An Analysis of Successful Hit-to-Clinical Candidate Pairs

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.