Natural Product Drug Discovery Research Articles

Targeting Nuclear Receptors with Marine Natural Products

Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators.

Aggressive dereplication using UHPLC–DAD–QTOF: screening extracts for up to 3000 fungal secondary metabolites

In natural-product drug discovery, finding new compounds is the main task, and thus fast dereplication of known compounds is essential. This is usually performed by manual liquid chromatography-ultraviolet (LC-UV) or visible light-mass spectroscopy (Vis-MS) interpretation of detected peaks, often assisted by automated identification of previously identified compounds. We used a 15 min high-performance liquid chromatography–diode array detection (UHPLC–DAD)–high-resolution MS method (electrospray ionization (ESI)+ or ESI−), followed by 10–60 s of automated data analysis for up to 3000 relevant elemental compositions. By overlaying automatically generated extracted-ion chromatograms from detected compounds on the base peak chromatogram, all major potentially novel peaks could be visualized. Peaks corresponding to compounds available as reference standards, previously identified compounds, and major contaminants from solvents, media, filters etc. were labeled to differentiate these from compounds only identified by elemental composition. This enabled fast manual evaluation of both known peaks and potential novel-compound peaks, by manual verification of: the adduct pattern, UV–Vis, retention time compared with log D, co-identified biosynthetic related compounds, and elution order. System performance, including adduct patterns, in-source fragmentation, and ion-cooler bias, was investigated on reference standards, and the overall method was used on extracts of Aspergillus carbonarius and Penicillium melanoconidium, revealing new nitrogen-containing biomarkers for both species.Electronic supplementary materialThe online version of this article (doi:10.1007/s00216-013-7582-x) contains supplementary material, which is available to authorized users.

Exploring the potential of endophytes from medicinal plants as sources of antimycobacterial compounds

Natural product drug discovery has regained interest due to low production costs, structural diversity, and multiple uses of active compounds to treat various diseases. Attention has been directed towards medicinal plants as these plants have been traditionally used for generations to treat symptoms of numerous diseases.It is established that plants harbour microorganisms, collectively known as endophytes. Exploring the as-yet untapped natural products from the endophytes increases the chances of finding novel compounds. The concept of natural products targeting microbial pathogens has been applied to isolate novel antimycobacterial compounds, and the rapid development of drug-resistant Mycobacterium tuberculosis has significantly increased the need for new treatments against this pathogen. It remains important to continuously screen for novel compounds from natural sources, particularly from rarely encountered microorganisms, such as the endophytes.This review focuses on bioprospecting for polyketides and small peptides exhibiting antituberculosis activity, although current treatments against tuberculosis are described. It is established that natural products from these structure classes are often biosynthesised by microorganisms. Therefore it is hypothesised that some bioactive polyketides and peptides originally isolated from plants are in fact produced by their endophytes. This is of interest for further endophyte natural product investigations.

Anti-Chikungunya Viral Activities of Aplysiatoxin-Related Compounds from the Marine Cyanobacterium Trichodesmium erythraeum

Tropical filamentous marine cyanobacteria have emerged as a viable source of novel bioactive natural products for drug discovery and development. In the present study, aplysiatoxin (1), debromoaplysiatoxin (2) and anhydrodebromoaplysiatoxin (3), as well as two new analogues, 3-methoxyaplysiatoxin (4) and 3-methoxydebromoaplysiatoxin (5), are reported for the first time from the marine cyanobacterium Trichodesmium erythraeum. The identification of the bloom-forming cyanobacterial strain was confirmed based on phylogenetic analysis of its 16S rRNA sequences. Structural determination of the new analogues was achieved by extensive NMR spectroscopic analysis and comparison with NMR spectral data of known compounds. In addition, the antiviral activities of these marine toxins were assessed using Chikungunya virus (CHIKV)-infected cells. Post-treatment experiments using the debrominated analogues, namely compounds 2, 3 and 5, displayed dose-dependent inhibition of CHIKV when tested at concentrations ranging from 0.1 µM to 10.0 µM. Furthermore, debromoaplysiatoxin (2) and 3-methoxydebromoaplysiatoxin (5) exhibited significant anti-CHIKV activities with EC50 values of 1.3 μM and 2.7 μM, respectively, and selectivity indices of 10.9 and 9.2, respectively.

