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Structure–Activity Relationships (SAR) of Natural Products

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 47845

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Special Issue Editors

Prof. Dr. Wolfgang Sippl

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Guest Editor

Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, 06120 Halle (Saale), Germany
Interests: epigenetics; PROTACs; drug design; drug discovery; small molecule inhibitors
Special Issues, Collections and Topics in MDPI journals

Dr. Fidele Ntie-Kang

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Guest Editor

University of Buea, Buea, Cameroon
Interests: natural products; structure-based design drug design and discovery; QSAR; pharmacophore modeling; natural product database development; ADMET prediction; virtual screening; ecotoxicity

Special Issue Information

Dear Colleagues,

We are pleased to host a Special Issue in the journal Molecules (IF: 3.098) on “Structure–Activity Relationships (SAR) of Natural Products (NPs)” in drug discovery. This topic has recently drawn a lot of attention and there is increasing interest in NPs as a “source of inspiration” for the discovery of new lead compounds. This is because compounds from natural sources are finetuned to bind to specific classes of drug targets. Thus, NPs are gaining attention as sources of lead compounds with novel scaffolds. In this Special Issue, we focus on NPs and NP mimics and their derivatives, which play a role in several biochemical processes, including those showing potential for development into drugs.

Goal: This Special Issue is focused on NPs from fungal, microbial, marine and plant sources, which host biosynthesis processes for making secondary metabolites. Synthetically modified compounds, particularly those derived from QSAR or SAR studies through computer modeling, in vitro and in vivo testing are very welcome.

Scope: Submissions are welcome in (but not limited to) the following topics:

Bioactive NPs against neglected tropical diseases and cancer
Insight from binding free energy calculations, docking, parmacophore modeling and molecular dynamics involving small molecule NPs and NP mimics.
Structure–activity relations in plant-based and marine-based alkaloids
Natural remedies and pharmacogenomics of age-related and neurodegenerative disorders.
Natural products in environmental remediation
Implications of compounds of natural origin in disease-associated epigenetic mechanisms
Chemoinformatics exploration of the chemical space and target space of natural products with epigenetic functions
Bromodomain inhibitors of natural origin
Epigenetics in plant, fungal and microbial biosynthesis
Network pharmacology associated with treatment with natural remedies
Protein glycosylation and implications for genes, environment and disease

Details for authors: Submissions (editorials, reviews, original research, etc.) are welcome.

Prof. Wolfgang Sippl
Dr. Fidele Ntie-Kang
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

natural products
structure–activity relationship
drug discovery
small molecules

Published Papers (10 papers)

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Editorial

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4 pages, 205 KiB

Open AccessEditorial

Editorial to Special Issue—“Structure-Activity Relationships (SAR) of Natural Products”

by Wolfgang Sippl and Fidele Ntie-Kang

Molecules 2021, 26(2), 250; https://doi.org/10.3390/molecules26020250 - 06 Jan 2021

Cited by 2 | Viewed by 2029

Abstract

The topic of structure-activity-relationships (SAR) has recently drawn a lot of attention, and there is increasing interest in natural products (NPs) as a “source of inspiration” for the discovery of new lead compounds [...] Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

Research

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19 pages, 2508 KiB

Open AccessArticle

Alkaloids with Anti-Onchocercal Activity from Voacanga africana Stapf (Apocynaceae): Identification and Molecular Modeling

by Smith B. Babiaka, Conrad V. Simoben, Kennedy O. Abuga, James A. Mbah, Rajshekhar Karpoormath, Dennis Ongarora, Hannington Mugo, Elvis Monya, Fidelis Cho-Ngwa, Wolfgang Sippl, Edric Joel Loveridge and Fidele Ntie-Kang

Molecules 2021, 26(1), 70; https://doi.org/10.3390/molecules26010070 - 25 Dec 2020

Cited by 8 | Viewed by 2882

Abstract

A new iboga-vobasine-type isomeric bisindole alkaloid named voacamine A (1), along with eight known compounds—voacangine (2), voacristine (3), coronaridine (4), tabernanthine (5), iboxygaine (6), voacamine (7), voacorine (8) and conoduramine (9)—were isolated from the stem bark of Voacangaafricana. The structures of the compounds were determined by comprehensive spectroscopic analyses. Compounds 1, 2, 3, 4, 6, 7 and 8 were found to inhibit the motility of both the microfilariae (Mf) and adult male worms of Onchocerca ochengi, in a dose-dependent manner, but were only moderately active on the adult female worms upon biochemical assessment at 30 μM drug concentrations. The IC₅₀ values of the isolates are 2.49–5.49 µM for microfilariae and 3.45–17.87 µM for adult males. Homology modeling was used to generate a 3D model of the O. ochengi thioredoxin reductase target and docking simulation, followed by molecular dynamics and binding free energy calculations attempted to offer an explanation of the anti-onchocercal structure–activity relationship (SAR) of the isolated compounds. These alkaloids are new potential leads for the development of antifilarial drugs. The results of this study validate the traditional use of V. africana in the treatment of human onchocerciasis. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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34 pages, 4933 KiB

