Where Do Recent Small Molecule Clinical Development Candidates Come From?
Where Do Recent Small Molecule Clinical Development Candidates Come From?
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DOI：
10.1021/acs.jmedchem.8b00675
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发表时间：
2018-11-08
影响因子：
7.3
通讯作者：
Bostrom, Jonas
中科院分区：
文献类型：
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作者：
Brown, Dean G.;Bostrom, Jonas
对《药物化学杂志》发表的66名临床候选药物进行了分析，以揭示哪些线索产生策略最常用于识别候选药物。最常见的铅生成策略(生产候选药物)是基于从先前已知的化合物获得的起点(43%)，然后是随机的高通量筛选(29%)。其余的方法包括聚焦筛选、基于结构的药物设计(SBDD)、基于片段的先导生成(FBLG)和DNA编码文库筛选(DEL)。对Hit-to临床配对的物理化学性质的分析表明，平均分子量增加(Delta min=+85)，但亲脂性没有变化(Delta ClogP=-0.2)，尽管注意到例外情况。大多数(>；50%)的临床候选人被发现在结构上与他们的起点非常不同，并且更加复杂。最后，讨论了几种使用SBDD方法的共价弹头修饰非共价支架的报道。
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 (Delta MIN = +85) but no change in lipophilicity (Delta clogP = -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.