; Process; Production; Property; Protein Isoforms; Recombinant Proteins; Research; Research Support; Role; Safety; Services; Sperm Maturation; Spermatogenesis; Woman; X-Ray Crystallography; assay development; computational chemistry; design; drug development; high throughput screening; in silico; men; preclinical evaluation; recombinant peptide; screening; small molecule

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).

背景： 尤尼斯·肯尼迪·施莱弗国家儿童健康和人类发展研究所(NICHD)内的避孕研究分部(CRB)支持研究开发能够扰乱卵子发生、精子发生、正常排卵、精子成熟和/或提供安全有效避孕措施的化合物，这些化合物可以为男性和/或女性提供安全有效的避孕措施。化学筛选和优化设施(CSOF)旨在通过识别、优化和进行小规模生产达到避孕效果的分子制剂来发挥独特的作用。CSOF根据新避孕方法的开发提供全面的项目管理和支持这些目标的能力，这些方法包括但不限于重组多肽和蛋白质的产生、分析开发和高通量筛选(HTS)、X射线结晶学、计算化学、药物化学和药理学。CSOF确定和优化的化合物将根据非良好制造规范(Non-GMP)进行制备，以进行进一步的临床前评估。CSOF在CRB的药物开发任务中发挥着关键作用。 范围和目标： 实现这一目标的一种方法包括高通量筛选研究，目的是鉴定命中化合物。本任务单指导的研究将利用能够高通量筛选的内部方法或适当的分包设施，确认Tory分析(根据需要)或采用计算机方法(根据需要)，或者将与负责所有生化和/或生物分析的成功服务请求申请者一起进行。具体地说，该任务顺序用于识别小分子(S)命中，该小分子命中涉及用于抑制或激活过程的验证目标，净结果为男性和/或女性避孕。对于给定的服务请求，预计将在长达12个月的时间内识别多达100个新的化学实体，其生物特性与传统的生物利用度设计参数(例如利平斯基规则5)一致。在这一结论中，确认的命中化合物/小分子(S)将显著改善已建立的阳性对照的配基亲和力(例如，IC50；1um，比阳性对照提高100倍)，如使用鉴定的生化分析、假阳性考虑、安全性考虑(符合疼痛)和异构体选择性(-gt；25倍，如果适用)所证明的那样。