Prediction of Compound-Target Interactions of Natural Products Using Large-scale Drug and Protein Information

Organisms from all kingdoms of life have evolved a vast array of peptidic natural products to defend against microbes. These are known collectively as antimicrobial peptides (AMPs) or host defence peptides, reflecting their abilities not only to directly kill microbes, but also to modulate host immune responses. Despite decades of investigation, AMPs have yet to live up to their promise as lead therapeutics, a reality that reflects, in part, our incomplete understanding of these diverse agents in their various physiological contexts. Towards improving our understanding of AMP biology and the ways in which this can be best leveraged for therapeutic development, we are interested in large-scale comparisons of the antimicrobial and immunological activities of human AMPs, an undertaking that requires an efficient workflow for AMP synthesis and subsequent characterization. We describe here the application of flow chemistry and reverse-phase flash chromatography to the generation of 43AMPs, approaches that, when combined, significantly expedite synthesis and purification, potentially facilitating more systematic approaches to downstream testing and engineering.

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Using UHPLC-MS Profiling for the Discovery of New Dihydro-β-Agarofurans from Australian Celastraceae Plant Extracts

Molecules ◽

10.3390/molecules24050859 ◽

2019 ◽

Vol 24 (5) ◽

pp. 859 ◽

Cited By ~ 1

Author(s):

Mario Wibowo ◽

Paul Forster ◽

Gordon Guymer ◽

Andreas Hofmann ◽

Rohan Davis

Keyword(s):

Natural Products ◽

Detailed Analysis ◽

Plant Extracts ◽

Analytical Method ◽

Large Scale ◽

Endemic Plant ◽

Plant Materials ◽

Scientific Databases ◽

New Compounds ◽

Mixed Samples

An analytical method using UHPLC-MS was developed and applied to 16 crude CH2Cl2 extracts from Australian Celastraceae plants; the endemic plant materials were accessed from Griffith University’s NatureBank resource and included bark, fruit, leaf, root, twig and mixed samples, all of which were collected from Queensland, Australia. The generated UHPLC-MS data were analysed and dereplicated using the scientific databases Dictionary of Natural Products and SciFinder Scholar in order to potentially identify new dihydro-β-agarofurans from local Celastraceae plants. These investigations led to the large-scale extraction and isolation work on a prioritised fruit sample that belonged to the rainforest plant Denhamia celastroides. Chemical investigations resulted in the purification of four new natural products, denhaminols O–R (1–4), along with the related and known compound, denhaminol G (5). The structures of all the new compounds were determined via detailed analysis of NMR and MS data.

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Pathogenic Viruses Commonly Present in the Oral Cavity and Relevant Antiviral Compounds Derived from Natural Products

Medicines ◽

10.3390/medicines5040120 ◽

2018 ◽

Vol 5 (4) ◽

pp. 120 ◽

Cited By ~ 4

Author(s):

Daisuke Asai ◽

Hideki Nakashima

Keyword(s):

Natural Products ◽

Oral Cavity ◽

Rational Design ◽

Large Scale ◽

Antiviral Agents ◽

Marine Sponges ◽

Design Strategies ◽

Screening Programs ◽

Human Oral Cavity ◽

Antiviral Compounds

Many viruses, such as human herpesviruses, may be present in the human oral cavity, but most are usually asymptomatic. However, if individuals become immunocompromised by age, illness, or as a side effect of therapy, these dormant viruses can be activated and produce a variety of pathological changes in the oral mucosa. Unfortunately, available treatments for viral infectious diseases are limited, because (1) there are diseases for which no treatment is available; (2) drug-resistant strains of virus may appear; (3) incomplete eradication of virus may lead to recurrence. Rational design strategies are widely used to optimize the potency and selectivity of drug candidates, but discovery of leads for new antiviral agents, especially leads with novel structures, still relies mostly on large-scale screening programs, and many hits are found among natural products, such as extracts of marine sponges, sea algae, plants, and arthropods. Here, we review representative viruses found in the human oral cavity and their effects, together with relevant antiviral compounds derived from natural products. We also highlight some recent emerging pharmaceutical technologies with potential to deliver antivirals more effectively for disease prevention and therapy.

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Predicting the Drug Safety for Traditional Chinese Medicine through a Comparative Analysis of Withdrawn Drugs Using Pharmacological Network

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/256782 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Mengzhu Xue ◽

Shoude Zhang ◽

Chaoqian Cai ◽

Xiaojuan Yu ◽

Lei Shan ◽

...

