The landscape of natural product diversity and their pharmacological relevance from a focus on the Dictionary of Natural Products® François Chassagne, Guillaume Cabanac, Gilles Hubert, Bruno David, Guillaume Marti To cite this version: François Chassagne, Guillaume Cabanac, Gilles Hubert, Bruno David, Guillaume Marti. The land- scape of natural product diversity and their pharmacological relevance from a focus on the Dictio- nary of Natural Products®. Phytochemistry Reviews, Springer Verlag, 2019, 18 (3), pp.601-622. 10.1007/s11101-019-09606-2. hal-02915232 HAL Id: hal-02915232 https://hal.archives-ouvertes.fr/hal-02915232 Submitted on 13 Aug 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. This is the accepted version of a paper accepted in Phytochemistry Reviews that appeared online on April 24, 2019 at https://doi.org/10.1007/s11101-019-09606-2. The landscape of natural product diversity and their pharmacological relevance from a focus on the Dictionary of Natural Products® François Chassagne, Guillaume Cabanac, Gilles Hubert, Bruno David, Guillaume Marti F. Chassagne (*) Center for the Study of Human Health, Emory University 615 Michael Street, Whitehead Building, Room 111 Atlanta, GA, 30322, USA. email: [email protected] F. Chassagne, G. Cabanac, G. Hubert, G. Marti Informatics Research Institute of Toulouse (IRIT), Computer Science Department, UMR 5505 CNRS, Université Toulouse 3 – Paul Sabatier, 118, Route de Narbonne, 31062 Toulouse, France B. David Green Mission Pierre Fabre Institut de Recherche Pierre Fabre 3, Avenue Hubert Curien - BP 13562, 31562 Toulouse, France G. Marti PharmaDev, UMR 152 IRD, Université Toulouse 3 – Paul Sabatier, 35 Chemin des Maraîchers, 31400 Toulouse, France Abstract Nature is considered a prolific source of diverse biologically active chemotypes. While most reviews have focused on the characteristics of the chemical backbones of natural products (NPs), few have tried to provide an overview of their origins (the living organisms in which they are produced), chemical classes, and biological activities. This review discusses the current knowledge on NP diversity by focusing on the Dictionary of Natural Products® (DNP). We datamined the 300,000 NPs covered by the DNP to reveal relevant, albeit dormant, knowledge about NP diversity. This holistic picture of NPs allows us to discuss the most abundant biological sources of NPs investigated in relation to their chemical features and biological activities. In a nutshell, a large part of NPs originated from plants (67%), especially from the Compositae and Leguminosae families. Among all kingdoms, NPs isolated from Streptomyces spp. were largely represented, while terpenoids and alkaloids were the two most represented chemical classes. Out of all NPs documented, only 3,882 were reported to be bioactive (1,163 from plants and 1,006 from bacteria), with antibacterial, antibiotics, and antineoplastic agents being the most frequent therapeutic classes. In this paper, we also address the advantages and limitations of NP research from a pharmaceutical industry perspective. This work will provide useful insights and guidance to researchers involved in drug discovery from NPs. Keywords Biological activity, Drug Discovery, Genetic resources, Pharmaceutical industry, Plants 2 Abbreviations Angiotensin Converting Enzyme ACE Chemical Abstracts Services CAS Dictionary of Natural Products® DNP HTS High Throughput Screening NP Natural Product PSK Polysaccharide Krestin PSP Polysaccharopeptide 3 Introduction Natural products (NPs) have been used in various branches of traditional medicine for millennia. The oldest written records of NPs as medicine date as far back as 4,600 years ago (Dias et al. 2012; Cragg and Newman 2013). Due to their chemical diversity, their structural complexity, and their biological selectivity, NPs are considered to be a great source of inspiration for the development of potential novel drugs (Clardy and Walsh 2004; Atanasov et al. 2015). From 1981 to 2014, about 51% of all new approved drugs were of (or derived from) natural sources, amounting to 65% of all antibacterial compounds and 73% of all anticancer compounds (Newman and Cragg 2016). It is expected that newly discovered natural compounds will continue to play an important role in drug discovery (Baker et al. 2007; Harvey et al. 2015). Natural product databases have been developed to assist with in silico and in vitro screening in drug discovery. A number of NP libraries are already available and include general