In the pursuit of drug discovery efforts, it can be tempting to try to accelerate access to chemical starting points using predictive methods to minimize the size of screening sets based on structural homology with natural substrates or other previously reported ligands.  However, staged investments in exploratory screening strategies can often reveal that targets can be successfully engaged with drug-like starting points bearing little resemblance to their native biological ligands.  In addition to the advantages of evaluating structural diversity, atypical mechanisms of drug action (eg, non-competitive or un-competitive binding) can also be discovered that can help accelerate the resolution of challenges such as translation to in vivo efficacy or selectivity vs target family homologs.  Thus, a thorough experimental evaluation of the intersection between the available chemistry space and the biology of interest can pay significant dividends by enabling teams to initiate research efforts from starting points that are much closer to the finish line.  Selected vignettes from our research efforts will be presented to illustrate the advantages of “finding out what you don’t know”.<br/>

Find out what you don't know: A recurring lesson from years of lead generation research

254th National Meeting (2017)

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