An Analysis of Successful Hit-to-Clinical Candidate Pairs

An analysis of 156 published clinical candidates from
the Journal of Medicinal Chemistry between 2018 and
2021 was
conducted to identify lead generation strategies most frequently employed
leading to drug candidates. As in a previous publication, the most
frequent lead generation strategies resulting in clinical candidates
were 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 virtual
screening. An analysis of similarity was also conducted based on Tanimoto-MCS
and revealed most clinical candidates were distant from their original
hits; however, most shared a key pharmacophore that translated from
hit-to-clinical candidate. An examination of frequency of oxygen,
nitrogen, fluorine, chlorine, and sulfur incorporation in clinical
candidates was also conducted. The three most similar and least similar
hit-to-clinical pairs from random screening were examined to provide
perspective on changes that occur that lead to successful clinical
candidates.