Keyword(s):

Clinical Trials ◽

Natural Products ◽

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Drug Safety ◽

Large Scale ◽

Drug Candidate ◽

Topology Analysis ◽

Drug Safety Surveillance ◽

Approved Drugs

As the major issue to limit the use of drugs, drug safety leads to the attrition or failure in clinical trials of drugs. Therefore, it would be more efficient to minimize therapeutic risks if it could be predicted before large-scale clinical trials. Here, we integrated a network topology analysis with cheminformatics measurements on drug information from the DrugBank database to detect the discrepancies between approved drugs and withdrawn drugs and give drug safety indications. Thus, 47 approved drugs were unfolded with higher similarity measurements to withdrawn ones by the same target and confirmed to be already withdrawn or discontinued in certain countries or regions in subsequent investigations. Accordingly, with the 2D chemical fingerprint similarity calculation as a medium, the method was applied to predict pharmacovigilance for natural products from an in-house traditional Chinese medicine (TCM) database. Among them, Silibinin was highlighted for the high similarity to the withdrawn drug Plicamycin although it was regarded as a promising drug candidate with a lower toxicity in existing reports. In summary, the network approach integrated with cheminformatics could provide drug safety indications effectively, especially for compounds with unknown targets or mechanisms like natural products. It would be helpful for drug safety surveillance in all phases of drug development.

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Neuroprotective Strategies for Neurological Disorders by Natural Products: An update

Current Neuropharmacology ◽

10.2174/1570159x16666180911124605 ◽

2019 ◽

Vol 17 (3) ◽

pp. 247-267 ◽

Cited By ~ 21

Author(s):

Muneeb U. Rehman ◽

Adil Farooq Wali ◽

Anas Ahmad ◽

Sheeba Shakeel ◽

Saiema Rasool ◽

...

Keyword(s):

Natural Products ◽

Large Scale ◽

Biological Properties ◽

In Vivo Studies ◽

Preclinical Models ◽

Neuroprotective Effects ◽

Neuroprotective Strategies ◽

Inflammatory Processes

Nature has bestowed mankind with surplus resources (natural products) on land and water. Natural products have a significant role in the prevention of disease and boosting of health in humans and animals. These natural products have been experimentally documented to possess various biological properties such as antioxidant, anti-inflammatory and anti-apoptotic activities. In vitro and in vivo studies have further established the usefulness of natural products in various preclinical models of neurodegenerative disorders. Natural products include phytoconstituents, like polyphenolic antioxidants, found in herbs, fruits, nuts, vegetables and also in marine and freshwater flora. These phytoconstituents may potentially suppress neurodegeneration and improve memory as well as cognitive functions of the brain. Also, they are known to play a pivotal role in the prevention and cure of different neurodegenerative diseases, such as Alzheimer’s disease, epilepsy, Parkinson’s disease and other neuronal disorders. The large-scale neuro-pharmacological activities of natural products have been documented due to the result of either the inhibition of inflammatory processes, or the up-regulation of various cell survival proteins or a combination of both. Due to the scarcity of human studies on neuroprotective effects of natural products, this review focuses on the various established activities of natural products in in vitro and in vivo preclinical models, and their potential neuro-therapeutic applications using the available knowledge in the literature.

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Making drugs out of sunlight and ‘thin air’: an emerging synergy of synthetic biology and natural product chemistry

The Biochemist ◽

10.1042/bio20200044 ◽

2020 ◽

Vol 42 (4) ◽

pp. 34-39

Author(s):

Michael J. Stephenson ◽

Anne Osbourn

Keyword(s):

Natural Products ◽

Synthetic Biology ◽

Natural Product ◽

Large Scale ◽

Production Systems ◽

Biological Activities ◽

Structural Complexity ◽

Scale Production ◽

Natural Product Chemistry ◽

Product Chemistry

Nature has long served as a rich source of structurally diverse small organic molecules with medicinally relevant biological activities. Despite the historical success of these so-called natural products, the enthusiasm of big pharma to explore these compounds as leads in drug design has waxed and waned. A major contributor to this is their often inherent structural complexity. Such compounds are difficult (often impossible) to access synthetically, a hurdle that can stifle lead development and hinder sustainable large-scale production of promising leads for clinical evaluation. However, in recent years, an emerging synergy between synthetic biology and natural product chemistry offers the potential for a renaissance in our ability to access natural products for drug discovery and development. Advances in genome sequencing, bioinformatics and the maturing of heterologous expression platforms are increasing, enabling the study, and ultimately, the manipulation of plant biosynthetic pathways. The triterpenes are one of the most structurally diverse families of natural products and arguably one of the most underrepresented in the clinic. The plant kingdom is the richest source of triterpene diversity, with >20,000 triterpenes reported so far. Transient expression of genes for candidate enzymes and pathways in amenable plant species is emerging as a powerful and rapid means of investigating and harnessing the plant enzymes involved in generating this diversity. Such platforms also have the potential to serve as production systems in their own right, with the possibility of upscaling these discoveries into commercially useful products using the same overall basic procedure. Ultimately, the carbon source for generation of high-value compounds in plants is photosynthesis. Therefore, we could, with the help of plants, be producing new medicines out of sunlight and ‘thin air’ in green factories in the not too distant future.

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Natural Products-Derived Chemicals: Breaking Barriers to Novel Anti-HSV Drug Development

Viruses ◽

10.3390/v12020154 ◽

2020 ◽

Vol 12 (2) ◽

pp. 154 ◽

Cited By ~ 6

Author(s):

Jakub Treml ◽

Markéta Gazdová ◽

Karel Šmejkal ◽

Miroslava Šudomová ◽

Peter Kubatka ◽

...

