Abstract
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.
Highlights
High-throughput screening (HTS) is an essential enabling technology for translational research that can have endpoints of drug discovery or probe discovery [1]
FACs analysis showed a 2–5-fold increase in fetal globin positive cells. These results indicate that the actives identified in the high throughput screening assay using a reporter assay were functional as HbF inducers under a physiologically relevant human primary erythroid cells
FACs analysis showed a 2–5‐fold increase in fetal globin positive cells. These results indicate that the actives identified in the high throughput screening assay using a reporter Haisgsha-Tyhrowugehrpeut a2l0s1o8, 7fu, 4nctional as HbF inducers under a physiologically relevant human pr1i0mofa1r4y erythroid cells
Summary
High-throughput screening (HTS) is an essential enabling technology for translational research that can have endpoints of drug discovery or probe discovery [1]. The end point of drug discovery is a complex process that leads to identification of a drug candidate that has potential for becoming a marketed drug Drug discovery is both a cost- and time-intensive process that requires integration of expertise from various specialized teams and can take up to 15 years to bring a candidate molecule to the market. The high costs and risks and long timelines of real world drug discovery are not compatible with the much shorter project milestones and small research budgets of the academic world [2]. Notable exceptions to this generalization include academic labs that pursue comprehensive early and pre-clinical drug discovery research programs. Probe discovery accommodates the vast array of targets and biological systems that academics pursue regardless of commercial return on investment value
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