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Cheminformatic Analysis of Natural Products and Their Chemical Space

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Cheminformatic Analysis of Natural Products and Their Chemical Space NATURAL PRODUCTS IN DRUG DISCOVERY355 doi:10.2533/chimia.2007.355 CHIMIA 2007, 61,No. 6 Chimia 61 (2007) 355–360 ©Schweizerische Chemische Gesellschaft ISSN 0009–4293 Cheminformatic Analysis of Natural Products and their Chemical Space Stefan Wetzela ,Ansgar Schuffenhauerb ,Silvio Roggob ,Peter Ertlb ,and Herbert Waldmann*a Abstract: Cheminformatic methods allow the detailed characterization of particular and characteristic properties of natural products (NPs) and comparison with related characteristics of drugs and other compounds. An overview of the most important properties of natural products and analogues and their difference with respect to drugs and synthetic compounds is presented. Moreover,different approaches to charting the chemical space populated by natural products arereviewed and their underlying principles aredelineated. Some insights about NP chemical space aredescribed together with possible applications of methods charting chemical space. Strengths and weak- nesses of the different approaches will be discussed with respect to possible applications in compound collection design. Keywords: Chemical space ·ChemGPS ·Cheminformatics ·Natural products ·SCONP 1. Introduction al constitute biologically validated starting may be applied in the synthesis of com- points for library design and manyoftheir pounds with NP-likeproperties. There are Natural products (NPs) have been selected core structures have been recognized to be several publications describing the results of during evolution to bind to various proteins privileged structures.[4,5] Known examples statistical analyses of NP properties. In 1999 during their life-cycle, e.g. in biosynthesis for privileged structures in NPs that have Henkel et al. published afirst comparison and degradation and while exerting their successfully been applied in library design of molecular properties of natural products, mode of action. Thus NP structures are are the benzodiazepine[4] and the indole synthetic compounds and drugs.[10] Two good starting points for the discovery and scaffolds.[6,7] years later,Lee and Schneider[11] published development of protein ligands and, there- With the upcoming newfocus on NPs apaper evaluating trade drugs and natural fore, ultimately for drug discovery.Indeed in drug discovery interest in their chemical products also addressing the general no- manycurrent drugs originate from NPs and structural properties and in ways to ex- tion that natural products may not be very although their structures were chemically plore them in drug discovery have increased drug-like. In 2003 Feher and Schmidt[12] modified in manycases.[1] After arecession as well. Modern cheminformatics methods published one of the most comprehensive of NPs in the pharmaceutical industry in the allowthe rapid prediction of aplethora of comparisons of NPs, drugs and combina- 1990s recent years have witnessed acome- chemical and physico-chemical properties torial chemistry compounds and compared back of NPs in drug discovery.NPs were of available NP structures.[8] Nowadays, these three groups using 40 different prop- often viewed as being ‘too complex’ and manyofthese properties are routinely used erties. Ertl and Schuffenhauer analyzed ‘sufficiently examined’ butonce again are in library design and optimization. The properties and structural features of more recognized as avaluable source of interest- most prominent and widely used example than 130,000 NP molecules and identified ing and diverse structures.[2,3] NPs in gener- may be Lipinski’s‘Rule-of-Five’. The substructures typical for particular classes Rule-of-Five denotes aset of property rules of source organisms.[13] One of the most re- describing orally bioavailable drug space. cent analyses of natural product properties Theywere empirically derivedfrom known and scaffolds wasconducted by Grabowski orally available drugs.[9] Chemical proper- and Schneider in 2007.[14] In the following ties constitute one waytodescribe the part paragraphs the results of these publications of chemical space occupied by acompound will be summarized. set; structural features is another.Several Henkel et al. analyzed twonatural approaches have been taken to map and product databases, the Dictionary of Natu- navigate chemical space reflecting chemi- ral Products (DNP)[15] and the Bioactive a * Correspondence:Prof. Dr.H.Waldmann cal properties and structure. Natural Product Database.