Natural Product Drug Discovery Research Articles

IMPDB: Indian Medicinal Phytochemical Database Curated for Drug Designing

Background: A paradigm shift towards a multifaceted natural product drug discovery approach has been observed globally. Today, many modern drugs have originated from ethnopharmacology and traditional medicine. The traditionally used medicinal plants are a rich source of biologically active phytochemicals. A paradigm shift has been observed in pharmaceutical industries towards the use of those phytochemicals for the development of drugs over synthetic compounds for minimization of side effects. Methodology: The data have been generated from the printed “Database on Medicinal Plants Used in Ayurveda” published by the Central Council for Research in Ayurvedic Sciences, Government of India. The curation of the phytochemicals and calculation of their physicochemical and drug-like properties has been done using Discovery Studio v 4.5, and the database IMPDB is designed by adhering to the principles of database design and developed using PHP as front-end and MySQL as back-end. The data in IMPDB were analyzed further and comparative analysis of physicochemical properties of IMPDB phytochemicals with other small molecule databases, followed by druggability and novelty analysis of phytochemicals of the database were conducted with wQED score and molecular fingerprinting methods. In addition to that, ADMET properties of IMPDB phytochemical were compared with FDA-approved drugs. Results: Druggability analysis of IMPDB phytochemical shows a substantial number of them are druggable. An extensive review of the existing database was conducted and the quality of data of existing databases was matched with IMPDB data, and IMPDB data was found at par with the standard databases in the same domain, in certain parameters the quality of data of IMPDB was found better. In addition to that, novelty analysis of IMPDB data in comparison to 2068 FDA-approved drugs reveals that 99.96–99.99% of the phytochemical of IMPDB is novel and to some extent better in terms of ADMET properties. The database is available from https://impdb.org.in/ . Conclusion: IMPDB can be a useful database for the drug development industry and a need for the future pharmaceutical industry.

Construction strategies and prospect of the Global Medicinal Plant Stem Cell Bank

Medicinal plant stem cells are separated from the meristem and vascular cambium of medicinal plants, which can produce active components for preventing and treating diseases and improving body physical functions under certain conditions. Medicinal plant stem cells come from a broad category of medicinal plants, including ethnic medicinal plants, folk medicinal plants, original plants of health products, vegetables, fruits, and other potential medicinal plants. At present, the techniques for the isolation, identification, preservation and culture of medicinal plant stem cells have become increasingly mature, and the mechanism of stem cell differentiation, growth and regulation of secondary metabolites has been studied in depth. Medicinal plant stem cells have a broad application prospect in medicine, health food, food and medical beauty products. As a strategic resource, the construction of the "Global Medicinal Plant Stem Cell Bank" was first proposed to preserve various kinds of medicinal plant resources in the world, and it will go global relying on the internationalization strategy of traditional Chinese medicine. The bank should follow safety, environmental protection, advanced and practical design principles. The main construction contents include the original plant bank, stem cell bank, component resource bank, gene bank, database and resource sharing system, with genetic and data resources incorporated into the scope of protection and utilization. The bank will establish a new strategy for medicinal plant resources protection and regeneration, and provide a new resource for natural products drug discovery and a technology sharing platform for various medicinal plant stem cells. As a resource treasury, a source of innovative technologies and a center of cooperation, it will become the core driving force of the global medicinal plant stem cell industry.

Fruit Peels: Food Waste as a Valuable Source of Bioactive Natural Products for Drug Discovery.

Fruits along with vegetables are crucial for a balanced diet. These not only have delicious flavors but are also reported to decrease the risk of contracting various chronic diseases. Fruit by-products are produced in huge quantity during industrial processing and constitute a serious issue because they may pose a harmful risk to the environment. The proposal of employing fruit by-products, particularly fruit peels, has gradually attained popularity because scientists found that in many instances peels displayed better biological and pharmacological applications than other sections of the fruit. The aim of this review is to highlight the importance of fruit peel extracts and natural products obtained in food industries along with their other potential biological applications.

