Innovative Drug Research and Bioinformatics Group, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Innovative Drug Research and Bioinformatics Group, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
Anticancer Agents Med Chem. 2019;19(2):194-203. doi: 10.2174/1871520618666181029132017.
Despite the substantial contribution of natural products to the FDA drug approval list, the discovery of anti-cancer drugs from the huge amount of species on the planet remains looking for a needle in a haystack.
Drug-productive clusters in the phylogenetic tree are thus proposed to narrow the searching scope by focusing on much smaller amount of species within each cluster, which enable prioritized and rational bioprospecting for novel drug-like scaffolds. However, the way anti-cancer nature-derived drugs distribute in phylogenetic tree has not been reported, and it is oversimplified to just focus anti-cancer drug discovery on the drug-productive clusters, since the number of species in each cluster remains too large to be managed.
In this study, 260 anti-cancer drugs approved in the past 70 years were comprehensively analyzed by hierarchical clustering of phylogenetic distribution.
207 out of these 260 drugs were derived from or inspired by the natural products isolated from 58 species. Phylogenetic distribution of those drugs further revealed that nature-derived anti-cancer drugs originated mostly from drug-productive families that tend to be clustered rather than scattered on the phylogenetic tree. Moreover, based on their productivity, drug-producing species were categorized into productive (CPS), newly emerging (CNS) and lessproductive (CLS). Statistical significances in druglikeness between drugs from CPS and CLS were observed, and drugs from CNS were found to share similar drug-like properties to those from CPS.
This finding indicated a great raise in drug approval standard, which suggested us to focus bioprospecting on the species yielding multiple drugs and keeping productive for long period of time.
尽管天然产物对 FDA 批准的药物清单做出了巨大贡献，但从地球上大量物种中发现抗癌药物仍然是大海捞针。
因此，提议在系统发育树上建立产药簇，通过将每个簇内的物种数量缩小到更小的范围，从而缩小搜索范围，使新型类似药物骨架的优先和合理的生物勘探成为可能。然而，抗癌天然产物药物在系统发育树上的分布方式尚未报道，仅仅将抗癌药物发现集中在产药簇上是过于简单的，因为每个簇中的物种数量仍然太大而难以管理。
在这项研究中，通过系统发育分布的层次聚类，对过去 70 年中批准的 260 种抗癌药物进行了全面分析。
在这 260 种药物中，有 207 种药物源自或受从 58 种物种中分离出来的天然产物的启发。这些药物的系统发育分布进一步表明，天然抗癌药物主要源自产药家族，这些家族倾向于聚类而不是分散在系统发育树上。此外，根据其生产力，产药物种被分为高产（CPS）、新出现（CNS）和低产（CLS）。从 CPS 和 CLS 中提取的药物在类药性方面存在显著差异，而 CNS 中的药物则被发现具有与 CPS 相似的类药性。
这一发现表明药物批准标准有了很大提高，这表明我们应该将生物勘探集中在能够长期产生多种药物且具有生产力的物种上。