Virtual target screening to rapidly identify potential protein targets of natural products in drug discovery

Inherent biological viability and diversity of natural products make them a potentially rich source for new therapeutics. However, identification of bioactive compounds with desired therapeutic effects and identification of their protein targets is a laborious, expensive process. Extracts from organism samples may show desired activity in phenotypic assays but specific bioactive compounds must be isolated through further separation methods and protein targets must be identified by more specific phenotypic and <em>in vitro</em> experimental assays. Still, questions remain as to whether all relevant protein targets for a compound have been identified. The desire is to understand breadth of purposing for the compound to maximize its use and intellectual property, and to avoid further development of compounds with insurmountable adverse effects. Previously we developed a Virtual Target Screening system that computationally screens one or more compounds against a collection of virtual protein structures. By scoring each compound-protein interaction, we can compare against averaged scores of synthetic drug-like compounds to determine if a particular protein would be a potential target of a compound of interest. Here we provide examples of natural products screened through our system as we assess advantages and shortcomings of our current system in regards to natural product drug discovery.

Pharmacognosy: Science of natural products in drug discovery

Pharmacognosy deals with the natural drugs obtained from organisms such as most plants, microbes, and animals. Up to date, many important drugs including morphine, atropine, galanthamine, etc. have originated from natural sources which continue to be good model molecules in drug discovery. Traditional medicine is also a part of pharmacognosy and most of the third world countries still depend on the use of herbal medicines. Consequently, pharmacognosy always keeps its popularity in pharmaceutical sciences and plays a critical role in drug discovery.

Chapter Twenty-Two - Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development

The cytochrome P450 (CYP) enzymes are a versatile superfamily of heme-containing monooxygenases, perhaps best known for their role in the oxidation of xenobiotic compounds. However, due to their unique oxidative chemistry, CYPs are also important in natural product drug discovery and in the generation of active metabolites with unique therapeutic properties. New tools for the analysis and production of CYP metabolites, including microscale analytical technologies and combinatorial biosynthesis, are providing medicinal chemists with the opportunity to use CYPs as a novel platform for lead discovery and development. In this review, we will highlight some of the recent examples of drug leads identified from CYP metabolites and the exciting possibilities of using CYPs as catalysts for future drug discovery.

&amp;lt;i&amp;gt;Drymaria cordata&amp;lt;/i&amp;gt; (Linn.) Willd (Caryophyllaceae): Ethnobotany, Pharmacology and Phytochemistry

In the present paper the isolation and characterization of seven major glycolipid classes (stigmasterol, acylated stigmasteryl glucoside, stigmasteryl glucoside, monogalactosyldiacylglycerol, digalactosyldiacylglycerol, cerebroside and glucocerebroside) from Drymaria cordata (Linn.) Willd (Caryophyllaceae Family) are reported after an attempt has been made to congregate the traditional and pharmacological studies done on this important medicinal plant. Drymaria cordata is a weak spreading herb found widely dispersed in damp places all over the tropics of Africa, Asia and the Americas. There are many reports on its folk and traditional uses that include snake bite, skin diseases, peptic ulcer, headaches or nephritis, female infertility, sleeping disorders, convulsions, and febrile conditions in children. The plant has been examined on the basis of scientific in vitro and in vivo evaluations possessing the major pharmacological activities that include analgesic activity, antitussive activity, anxiolytic activity, antipyretic activity, antinociceptive activity, anti-inflammatory and antibacterial activities. The information summarized here is intended to serve as a reference tool for practitioners in the fields of ethnopharmacology, natural product chemistry and drug discovery related research.

A Brief Understanding of Process Optimisation in Microwave‐assisted Extraction of Botanical Materials: Options and Opportunities with Chemometric Tools

Extraction forms the very basic step in research on natural products for drug discovery. A poorly optimised and planned extraction methodology can jeopardise the entire mission. To provide a vivid picture of different chemometric tools and planning for process optimisation and method development in extraction of botanical material, with emphasis on microwave-assisted extraction (MAE) of botanical material. A review of studies involving the application of chemometric tools in combination with MAE of botanical materials was undertaken in order to discover what the significant extraction factors were. Optimising a response by fine-tuning those factors, experimental design or statistical design of experiment (DoE), which is a core area of study in chemometrics, was then used for statistical analysis and interpretations. In this review a brief explanation of the different aspects and methodologies related to MAE of botanical materials that were subjected to experimental design, along with some general chemometric tools and the steps involved in the practice of MAE, are presented. A detailed study on various factors and responses involved in the optimisation is also presented. This article will assist in obtaining a better insight into the chemometric strategies of process optimisation and method development, which will in turn improve the decision-making process in selecting influential extraction parameters.

Isolation and structure elucidation of new myrsinane-type diterpene polyesters from Euphorbia falcata L.

Diterpenes occurring in plants of the Euphorbiaceae family are of considerable interest as concerns natural product drug discovery programs because of the wide range of potentially valuable biological activities and the broad structural diversity due to the different polycyclic and macrocyclic skeletons and various aliphatic and aromatic ester groups.