databases such as SuperNatural 2 (≈ 326,000 NP) (Banerjee et al. 2015) and the Universal Natural Products Database (≈ 229,000 compounds) (Chen et al. 2017b). Specialized databases have also been designed, including those focusing on indigenous medicines such as AfroDb for African medicinal plants (Ntie-Kang et al. 2013), NuBBE for Brazilian biodiversity (Valli et al. 2013), iSMART, and TCMID for traditional Chinese medicine (Chang et al. 2011; Xue et al. 2013); and those focusing on specific types of NPs such as HIT for herbal ingredients and their targets (Ye et al. 2011), SuperToxic for toxic compounds (Schmidt et al. 2009), NPACT for anticancer NPs (Mangal et al. 2013), and MarinLit for marine NPs (Chen et al. 2017b). 4 The Dictionary of Natural Products® (CRC Press, v. 27.1) (DNP) is a compilation of all known compounds derived from natural sources and can be considered as one of the most comprehensive libraries of NPs available to date (Quinn et al. 2008; Gaudêncio and Pereira 2015; Chen et al. 2017b). The latest version of the DNP (v. 27.1, at the time of writing) provides data for nearly 300,000 natural compounds, and it contains information on the chemical, physical, and biological properties of compounds; along with their systematic and common names, literature references, molecular structures, and natural sources for purification (including family, genus, and species). Due to its rich content, the DNP can be considered as a body of knowledge for NPs and can be used to guide investigations in NP-based drug discovery. Since its development, several studies have used and explored the content of the DNP. One of the first comprehensive reports was published by Henkel et al. (1999) who investigated the differences between the structural properties of NPs found in the DNP and those of synthetic substances; then Whittle et al. (2003) evaluated various similarity measures for screening molecular fingerprints from the DNP; later Koch et al. (2005) introduced a structural classification of NPs to chart biologically relevant chemical space. With the same objective, Rosén et al. (2009) compared the chemical space of bioactive medicinal chemistry compounds from the WOMBAT database to that of products from the DNP; in 2008, Quinn et al. (2008) used the DNP to develop a library of NPs that exhibit drug-like properties; also Kong et al. (2011) performed a historical analysis on the structural novelty of products from the DNP; more recently, Pascolutti et al. (2015) identified fragment-sized NPs from the DNP to capture the structural diversity of nature. These studies mainly focused on the characteristics of the chemical backbones of the NP 5 contained in this database, but none of them strove to provide an overview of their origins (the living organisms in which they are produced), chemical classes, and biological activities. To the best of our knowledge, only Bérdy (2005) summarized compounds isolated from natural sources, but his review was limited to bioactive compounds from microbial sources. In this review, we unveil the current knowledge on NP diversity based on a descriptive study of the DNP (v. 27.1). This includes a characterization of all compounds (primary and secondary metabolites) from the DNP in relation to their natural sources (all types of organisms are considered), chemical classes, and biological activities (NPs without bioactivities are also reviewed). Natural products with biological activities annotated in the DNP are defined as “compounds with established activity and being used as drugs or under investigation for drug use” (Taylor & Francis group, pers. comm.). Finally, we also discuss the potential application of NPs in the pharmaceutical industry. 6 Defining the number of NPs already identified A key issue in NP research is the estimation of the number of known NPs. First, Bérdy (2005) estimated the approximate number of known NPs to be close to one million. Later, the same author proposed that the number of published natural compounds was actually between 300,000 and 600,000 (Bérdy 2012). However, little information was provided on the methodology used to infer these figures. Other authors based their estimations on the number of compounds tabulated in the NP databases (Blunt et al. 2012). At present, in the general NP databases, the number of compounds described amounts to 326,000 NPs in Super Natural 2, 293,798 NPs in the DNP, 283,000 NPs in the Chemical Abstract Services (CAS) registry, and 220,000 NPs in Reaxys (Gaudêncio and Pereira 2015;