Many of the key steps in early drug discovery have benefited from the application of affinity-based mass spectroscopy screening technologies, including lead identification in HTS, target identification and purification, the characterization of modification sites on proteins, and the detection and optimization of preclinical candidates. Although many affinity methods have been around for decades, only recently have their utility been truly recognized and shown great promise in supporting the pharmaceutical industry's future lead discovery needs. When combined with mass spectrometry, affinity techniques offer high-resolution structural and biophysical insights into lead identification. They have been used to address some difficult and limiting factors in the early stages of drug discovery, including exploring the drugability of a biological target, providing both rank ordering and affinity measurements of bound ligand(s), and facilitating rapid SAR development to get lead compounds to the clinic faster. The development of several high throughput ultrafiltration affinity screening methods coupled to MS have greatly aided these endeavors. Such technologies work with any soluble target and small molecule library, they are amenable to parallelization, allowing for efficient and robust study of many targets against very large libraries on the basis of affinity, and they are designed to identify target-specific binders over a broad range of structural classes and affinities. The growing efficacy of these methodologies have surfaced at a time where the need for more efficient HTS assays and tools used for early lead identification in the pharmaceutical industry is at its highest point in history. Presently, more funds are spent on drug discovery than those returned from the steadily decreasing number of drugs reaching the market, and the result is increasing economic pressure on many big pharmaceutical companies. However, based on the promising reports of late, we anticipate a significant increase in the number of leads identified using affinity-based mass spec-trometry technologies in the near future.
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