Lead Molecules from Natural Products: Discovery and New Trends


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The unsurpassed structural diversity found in natural products creates a high likelihood of finding protein-binding ligands. In contrast, natural product structures bear characteristics of both a high chemical diversity and biochemical specificity, making them favorable as lead structures for drug discovery.

While synthetic drugs and combinatorial molecules tend to contain significantly higher numbers of nitrogen-, sulfur-, and halogen-containing groups, natural products bear higher numbers of oxygen atoms.

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Natural products are marked by higher molecular complexity and rigidity than either synthetic drugs or combinatorial libraries. Advances in genomics and structural biology over the last decade have shown that the number of unique protein architectures folds in nature is significantly smaller than the number of protein families predicted by amino acid sequence similarity Chothia, Domains, the functional building blocks of proteins, are frequently conserved in structure, even between sequences with low degrees of homology. These units are combined in a modular fashion to fine tune the function of completed proteins, often with the same protein fold serving different functional roles.

Natural products are selected by molecular evolution to preferentially bind these folds. By virtue of their increased size and protein binding, natural products are effective scaffolds for selectively modulating cellular processes such as the immune response, signal transduction, mitosis and apoptosis programmed cell death ; Peczuh and Hamilton, A powerful example of this is in the case of FK, rapamycin , and ascomycin — three closely related natural products from soil actinomycetes branching filamentous gram-positive bacteria that show profoundly different cellular effects via the binding of intracellular immunophilin proteins i.

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All three of these compounds — FK Tacrolimus , rapamycin Sirolimus , and ascomycin Pimecrolimus — are now in clinical use, for notably different therapeutic indications short- and long-term transplant rejection and eczema, respectively. A contrasting case is found in tubulin-targeted anti-mitotic agents Jordan, Both the plant-derived taxane paclitaxel Taxol and the marine sponge-derived discodermolide bind to assembled microtubules and enhance their polymerization, while the Vinca also known as the periwinkle or myrtle plant alkaloids and marine tripeptide hemiasterlin again from sponges inhibit polymerization by binding the tubulin Vinca domain.

Others such as colchicine a treatment for gout and arthritis from the autumn crocus , podophyllotoxin treatment for genital warts derived from the podophyllum plant , and combretastatin an antitumor compound found in the bark of the African bush willow tree disrupt microtubule assembly by binding a site on tubulin distinct from that of the aforementioned compounds. Natural product libraries have a broader distribution of these physical properties versus synthetic and combinatorial counterparts and have no more liabilities in these areas than trade drugs Lee and Schneider, ; Henkel et al.

In some cases the secondary metabolite has been shown to have exquisite potency for a particular target, but is not practical for use as the therapeutic agent, owing to low selectivity, metabolic liabilities, pharmaceutical properties, or toxicity.

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This lack of selectivity can be overcome via selective antibody delivery. Calicheamicin is an exquisitely potent antibiotic with DNA-damaging properties produced by the bacterium Micromonospora echinospora. Although it is to 1, times more potent than conventionally used therapeutic agents, calicheamicin itself lacks the therapeutic index ratio of benefits over adverse effects required for systemic administration.

The potency of calicheamicin has been harnessed by immunoconjugation — a chemical linkage to a monoclonal antibody that specifically binds the CD33 cell surface antigen present on acute myeloid leukemia cells Damle and Frost, Upon internalization into lysosomal vesicles small spheres containing proteins that can cleave other compounds , Mylotarg is engineered to release calicheamicin, which migrates to the nucleus, cleaves DNA and results in tumor cell death. Advances in genomics and molecular biology have now made it possible to obtain relatively large quantities of protein targets for high-throughput cell-free assay systems Silverman et al.

However, the chemical complexity of natural product libraries often presented a challenge to the robustness of these modern HTS systems. For example, assays based on fluorescence techniques were subject to interference from natural product samples that contain compounds that are intrinsically light-absorbing or fluorescence-emitting. This liability is shared with synthetic screening libraries, but the issue is exacerbated with natural products, since the presence of these interference compounds may not be fully characterized. Technical improvements in assay platforms based on fluorescence intensity, time resolution, or polarization have now relieved many of these problems.