Keyword(s):

Drug Resistance ◽

Natural Products ◽

Drug Development ◽

Large Scale ◽

Biologically Active ◽

New Drugs ◽

In Vivo Studies ◽

Limited Attention ◽

Hsv Infections

Recently, the problem of viral infection, particularly the infection with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), has dramatically increased and caused a significant challenge to public health due to the rising problem of drug resistance. The antiherpetic drug resistance crisis has been attributed to the overuse of these medications, as well as the lack of new drug development by the pharmaceutical industry due to reduced economic inducements and challenging regulatory requirements. Therefore, the development of novel antiviral drugs against HSV infections would be a step forward in improving global combat against these infections. The incorporation of biologically active natural products into anti-HSV drug development at the clinical level has gained limited attention to date. Thus, the search for new drugs from natural products that could enter clinical practice with lessened resistance, less undesirable effects, and various mechanisms of action is greatly needed to break the barriers to novel antiherpetic drug development, which, in turn, will pave the road towards the efficient and safe treatment of HSV infections. In this review, we aim to provide an up-to-date overview of the recent advances in natural antiherpetic agents. Additionally, this paper covers a large scale of phenolic compounds, alkaloids, terpenoids, polysaccharides, peptides, and other miscellaneous compounds derived from various sources of natural origin (plants, marine organisms, microbial sources, lichen species, insects, and mushrooms) with promising activities against HSV infections; these are in vitro and in vivo studies. This work also highlights bioactive natural products that could be used as templates for the further development of anti-HSV drugs at both animal and clinical levels, along with the potential mechanisms by which these compounds induce anti-HSV properties. Future insights into the development of these molecules as safe and effective natural anti-HSV drugs are also debated.

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Finding New Molecular Targets of Familiar Natural Products Using In Silico Target Prediction

International Journal of Molecular Sciences ◽

10.3390/ijms21197102 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7102

Author(s):

Fabian Mayr ◽

Gabriele Möller ◽

Ulrike Garscha ◽

Jana Fischer ◽

Patricia Rodríguez Castaño ◽

...

Keyword(s):

Natural Products ◽

In Silico ◽

Large Scale ◽

Target Prediction ◽

Innovative Drug ◽

Protein Targets ◽

Modern Computer ◽

Cyclooxygenase 1 ◽

Pharmacological Targets ◽

Drug Leads

Natural products comprise a rich reservoir for innovative drug leads and are a constant source of bioactive compounds. To find pharmacological targets for new or already known natural products using modern computer-aided methods is a current endeavor in drug discovery. Nature’s treasures, however, could be used more effectively. Yet, reliable pipelines for the large-scale target prediction of natural products are still rare. We developed an in silico workflow consisting of four independent, stand-alone target prediction tools and evaluated its performance on dihydrochalcones (DHCs)—a well-known class of natural products. Thereby, we revealed four previously unreported protein targets for DHCs, namely 5-lipoxygenase, cyclooxygenase-1, 17β-hydroxysteroid dehydrogenase 3, and aldo-keto reductase 1C3. Moreover, we provide a thorough strategy on how to perform computational target predictions and guidance on using the respective tools.

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Prospective Function of Different Antioxidant Containing Natural Products in the Treatment of Neurodegenerative Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527319666200722153611 ◽

2020 ◽

Vol 19 ◽

Author(s):

Md. Habibur Rahman ◽

Rokeya Akter ◽

Mohammad Amjad Kamal

Keyword(s):

Natural Products ◽

Large Scale ◽

In Vivo Studies ◽

Preclinical Models ◽

Inflammatory Processes ◽

Cognitive Actions ◽

Neuro Protection ◽

Neuronal Disorders

: Nature has bestowed humanity through additional resources natural products (NPs) on earth with water. However, NPs have a significant function in the avoidance of disease by boosting health in humans as well as animals. These NPs have been scientifically acknowledged to have a range of biological characteristics like antioxidant, anti-inflammatory actions. Both In vitro and in vivo studies have more recognised the convenience of NPs in different preclinical models of neurodegenerative disorders. Moreover, most NPs comprise phytoconstituents, including polyphenolic antioxidants; originate in herbs, fruits, nuts, vegetables as well as also in marine with freshwater flora. These phytoconstituents might actively repress neuro-degeneration and recover memory as like cognitive actions of the brain. Moreover, they are well recognized to participate in an essential position in the prevention like heal of different neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, epilepsy, and additional neuronal disorders. In general, the large-scale neuro-pharmacological actions of NPs have been familiar owing to the consequence of also the inhibition of inflammatory processes, or the up-regulation of various cell endurance proteins or a mixture of together. Owing to the shortage of human studies on neuroprotective belongings of NPs, this review highlights a variety of documented actions of NPs in vitro and in vivo preclinical models and their possible neuro-protection applications by the accessible awareness in writing.

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