An analysis of 156 published clinical candidates fromthe Journal of Medicinal Chemistry between 2018 and2021 wasconducted to identify lead generation strategies most frequently employedleading to drug candidates. As in a previous publication, the mostfrequent lead generation strategies resulting in clinical candidateswere from known compounds (59) followed by random screening approaches(21). The remainder of the approaches included directed screening,fragment screening, DNA-encoded library screening (DEL), and virtualscreening. An analysis of similarity was also conducted based on Tanimoto-MCSand revealed most clinical candidates were distant from their originalhits; however, most shared a key pharmacophore that translated fromhit-to-clinical candidate. An examination of frequency of oxygen,nitrogen, fluorine, chlorine, and sulfur incorporation in clinicalcandidates was also conducted. The three most similar and least similarhit-to-clinical pairs from random screening were examined to provideperspective on changes that occur that lead to successful clinicalcandidates.
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