Hit Discovery, Discovery Sciences, IMED Biotech Unit , AstraZeneca , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.
Medicinal Chemistry, Cardiovascular, Renal and Metabolism, IMED Biotech Unit , AstraZeneca , Pepparedsleden 1 , Gothenburg SE-431 83 , Sweden.
J Med Chem. 2018 Nov 8;61(21):9442-9468. doi: 10.1021/acs.jmedchem.8b00675. Epub 2018 Jul 9.
An analysis of 66 published clinical candidates from Journal of Medicinal Chemistry has been conducted to shed light on which lead generation strategies are most frequently employed in identifying drug candidates. The most frequent lead generation strategy (producing a drug candidate) was based on starting points derived from previously known compounds (43%) followed by random high throughput screening (29%). The remainder of approaches included focused screening, structure-based drug design (SBDD), fragment-based lead generation (FBLG), and DNA-encoded library screening (DEL). An analysis of physicochemical properties on the hit-to-clinical pairs shows an average increase in molecular weight (ΔMW = +85) but no change in lipophilicity (ΔclogP = -0.2), although exceptions are noted. The majority (>50%) of clinical candidates were found to be structurally very different from their starting point and were more complex. Finally, several reports of noncovalent scaffolds modified by a covalent warhead using SBDD approaches are discussed.
对《药物化学杂志》（Journal of Medicinal Chemistry）中 66 个已发表的临床候选药物进行了分析，以阐明在确定药物候选物时最常采用的哪些先导化合物生成策略。最常采用的先导化合物生成策略（产生药物候选物）是基于源自先前已知化合物的起始点（43%），其次是随机高通量筛选（29%）。其余方法包括有针对性的筛选、基于结构的药物设计（SBDD）、基于片段的先导化合物生成（FBLG）和 DNA 编码文库筛选（DEL）。对命中至临床配对物的物理化学性质进行分析表明，分子量平均增加（ΔMW = +85），但脂溶性（Δ clogP = -0.2）没有变化，尽管有例外。大多数（>50%）临床候选药物与起始点相比在结构上有很大的不同，而且更加复杂。最后，讨论了一些使用 SBDD 方法通过共价弹头修饰非共价支架的报告。