Bridge between Total Synthesis of Bioactive Natural Products and Development of Drug Leads

Although natural products are rich sources for drug discovery, only a small percentage of natural products themselves have been approved for clinical use, thus it is necessary to modulate various properties, such as efficacy, toxicity, and metabolic stability. A question in natural product drug discovery is how to logically design natural product derivatives with desired biological properties. This review describes our recent studies regarding the medicinal chemistry of tunicamycin. Tunicamycin inhibits bacterial phospho-N-acetylmuramic acid (MurNAc)-pentapeptide translocase (MraY), which is an essential enzyme in bacteria and a good target for antibacterial drug discovery. The usefulness of tunicamycin as antibacterial agents is limited by off-target inhibition of human UDP-N-acetylglucosamine (GlcNAc): polyprenol phosphate translocase (GPT). We positioned the total synthesis of tunicamycin as a starting point for the research and have accomplished the synthesis of tunicamycin V by using the Achmatowicz reaction, [3,3] sigmatropic rearrangement of allyl cyanate, and stereoselective glycosylation as key reactions. Next, the minimum structural requirements for tunicamycin V for MraY inhibition were established by systematic structure-activity relationship studies with truncated analogs of tunicamycin V. Our collaborative study elucidated a crystal structure of human GPT in complex with tunicamycin. This structural information was then exploited to rationally design an MraY-specific inhibitor of tunicamycin V in which the GlcNAc moiety was modified to a MurNAc amide. The analog was identified as a highly selective MraYAA inhibitor.

Pitanga (Eugenia uniflora L.) as a source of bioactive compounds for health benefits: A review

• E. uniflora presents a significant amount of bioactive compounds beneficial for health. • Little is known about the potential toxicity induced by E. uniflora . • The application of E. uniflora shows a range of biological properties. • Anti-inflammatory and anti-oxidant are some of the properties of E. uniflora. • In vivo studies of E. uniflora are incipient and may be the target of new research. The pitangueira ( Eugenia uniflora ) is a tree native to Brazil but is cultivated in several subtropical countries. A great diversity of nutrients and bioactive compounds have been found in the leaves and fruits of E. uniflora , which supports its use in folk medicine to treat diseases such as stomach and intestinal disorders, fever and general inflammation. Antimicrobial, antiviral, antifungal and antioxidant effects on metabolism have been reported for this plant. This review discusses the phytochemical profile, toxicity and pharmacological action of E. uniflora leaves and fruits and points out that gaps in the literature that need to be investigated further. This review also discusses studies developed with E. uniflora demonstrating its promising therapeutic potential for several diseases with an apparent low toxicity in mammals. The compilation of the main pharmacological and toxicological results, as well as the phytochemical characterization of the varieties and constituents of E. uniflora are general aspects that this review attempts to demonstrate in order to contribute to the new approaches and developments to plant-derived natural product drug discovery. However, further studies are required to establish the nutraceutical effects and uses of E. uniflora as an important and safe supplement for human health.

Curcumin-Injected Musca domestica Larval Hemolymph: Cecropin Upregulation and Potential Anticancer Effect.

Over recent decades, much attention has been given to imply the natural products in cancer therapy alone or in combination with other established procedures. Insects have a rich history in traditional medicine across the globe, which holds promise for the future of natural product drug discovery. Cecropins, peptides produced by insects, are components of a defense system against infections and are well known to exert antimicrobial and antitumor capabilities. The present study aimed to investigate, for the first time, the role of curcumin in enhancing the anticancer effect of Musca domestica larval hemolymph. Third larval instars of M. domestica were injected with curcumin and the hemolymph was picked at 4, 8, and 24 h post-curcumin injection. M. domestica cecropin A (MdCecA) was evaluated in control and injected larval hemolymphs. The cytotoxicity on breast cancer cell lines (MCF-7) and normal Vero cells was assessed to be comparable to control larval hemolymph. Curcumin-injected larval hemolymphs exhibited significant cytotoxicity with respect to the uninjected ones against MCF-7; however, Vero cells showed no cytotoxicity. The IC50 was 106 ± 2.9 and 388 ± 9.2 μg/mL for the hemolymphs of injected larvae at 4 and 8 h, respectively, while the control larval hemolymph revealed the IC50 of >500 μg/mL. For mechanistic anticancer evaluation, concentrations of 30, 60, and 100 μg/mL of curcumin-injected larval hemolymphs were examined. A significant G2/M cell cycle arrest was observed, confirming the anti-proliferative properties of hemolymphs over the tested concentrations. The MdCecA transcripts were significantly (p < 0.05) upregulated at 4 and 8 h post-injection, while a significant downregulation was observed after 24 h. Cecropin quantification by LC–MS revealed that MdCecA peptides have the highest expression in the hemolymph of the treated larvae at 8 h relative to the control group. The upregulation of cecropin expression at mRNA and protein levels may be attributed to the curcumin stimulation and linked to the increased cytotoxicity toward the cancer cell line. In conclusion, the results suggest that the apoptotic and anti-proliferative effects of M. domestica hemolymph on MCF-7 cells following the curcumin injection can be used as a natural candidate in future pharmaceutical industries.

