Early Probe and Drug Discovery in Academia: A Minireview.
Early Probe and Drug Discovery in Academia: A Minireview.
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DOI：
10.3390/ht7010004
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发表时间：
2018-02-09
期刊：
影响因子：
--
通讯作者：
Roy A
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文献类型：
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作者：
Roy A
药物发现涵盖从靶标选择和验证到开发候选药物选择的过程。虽然全面的药物发现工作流程主要在大型制药领域实施，但学术界的早期发现重点是识别可作为研究靶点或途径的工具的探针分子。尽管私营部门和学术部门的最终目标存在差异，但早期发现研究的最佳实践定义了相同的基本原则。成功的早期发现计划建立在强大的目标定义和验证的基础上，使用与所研究的生物系统功能相关的多种生化和基于细胞的检测方法。被确定为命中的化学物质经过了广泛的支架优化，并在体外和动物模型中以其靶标特异性和脱靶效应为特征。虽然筛选活动中的活性化合物通过高度严格的化学和吸收、分布、代谢和排泄 (ADME) 过滤器进行先导化合物鉴定，但探针发现涉及有限的药物化学优化。探针发现的目标是鉴定在所研究的目标背景下具有亚微米活性和合理选择性的化合物。从探针发现中鉴定出的化合物也可以作为先导化合物优化研究的起始支架。
Drug discovery encompasses processes ranging from target selection and validation to the selection of a development candidate. While comprehensive drug discovery work flows are implemented predominantly in the big pharma domain, early discovery focus in academia serves to identify probe molecules that can serve as tools to study targets or pathways. Despite differences in the ultimate goals of the private and academic sectors, the same basic principles define the best practices in early discovery research. A successful early discovery program is built on strong target definition and validation using a diverse set of biochemical and cell-based assays with functional relevance to the biological system being studied. The chemicals identified as hits undergo extensive scaffold optimization and are characterized for their target specificity and off-target effects in in vitro and in animal models. While the active compounds from screening campaigns pass through highly stringent chemical and Absorption, Distribution, Metabolism, and Excretion (ADME) filters for lead identification, the probe discovery involves limited medicinal chemistry optimization. The goal of probe discovery is identification of a compound with sub-µM activity and reasonable selectivity in the context of the target being studied. The compounds identified from probe discovery can also serve as starting scaffolds for lead optimization studies.