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It has also been effective to chemically pre-fractionate natural product libraries in order to reduce interferences and facilitate the detection of trace active metabolites. Significant successes have been realized in the screening of natural product libraries against nucleic acid targets using mass spectrometry. These and other developments make it likely that future lead generation via screening of natural products need not be limited by HTS technology. Natural products frequently occur as complexes of structurally related analogs.

While the full biological significance of this phenomenon is not clear, this has historically presented a challenge to their development as drugs Firn and Jones, By application of modern chromatographic and spectroscopic techniques, investigators are now able to unravel these cases, and exploit the chemical diversity offered in them to obtain analogs with improved potency and drug-like properties.

An illustration of this principle is found in the mannopeptimycin family of antibiotics , a series of novel glycopeptides with a unique mode of action, and potent activity against resistant bacterial strains He et al. While the major component of the complex, mannopeptimycin a, has a poor profile of activity, natural co-occurring analogs have potent antibacterial activity. This limited but important initial structure-activity information was pivotal in designing an analog with improved antibacterial potency and a favorable therapeutic window Figure 2.

To be a potential drug lead, the natural product of interest must be extracted from the source, concentrated, fractionated and purified, yielding essentially a single biologically active compound. Historically, this process has suffered from three major hurdles.

Correlation of both molecular weight and UV absorption data with known compounds by database searching is normally sufficient to classify sets of compounds, and reduces the time required for dereplication to a matter of hours versus days or weeks previously. The second major hurdle in the process, structure determination of compounds that are new molecular entities NME , is an area that has been revolutionized by advances in spectroscopic techniques, particularly mass spectrometry and high resolution Nuclear Magnetic Resonance NMR.

Determination of the molecular formula is critical to the process and is now efficiently done by high-resolution mass spectrometry on picomole 10 quantities of material.


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NMR methods developed over the last 25 years, when combined with knowledge of the molecular formula, provide rich molecular connectivity data that permit the skilled researcher to essentially map out the structure of the compound. NPD have the potential to yield novel drugs having improved pharmacokinetic properties and biological activities, which provide therapeutic benefits in treating diseases.

Some examples of NPs as sources of drugs are shown in Figure 1. Acetylsalicylic acid Aspirin : an anti-inflammatory agent derived from salicin, which is isolated from the bark of the willow tree Salix alba L; Dias, Urban, Roessner, dopamine: a neurotransmitter obtained from phenylethylisoquinoline alkaloid by hydroxylation of tyrosine to L-3,4-dihydroxyphenylalanine DOPA followed by decarboxylation; solifenacin used to treat overactive bladder is derived from tetrahydroisoquinoline and has additional functional groups on this ring; and topotecan: an anticancer drug derived from camptothecin and has additional hydroxyl and 1- N,N -dimethylmethanamine groups Ehrenworth, Peralta-Yahya, Pure unaltered NPs PUNP include Yohimbine an indole alkaloid , quinine antimalarial therapeutic , the diterpene gibberellic acid a plant hormone , and adrenosterone steroid hormone Wetzel et al.

With the exponential increase in the number of viable novel drug targets, the quality and availability of a specific library for biological campaigns is a major issue. Therefore, populating the chemical space with innovative chemotypes besides HTS is a challenging process to rationally find hits and leads. As an alternative, cheminformatic methods are useful to filter and select compounds. With the upcoming focus on virtual high throughput screening vHTS , computational methods are being increasingly applied to accelerate drug discovery process Wetzel et al. Considering the uniqueness of structural patterns available from NP libraries, correlation of innovative scaffolds with the evolutive ability to bind biological targets is still an inspiring library design to populate new areas of chemical space, with higher chances of achieving increased hit rates in biochemical and biological screening.

NP-based drugs can be classified into different areas. For this review, we can classify NP-based drugs into fragment-like compounds with low molecular weight and complex scaffolds with high three-dimensionality and complexity. Recent approaches use NP-derived fragments or fragment-based drug discovery FBDD to explore a large fraction of chemical space and to suggest simple metrics for assessing synthetic compounds for NP likeness Over et al.

