title: Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting.
abstract: Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.
authors.affiliation: Key Laboratory of Chemical Biology, Guangdong Province Graduate School at Shenzhen, Tsinghua University, Shenzhen, Guangdong 518055, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Chu
authors.initials: C
authors.lastname: Qin
authors.forename: Lin
authors.initials: L
authors.lastname: Tao
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Zhe
authors.initials: Z
authors.lastname: Shi
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Ma
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.forename: Ying
authors.initials: Y
authors.lastname: Tan
authors.forename: Cheng
authors.initials: C
authors.lastname: Cui
authors.forename: Jinshun
authors.initials: J
authors.lastname: Lin
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
authors.forename: Yuzong
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D001419:Bacteria / Q000737:chemistry* / Q000145:classification; D001688:Biological Products / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D016000:Cluster Analysis; D055808:Drug Discovery; D005658:Fungi / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000145:classification / Q000302:isolation & purification; D010946:Plants, Medicinal / Q000737:chemistry*; D013045:Species Specificity; D013678:Technology, Pharmaceutical
chemical_list: D001688:Biological Products; D004364:Pharmaceutical Preparations