Chemoproteomics-driven drug discovery: addressing high attrition rates
Drug Discovery Today(2006)
Abstract
The advent of multiple high-throughput technologies has brought drug discovery round almost full circle, from pharmacological testing of compounds in vivo to engineered molecular target assays and back to integrated phenotypic screens in cells and organisms. In the past, primary screens to identify new pharmacological agents involved administering compounds to an animal and monitoring a pharmacologic endpoint. For example, antihypertensive agents were identified by dosing spontaneously hypertensive rats with compounds and observing whether their blood pressure dropped. In taking this phenomenological approach, scientists were focused on the final goal, in this example lowering of blood pressure, rather than developing an understanding of the target, or targets, the compounds were impacting. With the evolution of rational target-based approaches, scientists were able to study the direct interaction of compounds with their intended targets, expecting that this would lead to more-selective and safer therapeutics. With the industrialization of screening, referred to as HTS, hundreds of thousands of compounds were screened in robot-driven assays against targets of interest (with this goal in mind). However, an unintentional outcome of the migration from in vivo primary screens to highly target-specific HTS assays was a reduction in biological context caused by the separation of the target from other cellular proteins and processes that might impact its function. Recognition of the potential consequences of this over-simplification drove the modification of HTS processes and equipment to be compatible with cellular assays.
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Key words
drug discovery,chemoproteomics-driven
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