Jnana Therapeutics, One Design Center Pl Suite 19-400, Boston, Massachusetts 02210, United States.
J Med Chem. 2023 Jun 8;66(11):7101-7139. doi: 10.1021/acs.jmedchem.3c00521. Epub 2023 May 24.
An analysis of 156 published clinical candidates from the 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.
对 2018 年至 2021 年间发表的 156 个临床候选药物进行了分析，以确定导致药物候选物的最常用的先导化合物发现策略。与之前的出版物一样，导致临床候选物的最常见的先导化合物发现策略是基于已知化合物（59%），其次是随机筛选方法（21%）。其余方法包括定向筛选、片段筛选、DNA 编码化合物库筛选（DEL）和虚拟筛选。还根据 Tanimoto-MCS 进行了相似性分析，结果表明大多数临床候选物与其原始苗头化合物的距离较远；然而，它们大多共享一个关键的药效团，该药效团可以从苗头化合物转化为临床候选物。还对临床候选物中氧、氮、氟、氯和硫的掺入频率进行了考察。对随机筛选中最相似和最不相似的苗头-临床对进行了考察，以期了解导致成功的临床候选物的变化情况。