Endophytic Fungi: Key Insights, Emerging Prospects, and Challenges in Natural Product Drug Discovery.

Plant-associated endophytes define an important symbiotic association in nature and are established bio-reservoirs of plant-derived natural products. Endophytes colonize the internal tissues of a plant without causing any disease symptoms or apparent changes. Recently, there has been a growing interest in endophytes because of their beneficial effects on the production of novel metabolites of pharmacological significance. Studies have highlighted the socio-economic implications of endophytic fungi in agriculture, medicine, and the environment, with considerable success. Endophytic fungi-mediated biosynthesis of well-known metabolites includes taxol from Taxomyces andreanae, azadirachtin A and B from Eupenicillium parvum, vincristine from Fusarium oxysporum, and quinine from Phomopsis sp. The discovery of the billion-dollar anticancer drug taxol was a landmark in endophyte biology/research and established new paradigms for the metabolic potential of plant-associated endophytes. In addition, endophytic fungi have emerged as potential prolific producers of antimicrobials, antiseptics, and antibiotics of plant origin. Although extensively studied as a “production platform” of novel pharmacological metabolites, the molecular mechanisms of plant–endophyte dynamics remain less understood/explored for their efficient utilization in drug discovery. The emerging trends in endophytic fungi-mediated biosynthesis of novel bioactive metabolites, success stories of key pharmacological metabolites, strategies to overcome the existing challenges in endophyte biology, and future direction in endophytic fungi-based drug discovery forms the underlying theme of this article.

Modern Approaches in the Discovery and Development of Plant-Based Natural Products and Their Analogues as Potential Therapeutic Agents.

Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.

Natural product drug discovery in the artificial intelligence era.

Natural products (NPs) are primarily recognized as privileged structures to interact with protein drug targets. Their unique characteristics and structural diversity continue to marvel scientists for developing NP-inspired medicines, even though the pharmaceutical industry has largely given up. High-performance computer hardware, extensive storage, accessible software and affordable online education have democratized the use of artificial intelligence (AI) in many sectors and research areas. The last decades have introduced natural language processing and machine learning algorithms, two subfields of AI, to tackle NP drug discovery challenges and open up opportunities. In this article, we review and discuss the rational applications of AI approaches developed to assist in discovering bioactive NPs and capturing the molecular “patterns” of these privileged structures for combinatorial design or target selectivity.

Natural Products Drug Discovery: On Silica or In-Silico?

Natural products have been the most important source for drug development throughout the human history. Over time, the formulation of drugs has evolved from crude drugs to refined chemicals. In modern drug discovery, conventional natural products lead-finding usually uses a top-down approach, namely bio-guided fractionation. In this approach, the crude extracts are separated by chromatography and resulting fractions are tested for activity. Subsequently, active fractions are further refined until a single active compound is obtained. However, this is a painstakingly slow and expensive process. Among the alternatives that have been developed to improve this situation, metabolomics has proved to yield interesting results having been applied successfully to drug discovery in the last two decades. The metabolomics-based approach in lead-finding comprises two steps: (1) in-depth chemical profiling of target samples, e.g. plant extracts, and bioactivity assessment, (2) correlation of the chemical and biological data by chemometrics. In the first step of this approach, the target samples are chemically profiled in an untargeted manner to detect as many compounds as possible. So far, NMR spectroscopy, LC-MS, GC-MS, and MS/MS spectrometry are the most common profiling tools. The profile data are correlated with the biological activity with the help of various chemometric methods such as multivariate data analysis. This in-silico analysis has a high potential to replace or complement conventional on-silica bioassay-guided fractionation as it will greatly reduce the number of bioassays, and thus time and costs. Moreover, it may reveal synergistic mechanisms, when present, something for which the classical top-down approach is clearly not suited. This chapter aims to give an overview of successful approaches based on the application of chemical profiling with chemometrics in natural products drug discovery.

Artificial intelligence in microbial natural product drug discovery: current and emerging role.

Covering: up to the end of 2022Microorganisms are exceptional sources of a wide array of unique natural products and play a significant role in drug discovery. During the golden era, several life-saving antibiotics and anticancer agents were isolated from microbes; moreover, they are still widely used. However, difficulties in the isolation methods and repeated discoveries of the same molecules have caused a setback in the past. Artificial intelligence (AI) has had a profound impact on various research fields, and its application allows the effective performance of data analyses and predictions. With the advances in omics, it is possible to obtain a wealth of information for the identification, isolation, and target prediction of secondary metabolites. In this review, we discuss drug discovery based on natural products from microorganisms with the help of AI and machine learning.

