Wheat from Chaff: General and Mechanistic Triage of Screening Hits for Enzyme Targets

INTRODUCTION Since the 1990s, high-throughput screening (HTS) has been, and will likely continue to be, a key engine to discover novel chemical starting points for optimization into enzyme-targeted, small-molecule therapeutics. But even from the introduction of HTS into the pharmaceutical industry, there has been ongoing debate surrounding the effectiveness of this approach, its total impact on drug discovery, and its benefits versus cost to the bottom line of building strong drug pipelines and delivering new drugs to patients (for example, see Ref. 1). Pursuing false leads from a screening campaign is therefore unacceptable, given the associated cost, loss of time, and loss of opportunity to deliver much-needed new drug product.