Phenotypic Drug Discovery: History, Evolution, Future
David C. Swinney · Royal Society of Chemistry eBooks · 2020
Historically, empirical observations of phenotypic changes have played a pivotal role in the discovery of new medicines. Scientists and organizations that endeavor to discover new medicines employ all available knowledge and expertise to identify the best starting points and strategies. Unfortunately, knowledge gaps exist between the understanding of disease and the identification of useful therapeutics. History shows a progression in utilizing new knowledge to reduce the uncertainty and reliance on serendipity: from Ehrlich's ideas of ‘chemotherapy’ and ‘magic bullets’, to Black and Janssen's desire to start with ‘pharmacologically active compounds’, to Hitchings and Elion's strategy to utilize ‘new biochemical understandings’, and most recently, the use of genetics and genomics to identify drug targets. Throughout this evolution of knowledge and strategies, trial-and-error empiricism was required to bridge the translational knowledge gap in order to identify first-in-class compounds. Recently, the reliance upon empiricism was formalized as phenotypic drug discovery (PDD). At the core of PDD is an unbiased selection of drug candidates without prior assumptions as to how the candidate will work. PDD is evolving to a more formalized strategy to help address the uncertainty and risk associated with using empiricism to bridge mechanistic knowledge gaps.