Open AccessArticle

How to Separate Kinase Inhibition from Undesired Monoamine Oxidase A Inhibition—The Development of the DYRK1A Inhibitor AnnH75 from the Alkaloid Harmine

by Anne Wurzlbauer, Katharina Rüben, Ece Gürdal, Apirat Chaikuad, Stefan Knapp, Wolfgang Sippl, Walter Becker and Franz Bracher

Molecules 2020, 25(24), 5962; https://doi.org/10.3390/molecules25245962 - 16 Dec 2020

Cited by 10 | Viewed by 3118

Abstract

The β-carboline alkaloid harmine is a potent DYRK1A inhibitor, but suffers from undesired potent inhibition of MAO-A, which strongly limits its application. We synthesized more than 60 analogues of harmine, either by direct modification of the alkaloid or by de novo synthesis of β-carboline and related scaffolds aimed at learning about structure–activity relationships for inhibition of both DYRK1A and MAO-A, with the ultimate goal of separating desired DYRK1A inhibition from undesired MAO-A inhibition. Based on evidence from published crystal structures of harmine bound to each of these enzymes, we performed systematic structure modifications of harmine yielding DYRK1A-selective inhibitors characterized by small polar substituents at N-9 (which preserve DYRK1A inhibition and eliminate MAO-A inhibition) and beneficial residues at C-1 (methyl or chlorine). The top compound AnnH75 remains a potent DYRK1A inhibitor, and it is devoid of MAO-A inhibition. Its binding mode to DYRK1A was elucidated by crystal structure analysis, and docking experiments provided additional insights for this attractive series of DYRK1A and MAO-A inhibitors. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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19 pages, 5205 KiB

Open AccessArticle

Virtual Screening Identifies Chebulagic Acid as an Inhibitor of the M2(S31N) Viral Ion Channel and Influenza A Virus

by Maggie C. Duncan, Pascal Amoa Onguéné, Ibuki Kihara, Derrick N. Nebangwa, Maya E. Naidu, David E. Williams, Aruna D. Balgi, Kerstin Andrae-Marobela, Michel Roberge, Raymond J. Andersen, Masahiro Niikura, Fidele Ntie-Kang and Ian Tietjen

Molecules 2020, 25(12), 2903; https://doi.org/10.3390/molecules25122903 - 24 Jun 2020

Cited by 10 | Viewed by 2875

Abstract

The increasing prevalence of drug-resistant influenza viruses emphasizes the need for new antiviral countermeasures. The M2 protein of influenza A is a proton-gated, proton-selective ion channel, which is essential for influenza replication and an established antiviral target. However, all currently circulating influenza A virus strains are now resistant to licensed M2-targeting adamantane drugs, primarily due to the widespread prevalence of an M2 variant encoding a serine to asparagine 31 mutation (S31N). To identify new chemical leads that may target M2(S31N), we performed a virtual screen of molecules from two natural product libraries and identified chebulagic acid as a candidate M2(S31N) inhibitor and influenza antiviral. Chebulagic acid selectively restores growth of M2(S31N)-expressing yeast. Molecular modeling also suggests that chebulagic acid hydrolysis fragments preferentially interact with the highly-conserved histidine residue within the pore of M2(S31N) but not adamantane-sensitive M2(S31). In contrast, chebulagic acid inhibits in vitro influenza A replication regardless of M2 sequence, suggesting that it also acts on other influenza targets. Taken together, results implicate chebulagic acid and/or its hydrolysis fragments as new chemical leads for M2(S31N) and influenza-directed antiviral development. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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20 pages, 4487 KiB

Open AccessArticle

Enhancing the Membranolytic Activity of Chenopodium quinoa Saponins by Fast Microwave Hydrolysis

by Emmanuel Colson, Philippe Savarino, Emily J.S. Claereboudt, Gustavo Cabrera-Barjas, Magali Deleu, Laurence Lins, Igor Eeckhaut, Patrick Flammang and Pascal Gerbaux