Isolation and Structure Determination of New Secondary Metabolites from the Endangered Plant Rhododendron brachycarpum G.Don

In spite of the critical role of the natural products in drug discovery, little attention has been placed on endangered and rare plant species. Utilization of the secondary metabolites acquired from endangered species may help to rationalize the conservation efforts of such plants considering that they may serve as drug leads to benefit human health and create socioeconomic value. Our phyto-chemical investigation on the leaves of Rhododendron brachycarpum G.Don (Ericaceae), which is a Korean endangered plant, resulted in the isolation of new triterpenoid, flavonoid, and megastigmane glycosides. The isolation and structure determination of new compounds together with their bioactivities will be presented.

LCMS-Based Metabolomics to Stimulate Natural Products Drug Discovery from Marine Invertebrate Associated Actinobacteria

LCMS-Based Metabolomics to Stimulate Natural Products Drug Discovery from Marine Invertebrate Associated Actinobacteria

Insights and Lessons from the Front Lines: Starting and Sustaining a Natural Products Drug Discovery Company in Today's Marketplace

Insights and Lessons from the Front Lines: Starting and Sustaining a Natural Products Drug Discovery Company in Today's Marketplace

AN EMERGING MARINE BIOTECHNOLOGY: MARINE DRUG DISCOVERY

Marine natural resources offer an opportunity to discover a novel chemical diversity withinterest ing pharmacologically active compounds to treat many diseases such as cancer,inflammation, bacterial and parasitic infections, and many other diseases. Marine drug discoveryis a rising area in marine biotechnology. Several hits of marine-derived drug compounds wereapproved; two of them are Ziconotide and Trabectedin. In 2004, Ziconotide was approved as paintreatment drugs in the United States and Europe. Then, in 2007, Trabectedin was also approvedas anticancer drug in Europe. The main problem in marine drug discovery research is materialsupply problem. Up till now, strategies to overcome the problem are “Pharmaceutical aquaculture”of biologically active marine biota and chemical synthesis approach. Chemical synthesis approachis feasible solution to be used, especially when working with less complex structure of compounds.However, when working with structurally complex compounds where total or even semi synthesiswas very difficult to be provided, aquaculture can be a solution. Currently, the use of microbiology,biochemistry, genetic, bioinformatics, genomic and meta-genomic has been intensifying in orderto have a better result in marine natural product drug discovery. As chemical synthesis needs anexpensive investment of advanced technology and highly skilled human resources, thuspharmaceutical aquaculture is more practicable to overcome the material supply insufficiency inIndonesia. Up till now, many Indonesian marine bioprospectors have been working with culturablemarine microorganism to produce bioactive compounds and some others starting to work withgenomic and metagenomic-based drug discovery.

Use of natural products as chemical library for drug discovery and network pharmacology.

BackgroundNatural products have been an important source of lead compounds for drug discovery. How to find and evaluate bioactive natural products is critical to the achievement of drug/lead discovery from natural products.MethodologyWe collected 19,7201 natural products structures, reported biological activities and virtual screening results. Principal component analysis was employed to explore the chemical space, and we found that there was a large portion of overlap between natural products and FDA-approved drugs in the chemical space, which indicated that natural products had large quantity of potential lead compounds. We also explored the network properties of natural product-target networks and found that polypharmacology was greatly enriched to those compounds with large degree and high betweenness centrality. In order to make up for a lack of experimental data, high throughput virtual screening was employed. All natural products were docked to 332 target proteins of FDA-approved drugs. The most potential natural products for drug discovery and their indications were predicted based on a docking score-weighted prediction model.ConclusionsAnalysis of molecular descriptors, distribution in chemical space and biological activities of natural products was conducted in this article. Natural products have vast chemical diversity, good drug-like properties and can interact with multiple cellular target proteins.

Comparative study of chromatographic medium-associated mass and potential antitumor activity loss with bioactive extracts.

Natural product drug discovery programs often rely on the use of silica (Si) gel, reversed-phase media, or size-exclusion resins (e.g., RP-C18, Sephadex LH-20) for compound purification. The synthetic polymer-based sorbent Diaion HP20SS (cross-linked polystyrene matrix) is used as an alternative to prepare purified natural product libraries. To evaluate the impact of chromatographic media on the isolation of biologically active, yet chromatographically unstable natural products, Diaion HP20SS was evaluated side-by-side with normal-phase sorbents for irreversible binding of extract constituents and their effects on bioactivity. An array of chemically diverse natural product-rich extracts was selected as a test panel, and a cell-based reporter assay for hypoxia-inducible factor-1 (HIF-1) was employed to monitor potential change(s) in bioactivity. Silica gel caused significant irreversible binding of three out of 10 extracts. Curcuma longa, Saururus cernuus, and Citrus reticulata extracts showed decreased HIF-1 inhibitory activity after elution through Si gel. An additional nonpolar column wash of HP20SS with EtOAc retained considerable bioactivities of active extracts. In general, Si gel produced the greatest loss of bioactivity. However, HP20SS elution reduced significantly HIF-1 inhibitory activity of certain extracts (e.g., Asimina triloba).