Alternative and elegant synthesis of NP-inspired scaffolds is another area of increasing interest in recent years Paciaroni et al. BIOS involves a hierarchical classification of bioactive compounds according to structural relationships and type of bioactivity, and selection of scaffolds of bioactive molecule classes as starting points for the synthesis of compound collections, with focus on diversity. DOS is considered an efficient method to achieve structural diversity along with structural complexity Wetzel et al.

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Ring distortion involves the altering of complex ring systems through various chemical reactions that enable ring cleavage, expansion, rearrangement, and fusion. This method has started to gain attention recently Huigens et al. NP-derived fragments and ring-distortion strategies have the potential to identify drug candidates by accessing the unexplored chemical and biological spaces of NPs Figure 2 Crane et al.

Examples of natural products NP as sources of drugs blue rectangle and NP-inspiring compounds green rectangle. In this review, the strategies to reduce structural complexity or to introduce drastic structural modifications of NPs to obtain the desired biological parameters, such as potency or selectivity, are shown.

FBDD is an emerging approach for efficient lead discovery. FBDD, which is considered a complementary drug discovery strategy, involves the exploration of library of organic fragments and small molecules with low molecular weight as a starting point for the process. Baker, ; Chen et al.

FBDD allows exploiting larger areas of chemical space in compounds having low molecular weight during the process of drug discovery. However, this approach usually does not represent the real bioactivity of the tested compounds owing to low affinity for the target Scott et al. The possibility of adding functional groups increases the chances of improving bioactivity, making FBDD a process with high success rate depending on the number of compounds tested initially Figure 3.

One of the bottlenecks for the success of FBDD campaign is the quality of the tested libraries, which generally show the following features.

Nature’s Bounty: Revitalizing the Discovery of New Cancer Drugs from Natural Products

Barelier et al. Combining NPs and fragment approaches for drug discovery is a complex process when trying to fit the properties described above. NP-derived fragments can be highly different from synthetic compounds, when structural features, design, and obtention of a library component are compared. Genis, Kirpichenok, Kombarov, ; Austin et al. A previous study examined the Dictionary of NPs DNP Buckingham, and confirmed that the most frequent structural elements of NPs are characterized by a high content of sp 3 -hybridized carbon atoms; oxygen; spiro, bridged, and linked systems; and stereogenic centers, with high structural diversity Genis, Kirpichenok, Kombarov, ; Lee, Schneider, Furthermore, NPs populate areas of chemical space not occupied by average synthetic molecules Over et al.

In contrast, synthetic libraries are mainly characterized by sp 2 -rich compounds, with high content of nitrogen, covering well-explored regions of chemical space with less diversity in structure and molecular properties Genis, Kirpichenok, Kombarov, ; Thomas, Johannes, This could lead to the selection of more structures belonging to the same chemical space Cheshire, Generally, the differences given above can be assumed when comparing synthesized fragments and NP-based fragments, with focus on heteroatom distribution, number of rings, fraction of aromatic rings, degree of ring fusion, and degree of three-dimensionality.

Koch et al. Another aspect to be considered is the source of fragment components. While synthetic fragments are usually obtained by feasible synthesis in few steps or from available commercial sources, Murray, Rees, NP-derived fragments are obtained in diverse ways. Pascolutti et al. Fragment-derived NPs can be divided in two main groups: 1 Fragment-sized NPs, which are usually selected from available NPs based on fragment-like properties; and 2 NP-based fragments, which are designed or chemically derived from natural complex structures. Different strategies have been described in the literature for using fragments derived from NPs to develop bioactive compounds successfully.

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Fragment-sized NPs: it is possible to filter fragment-sized NPs from an NP library, and with this collection of compounds, chemical modifications or designing of fully synthetic new compounds can be initiated; 2.

Lead Molecules from Natural Products: Discovery and New Trends Lead Molecules from Natural Products: Discovery and New Trends
Lead Molecules from Natural Products: Discovery and New Trends Lead Molecules from Natural Products: Discovery and New Trends
Lead Molecules from Natural Products: Discovery and New Trends Lead Molecules from Natural Products: Discovery and New Trends
Lead Molecules from Natural Products: Discovery and New Trends Lead Molecules from Natural Products: Discovery and New Trends
Lead Molecules from Natural Products: Discovery and New Trends Lead Molecules from Natural Products: Discovery and New Trends

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