[16] Synthetic Tel.: +49231 133 2400 Fax: +49231 133 2499 compounds were taken from the Chemicals E-Mail: [email protected] Dictionary (ACD)[17] and the Bayer AG in- a Max-Planck Institut für MolekularePhysiologie 2. Natural Product Properties house collection. The analysis revealed that Abteilung IV –Chemische Biologie Otto-Hahn-Strasse 11 molecular weight distribution wascompa- D-44229 Dortmund The systematic evaluation of NP prop- rable for drugs and NPs butsynthetic com- and Universität Dortmund, Chemische Biologie erties yields abetter understanding of what pounds were found to have alower mo- Dortmund b Novartis Institutes for BioMedical Research distinguishes NPs from drugs or combinato- lecular weight. The average NP molecule CH-4002 Basel rial chemistry compounds. This knowledge wasfound to contain three stereogenic NATURAL PRODUCTS IN DRUG DISCOVERY356 CHIMIA 2007, 61,No. 6 centers, three times as manyasthe average logues of compound library vendors. Alto- animals) could identify some substructural drug molecule. The authors also reported gether,the authors calculated more than 40 features typical for these groups. that NPs contain more oxygen butsignifi- molecular properties for all test sets. They From the data described one can con- cantly less nitrogen compared to the other found the average number of stereogenic clude that NPs differ from drugs in several compound classes. Additionally,Henkel centers to be 6.2 for NPs and 2.3 for drugs. properties although the majority of them do et al. performed an analysis of pharmaco- Notably,these averages are twice as high not violate Lipinski’sRule-of-Five.Proper- phoric groups, i.e. structural units prone to as those found by Henkel et al.four years ties which distinguish NPs from drugs are interact with biological macromolecules. earlier while the ratio of 3:1 remained the heteroatom distribution, number of rings, These include different functional groups same. The NPs contained on average two fraction of aromatic rings and degree of likeacids or alcohols and their isosteres more oxygen atoms than the drugs which ring fusion. Certainly some of these dif- as well as structural motifs, e.g. aryl or is in agreement with Henkel et al.although ferences may reflect empirical knowledge alkyl moieties. As expected, NPs incorpo- not with the results of Lee and Schneider. and synthetic methodology applied in drug rate more oxygen-containing groups while Half as manynitrogen atoms were found in discovery.But others may be explained by drugs and synthetic compounds are abun- NPs compared to drugs and even much less the limitations of the biosynthesis of NPs, dant with nitrogen-containing ones. Since sulphur and halogens. NPs contain about e.g. the availability of certain elements. the statistics on heteroatoms as well as on tworings more than drugs while at the same The very lownitrogen content in NPs from pharmacophoric groups were reported as time their degree of ring fusion is twice as plants as shown by Henkel et al.[10] for ex- fraction of molecules incorporating them, high. NPs were found to be generally more ample, may partly be due to nitrogen being no average number per molecule can be unsaturated, howevertheycontain consid- agrowth-limiting factor for manyplants. In given. In general, differences in the phar- erably less aromatic rings. The number of contrast, the higher halogen content found macophoric groups of NPs and drugs tend rotatable bonds found in NPs is twoless in NPs originating from algae may reflect to be smaller than between NPs and syn- than in drugs. Together with the high degree the higher availability of halogens in the thetic compounds. Particularly interesting of unsaturation and ring fusion, this indi- marine environment. Some comparisons may be the largest differences which can cates that NPs are on average more rigid of NP properties to those of drugs may be found for arenes. NPs contain half as than drugs. Feher and Schmidt also distin- be partly biased because drugs are almost manyaryl groups as synthetics. Alcohols guished between genuine natural products exclusively small molecules while some are three times more frequent in NPs com- and ‘seminaturals’, i.e.derivatives. They NP classes also incorporate much larger pared to synthetic compounds. Henkel et found the seminatural compounds to be structures, e.g. macrocycles with different al. also did adetailed analysis of the NP more drug-likeintheir properties especially properties.[18] In general, one should keep compound classes represented in the DNP. with respect to the number of stereogenic in mind that natural products are often The result showed aclear predominance of centers, aromaticity,ring fusion and hetero- viewed as aparticular butmore or less ho- alkaloids and terpenes overmost other nat- atom distribution. mogenous and related class of compounds ural product classes in the DNP.Although Grabowski and Schneider[14] com- like, for example, drugs or synthetic com- this may have changed by nowitshould be pared the properties and scaffolds of pounds. But in fact theyconsist of manydi- kept in mind that
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