Molecules 2020, 25(7), 1731; https://doi.org/10.3390/molecules25071731 - 09 Apr 2020

Cited by 24 | Viewed by 3221

Abstract

Saponins are plant secondary metabolites. There are associated with defensive roles due to their cytotoxicity and are active against microorganisms. Saponins are frequently targeted to develop efficient drugs. Plant biomass containing saponins deserves sustained interest to develop high-added value applications. A key issue when considering the use of saponins for human healthcare is their toxicity that must be modulated before envisaging any biomedical application. This can only go through understanding the saponin-membrane interactions. Quinoa is abundantly consumed worldwide, but the quinoa husk is discarded due to its astringent taste associated with its saponin content. Here, we focus on the saponins of the quinoa husk extract (QE). We qualitatively and quantitively characterized the QE saponins using mass spectrometry. They are bidesmosidic molecules, with two oligosaccharidic chains appended on the aglycone with two different linkages; a glycosidic bond and an ester function. The latter can be hydrolyzed to prepare monodesmosidic molecules. The microwave-assisted hydrolysis reaction was optimized to produce monodesmosidic saponins. The membranolytic activity of the saponins was assayed based on their hemolytic activity that was shown to be drastically increased upon hydrolysis. In silico investigations confirmed that the monodesmosidic saponins interact preferentially with a model phospholipid bilayer, explaining the measured increased hemolytic activity. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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16 pages, 3401 KiB

Open AccessArticle

Protective Effect of Genistein against Compound 48/80 Induced Anaphylactoid Shock via Inhibiting MAS Related G Protein-Coupled Receptor X2 (MRGPRX2)

by Mukesh Kumar, Kailash Singh, Karthi Duraisamy, Ahmed A. Allam, Jamaan Ajarem and Billy Kwok Chong CHOW

Molecules 2020, 25(5), 1028; https://doi.org/10.3390/molecules25051028 - 25 Feb 2020

Cited by 19 | Viewed by 4894

Abstract

Anaphylactoid shock is a fatal hypersensitivity response caused by non-IgE mediated mast cell activation. These reactions are mediated by a family of G protein-coupled receptors (GPCRs) known as Mas related GPCRX2 (MRGPRX2). Several US FDA approved drugs which are used in day to day life have been reported to cause anaphylactoid shock. Surprisingly, no therapeutic drugs are available which can directly target MRGPRX2 for treatment of anaphylactoid shock. Genistein is a non-steroidal polyphenol known for its diverse physiological and pharmacological activities. In recent studies, Genistein has been reported for its anti-inflammatory activity on mast cells. However, the effects and mechanistic pathways of Genistein on anaphylactoid reaction remain unknown. In the present study, we designed a battery of in-vitro, in-silico and in-vivo experiments to evaluate the anti-anaphylactoid activity of Genistein in order to understand the possible molecular mechanisms of its action. The in-vitro results demonstrated the inhibitory activity of Genistein on MRGPRX2 activation. Further, a mouse model of anaphylactoid shock was used to evaluate the inhibitory activity of Genistein on blood vessel leakage and hind paw edema. Taken together, our findings have demonstrated a therapeutic potential of Genistein as a lead compound in the treatment of anaphylactoid shock via MRGPRX2. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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11 pages, 4596 KiB

Open AccessArticle

Structure-Guided Identification of Black Cohosh (Actaea racemosa) Triterpenoids with In Vitro Activity against Multiple Myeloma

by Karin Jöhrer, Hermann Stuppner, Richard Greil and Serhat Sezai Çiçek

Molecules 2020, 25(4), 766; https://doi.org/10.3390/molecules25040766 - 11 Feb 2020

Cited by 12 | Viewed by 3483

Abstract

Black cohosh is a well-established medicinal plant and preparations of its rootstock are used for the treatment of mild climacteric complaints. The compounds considered responsible for the therapeutic effect are triterpene glycosides, characterized by a cycloartane scaffold and a pentose moiety. Because some of these triterpenoids were found to exhibit relevant cytotoxic effects against human breast cancer cells, we decided to investigate their activity on multiple myeloma cell lines NCI-H929, OPM-2, and U266. In a systematic approach, we initially tested three known cytotoxic compounds of three different triterpenoid types, revealing the cimigenol-type triterpenoid as the most active constituent. In a second round, seven naturally occurring cimigenol derivatives were compared with respect to their sugar moiety and their substitution pattern at position C-25, leading to 25-O-methylcimigenol-3-O-α-L-arabinopyranoside as the most potent candidate. Interestingly, not only the methyl group at position C-25 increased the cytotoxic effect but also the arabinose moiety at position C-3 had an impact on the activity. The variety of cimigenol derivatives, moreover, allowed a detailed discussion of their structure–activity relationships, not only for their effect on multiple myeloma cells but also with regard to previous studies on the cytotoxicity of black cohosh triterpenoids. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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Review