Ethnobotany, phytochemistry and pharmacology of Ageratum conyzoides Linn (Asteraceae)

In the present review, an attempt has been made to congregate the traditional, phytochemical and pharmacological studies done on an important medicinal plant, Ageratum conyzoides Linn. (Family Asteraceae) which is widely spread all over the world, especially in the tropical and subtropical region. There are many reports on folk and traditional uses that include wound dressing, skin diseases, ophthalmic, colic, ulcers treatment, diarrhoea, dysentery, fever, gynecological diseases, sleeping sickness, mouthwash, anti-inflammatory, insecticides, etc. Phytochemical investigations have revealed that many components are bioactive due to the presence of broad range of secondary active metabolites such as terpenoids, flavonoids, alkaloids, steroids, and chromene. The plant has been examined on the basis of the scientific in vitro, in vivo or clinical evaluations possessing the major pharmacological activities that includes analgesic activity, antimicrobial activity, anti-inflammatory activity, spasmolytic effects, gamma radiation effects, anti cancer and radical scavenging activity, antimalarial activity and others activities. The information summarized here is intended to serve as a reference tool to practitioners in the fields of ethnopharmacology, natural product chemistry and drug discovery related research.

Dragon exploration system on marine sponge compounds interactions

BackgroundNatural products are considered a rich source of new chemical structures that may lead to the therapeutic agents in all major disease areas. About 50% of the drugs introduced in the market in the last 20 years were natural products/derivatives or natural products mimics, which clearly shows the influence of natural products in drug discovery.ResultsIn an effort to further support the research in this field, we have developed an integrative knowledge base on Marine Sponge Compounds Interactions (Dragon Exploration System on Marine Sponge Compounds Interactions - DESMSCI) as a web resource. This knowledge base provides information about the associations of the sponge compounds with different biological concepts such as human genes or proteins, diseases, as well as pathways, based on the literature information available in PubMed and information deposited in several other databases. As such, DESMSCI is aimed as a research support resource for problems on the utilization of marine sponge compounds. DESMSCI allows visualization of relationships between different chemical compounds and biological concepts through textual and tabular views, graphs and relational networks. In addition, DESMSCI has built in hypotheses discovery module that generates potentially new/interesting associations among different biomedical concepts. We also present a case study derived from the hypotheses generated by DESMSCI which provides a possible novel mode of action for variolins in Alzheimer’s disease.ConclusionDESMSCI is the first publicly available (http://www.cbrc.kaust.edu.sa/desmsci) comprehensive resource where users can explore information, compiled by text- and data-mining approaches, on biological and chemical data related to sponge compounds.

Phylogenetic Inferences Reveal a Large Extent of Novel Biodiversity in Chemically Rich Tropical Marine Cyanobacteria

Benthic marine cyanobacteria are known for their prolific biosynthetic capacities to produce structurally diverse secondary metabolites with biomedical application and their ability to form cyanobacterial harmful algal blooms. In an effort to provide taxonomic clarity to better guide future natural product drug discovery investigations and harmful algal bloom monitoring, this study investigated the taxonomy of tropical and subtropical natural product-producing marine cyanobacteria on the basis of their evolutionary relatedness. Our phylogenetic inferences of marine cyanobacterial strains responsible for over 100 bioactive secondary metabolites revealed an uneven taxonomic distribution, with a few groups being responsible for the vast majority of these molecules. Our data also suggest a high degree of novel biodiversity among natural product-producing strains that was previously overlooked by traditional morphology-based taxonomic approaches. This unrecognized biodiversity is primarily due to a lack of proper classification systems since the taxonomy of tropical and subtropical, benthic marine cyanobacteria has only recently been analyzed by phylogenetic methods. This evolutionary study provides a framework for a more robust classification system to better understand the taxonomy of tropical and subtropical marine cyanobacteria and the distribution of natural products in marine cyanobacteria.

The Success of Natural Products in Drug Discovery

Drug discovery leading to robust and viable lead candidates’ remains a challenging scientific task, which is the transition from a screening hit to a drug candidate, requires expertise and experience. Natural products and their derivatives have been recognized for many years as a source of therapeutic agents and of structural diversity. However, in addition to their chemical structure diversity and their biodiversity, the development of new technologies has revolutionized the screening of natural products in discovering new drugs. Applying these technologies compensates for the inherent limitations of natural products and offers a unique opportunity to re-establish natural products as a major source for drug discovery. The present article attempts to describe the utilization of compounds derived from natural resources as drug candidates, with a focus on the success of these resources in the process of finding and discovering new and effective drug compounds, an approach commonly referred to as “natural product drug discovery”.