Natural product drug discovery based on folklore

Natural product drug discovery based on folklore

Multiplexed Screening of Thousands of Natural Products for Protein-Ligand Binding in Native Mass Spectrometry.

The structural diversity of natural products offers unique opportunities for drug discovery, but challenges associated with their isolation and screening can hinder the identification of drug-like molecules from complex natural product extracts. Here we introduce a mass spectrometry-based approach that integrates untargeted metabolomics with multistage, high-resolution native mass spectrometry to rapidly identify natural products that bind to therapeutically relevant protein targets. By directly screening crude natural product extracts containing thousands of drug-like small molecules using a single, rapid measurement, we could identify novel natural product ligands of human drug targets without fractionation. This method should significantly increase the efficiency of target-based natural product drug discovery workflows.

Unleashing the Potential of Microbial Natural Products in Drug Discovery: Focusing on Streptomyces as Antimicrobials Goldmine.

The natural product specialized metabolites produced by microbes and plants are the backbone of our current drugs. Ironically, we are in a golden age of understanding natural product biosynthesis, biochemistry, and engineering. These advances have the potential to usher in a new era of natural product exploration and development, taking full advantage of the unique and favorable properties of natural product compounds in drug discovery. There is now an increasing realization that these privileged structures represent the optimal starting point for the development of clinically viable assets. Here, we outline the current state-of-the-art in antimicrobial natural product drug discovery, specifically Streptomyces species, with a specific focus on how the emerging field of synthetic biology is delivering the tools and technologies required to unlock the therapeutic potential of natural products. We illustrate how these approaches are circumventing many of the problems that have historically plagued conventional screening programs, enabling the expedient discovery of new molecules with novel functions.

Building Natural Product Libraries Using Quantitative Clade-Based and Chemical Clustering Strategies.

ABSTRACTThe success of natural product-based drug discovery is predicated on having chemical collections that offer broad coverage of metabolite diversity. We propose a simple set of tools combining genetic barcoding and metabolomics to help investigators build natural product libraries aimed at achieving predetermined levels of chemical coverage. It was found that such tools aided in identifying overlooked pockets of chemical diversity within taxa, which could be useful for refocusing collection strategies. We have used fungal isolates identified as Alternaria from a citizen-science-based soil collection to demonstrate the application of these tools for assessing and carrying out predictive measurements of chemical diversity in a natural product collection. Within Alternaria, different subclades were found to contain nonequivalent levels of chemical diversity. It was also determined that a surprisingly modest number of isolates (195 isolates) was sufficient to afford nearly 99% of Alternaria chemical features in the data set. However, this result must be considered in the context that 17.9% of chemical features appeared in single isolates, suggesting that fungi like Alternaria might be engaged in an ongoing process of actively exploring nature’s metabolic landscape. Our results demonstrate that combining modest investments in securing internal transcribed spacer (ITS)-based sequence information (i.e., establishing gene-based clades) with data from liquid chromatography-mass spectrometry (i.e., generating feature accumulation curves) offers a useful route to obtaining actionable insights into chemical diversity coverage trends in a natural product library. It is anticipated that these outcomes could be used to improve opportunities for accessing bioactive molecules that serve as the cornerstone of natural product-based drug discovery.IMPORTANCE Natural product drug discovery efforts rely on libraries of organisms to provide access to diverse pools of compounds. Actionable strategies to rationally maximize chemical diversity, rather than relying on serendipity, can add value to such efforts. Readily implementable biological (i.e., ITS sequence analysis) and chemical (i.e., mass spectrometry-based feature and scaffold measurements) diversity assessment tools can be employed to monitor and adjust library development tactics in real time. In summary, metabolomics-driven technologies and simple gene-based specimen barcoding approaches have broad applicability to building chemically diverse natural product libraries.

Review: Veratrum californicum Alkaloids.

Veratrum spp. grow throughout the world and are especially prevalent in high mountain meadows of North America. All parts of Veratrum plants have been used for the treatment of ailments including injuries, hypertension, and rheumatic pain since as far back as the 1600s. Of the 17–45 Veratrum spp., Veratrum californicum alkaloids have been proven to possess favorable medicinal properties associated with inhibition of hedgehog (Hh) pathway signaling. Aberrant Hh signaling leads to proliferation of over 20 cancers, including basal cell carcinoma, prostate and colon among others. Six of the most well-studied V. californicum alkaloids are cyclopamine (1), veratramine (2), isorubijervine (3), muldamine (4), cycloposine (5), and veratrosine (6). Recent inspection of the ethanolic extract from V. californicum root and rhizome via liquid chromatography–mass spectrometry has detected up to five additional alkaloids that are proposed to be verazine (7), etioline (8), tetrahydrojervine (9), dihydrojervine (10), 22-keto-26-aminocholesterol (11). For each alkaloid identified or proposed in V. californicum, this review surveys literature precedents for extraction methods, isolation, identification, characterization and bioactivity to guide natural product drug discovery associated with this medicinal plant.