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29 pages, 1890 KiB

Open AccessFeature PaperReview

Natural Products as Modulators of Sirtuins

by Berin Karaman Mayack, Wolfgang Sippl and Fidele Ntie-Kang

Molecules 2020, 25(14), 3287; https://doi.org/10.3390/molecules25143287 - 20 Jul 2020

Cited by 39 | Viewed by 5581

Abstract

Natural products have been used for the treatment of human diseases since ancient history. Over time, due to the lack of precise tools and techniques for the separation, purification, and structural elucidation of active constituents in natural resources there has been a decline in financial support and efforts in characterization of natural products. Advances in the design of chemical compounds and the understanding of their functions is of pharmacological importance for the biomedical field. However, natural products regained attention as sources of novel drug candidates upon recent developments and progress in technology. Natural compounds were shown to bear an inherent ability to bind to biomacromolecules and cover an unparalleled chemical space in comparison to most libraries used for high-throughput screening. Thus, natural products hold a great potential for the drug discovery of new scaffolds for therapeutic targets such as sirtuins. Sirtuins are Class III histone deacetylases that have been linked to many diseases such as Parkinson`s disease, Alzheimer’s disease, type II diabetes, and cancer linked to aging. In this review, we examine the revitalization of interest in natural products for drug discovery and discuss natural product modulators of sirtuins that could serve as a starting point for the development of isoform selective and highly potent drug-like compounds, as well as the potential application of naturally occurring sirtuin inhibitors in human health and those in clinical trials. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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48 pages, 5383 KiB

Open AccessReview

Structure-Activity-Relationship and Mechanistic Insights for Anti-HIV Natural Products

by Ramandeep Kaur, Pooja Sharma, Girish K. Gupta, Fidele Ntie-Kang and Dinesh Kumar

Molecules 2020, 25(9), 2070; https://doi.org/10.3390/molecules25092070 - 29 Apr 2020

Cited by 37 | Viewed by 12062

Abstract

Acquired Immunodeficiency Syndrome (AIDS), which chiefly originatesfroma retrovirus named Human Immunodeficiency Virus (HIV), has impacted about 70 million people worldwide. Even though several advances have been made in the field of antiretroviral combination therapy, HIV is still responsible for a considerable number of deaths in Africa. The current antiretroviral therapies have achieved success in providing instant HIV suppression but with countless undesirable adverse effects. Presently, the biodiversity of the plant kingdom is being explored by several researchers for the discovery of potent anti-HIV drugs with different mechanisms of action. The primary challenge is to afford a treatment that is free from any sort of risk of drug resistance and serious side effects. Hence, there is a strong demand to evaluate drugs derived from plants as well as their derivatives. Several plants, such as Andrographis paniculata, Dioscorea bulbifera, Aegle marmelos, Wistaria floribunda, Lindera chunii, Xanthoceras sorbifolia and others have displayed significant anti-HIV activity. Here, weattempt to summarize the main results, which focus on the structures of most potent plant-based natural products having anti-HIV activity along with their mechanisms of action and IC₅₀ values, structure-activity-relationships and important key findings. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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23 pages, 2814 KiB

Open AccessReview

Structure-Dependent Activity of Plant-Derived Sweeteners

by Serhat Sezai Ҫiçek

Molecules 2020, 25(8), 1946; https://doi.org/10.3390/molecules25081946 - 22 Apr 2020

Cited by 16 | Viewed by 5661

Abstract

Human sensation for sweet tastes and the thus resulting over-consumption of sugar in recent decades has led to an increasing number of people suffering from caries, diabetes, and obesity. Therefore, a demand for sugar substitutes has arisen, which increasingly has turned towards natural sweeteners over the last 20 years. In the same period, thanks to advances in bioinformatics and structural biology, understanding of the sweet taste receptor and its different binding sites has made significant progress, thus explaining the various chemical structures found for sweet tasting molecules. The present review summarizes the data on natural sweeteners and their most important (semi-synthetic) derivatives until the end of 2019 and discusses their structure–activity relationships, with an emphasis on small-molecule high-intensity sweeteners. Full article

(This article belongs to the Special Issue Structure–Activity Relationships (SAR) of Natural Products)

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