Natural products potential of Dictyoceratida sponges-associated micro-organisms.

The marine environment represents one of the most underexplored environments in the world. Marine sponges have a higher taxonomic diversity according to definite environmental conditions. They have been considered interesting sources for bioactive compounds. Dictyoceratida sponges are divided into five families which are widely distributed and habituating different types of micro-organisms. However, some secondary metabolites are probably not produced by the sponges themselves, but rather by their associated micro-organisms. These secondary metabolites are characterized by different chemical structures and consequently different biological activities. This review outlines the reported secondary metabolites from micro-organisms associated with Dictyoceratida sponges and their investigated biological activities from 1991 to 2019. The increasing research studies in this field can play a major role in marine microbial natural products drug discovery in the future.

Stereoselective Late-Stage Transformations of Indolo[2,3-a]quinolizines Skeleta to Nature-Inspired Scaffolds.

The indolo[2,3-a]quinolizines, canthines, and arborescidines natural products exhibit a wide range of bioactivities including anticancer, antiviral, antibacterial, and anti-inflammatory, among others. Therefore, the development of modular and efficient strategies to access the core scaffolds of these classes of natural products is a remarkable achievement. The Complexity-to-Diversity (CtD) strategy has become a powerful tool that transforms natural products into skeletal and stereochemical diversity. However, many of the reactions that could be utilized in this process are limited by the type of functional groups present in the starting material, which restrict transformations into a variety of products to achieve the desired diversity. In the course of employing a (CtD) strategy en route to the synthesis of nature-inspired compounds, unexpected stereoelectronic-driven rearrangement reactions have been discovered. These reactions provided a rapid access to indolo[2,3-a]quinolizines-, canthines-, and arborescidines-inspired alkaloids in a modular and diastereoselective manner. The disclosed strategies will be widely applicable to other late-stage natural product transformation programs and drug discovery initiatives.

Renewed interests in the discovery of bioactive actinomycete metabolites driven by emerging technologies.

Actinomycetes are prolific sources of bioactive molecules. Traditional workflows including bacterial isolation, fermentation, metabolite identification and structure elucidation have resulted in high rates of natural product rediscovery in recent years. Recent advancements in multi-omics techniques have uncovered cryptic gene clusters within the genomes of actinomycetes, potentially introducing vast resources for the investigation of bioactive molecules. While developments in culture techniques have allowed for the fermentation of difficult-to-culture actinomycetes, high-throughput metabolite screening has offered plenary tools to accelerate hits discovery. A variety of new bioactive molecules have been isolated from actinomycetes of unique environmental origins, such as endophytic and symbiotic actinomycetes. Synthetic biology and genome mining have also emerged as new frontiers for the discovery of bioactive molecules. This review covers the highlights of recent developments in actinomycete-derived natural product drug discovery.

Bacterial Natural Product Drug Discovery for New Antibiotics: Strategies for Tackling the Problem of Antibiotic Resistance by Efficient Bioprospecting.

The problem of antibiotic resistance has become a challenge for our public health and society; it has allowed infectious diseases to re-emerge as a risk to human health. New antibiotics that are introduced to the market face the rise of resistant pathogens after a certain period of use. The relatively fast development of resistance against some antibiotics seems to be closely linked to their microbial origin and function in nature. Antibiotics in clinical use are merely products of microorganisms or derivatives of microbial products. The evolution of these antimicrobial compounds has progressed with the evolution of the respective resistance mechanisms in microbes for billions of years. Thus, antimicrobial resistance genes are present within the environment and can be taken up by pathogens through horizontal gene transfer. Natural products from bacteria are an important source of leads for drug development, and microbial natural products have contributed the most antibiotics in current clinical use. Bioprospecting for new antibiotics is a labor-intensive task as obstacles such as redetection of known compounds and low compound yields consume significant resources. The number of bacterial isolates one can theoretically investigate for new secondary metabolites is, on the other hand, immense. Therefore, the available capacity for biodiscovery should be focused on the most promising sources for chemical novelty and bioactivity, employing the appropriate scientific tools. This can be done by first looking into under- or unexplored environments for bacterial isolates and by focusing on the promising candidates to reduce the number of subjects.