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Dereplication Analysis and Antitrypanosomal Potential of the Red Sea Sponge Amphimedon sp. Supported by Molecular Modelling
Abstract
The present investigation was oriented to the discovery of chemical compounds from the Red Sea sponge Amphimedon sp., as a source of active agents against Trypanosoma brucei, the causal agent of human sleeping sickness. Dereplication analysis of the active fraction from Amphimedon sp. using liquid chromatography coupled with high-resolution mass spectrometry revealed the chemical richness of this sponge with diverse alkaloidal classes such as purine, manzamine, bis-piperidine, and pyridine. Activity-guided fractionation of the total extract showed the antitrypanosomal activity concentrated in the ethyl acetate fraction (IC50 = 3.8 μg/ml). In silico modelling was carried out on the dereplicated compounds to provide an insight into their antitrypanosomal mechanism of action with docking study on eight trypanosomal proteins. Molecular dynamics was run for the complex of zamamidine D and ornithine decarboxylase, which illustrated that zamamidine D has the highest affinity to the ornithine decarboxylase enzyme. These results highlight the valuable chemical profile of Amphimedon sp., as a lead source for antitrypanosomal natural products.
First picture: Amphimedon sp.; Second: Trypanosoma brucei; Third: Molecular docking; Forth: Zamamidine D
... Artemisia annua crude extract was more active as an antimalarial agent than its marker pure metabolite, artemisinin (11) 4 . Metabolomics has become an emerging strategy that can be utilized for the comprehensive characterization of complex crude extracts along with targeting marker metabolites that can be associated with certain biological activities before commencing time-consuming purification procedures [5][6][7] . The combination of suitable analytical tools (e.g. ...
... The neural network-based software Prediction of Activity Spectra for Substances (PASS) 29 (www.way2d rug.com) was used for further prioritization of the antimalarial activity of the suggested compounds (1)(2)(3)(4)(5)(6)(7)(8). This software can predict > 4000 types of pharmacological and toxicological activities including their mechanism of action, with approximately 85% as acceptable precision, depending on the submitted compound structures that were subsequently screened utilizing the structure-activity relationship database (SARBase). ...
Fungal endophytes are a major source of anti-infective agents and other medically relevant compounds. However, their classical blinded-chemical investigation is a challenging process due to their highly complex chemical makeup. Thus, utilizing cheminformatics tools such as metabolomics and computer-aided modelling is of great help deal with such complexity and select the most probable bioactive candidates. In the present study, we have explored the fungal endophytes associated with the well-known antimalarial medicinal plant Artemisia annua for their production of further antimalarial agents. Based on the preliminary antimalarial screening of these endophytes and using LC-HRMS-based metabolomics and multivariate analyses, we suggested different potentially active metabolites (compounds 1–8 ). Further in silico investigation using the neural-network-based prediction software PASS led to the selection of a group of quinone derivatives (compounds 1–5) as the most possible active hits. Subsequent in vitro validation revealed emodin ( 1 ) and physcion ( 2 ) to be potent antimalarial candidates with IC 50 values of 0.9 and 1.9 µM, respectively. Our approach in the present investigation therefore can be applied as a preliminary evaluation step in the natural products drug discovery, which in turn can facilitate the isolation of selected metabolites notably the biologically active ones.
... Nakinadine B is a compound identified in marine sponge Amphimedon sp. and presenting antiviral activity against Hepatitis C [45]. More recently, Ali et al. [43] demonstrated in silico the inhibitory effect of nakinadine B against SARS-CoV-2 RNA-dependent-RNA polymerase protein. ...
Quorum sensing (QS) is a bacterial communication strategy controlling cells density, biofilm formation, virulence, sporulation, and survival. Since QS is considered a virulence factor in drug-resistant pathogenic bacteria, inhibition of QS can contribute to control the spread of these bacteria. We propose in this study to test in silico, 19 natural compounds for their potential to inhibit QS transcriptional regulators of Pseudomonas aeruginosa (LasR and PqsE) and Chromobacterium violaceum (CviR and CviR′). Molecular docking was performed to explore the binding energies between selected compounds, and QS signaling proteins. Additionally, molecular dynamics (MD) simulations of the complexes protein-ligand were tested to evaluate the stability of the protein and ligand complex throughout the simulation process. The simulation interaction diagram (SID) was achieved to compute the radius of gyration (rGyr), solvent accessible surface area (SASA), intramolecular HBs, molecular surface area (MolSA), and polar surface area (PSA). Additionally, the physicochemical properties, pharmacokinetics, drug-likeness, and toxicity analysis of the best-selected compounds were determined. Among these compounds, catechin and nakinadine B were identified as potent QS antagonists that showed the best XP GScore and stable interaction during molecular dynamic simulation. Catechin interacts with LasR and CviR′ displaying XP GScore −10.969 kcal/mol and −9.936kcal/mol respectively. Additionally, nakinadine B interacts with PqsE and CviR giving XP GScore −7.442 kcal/mol and −10.34 kcal/mol respectively. RMSD plot analysis showed that both catechin and nakinadine B were stable during 50 ns simulation time with the tested target proteins. The predictive result of toxicity demonstrated that catechin and nakinadine B doesn't induce cytotoxicity, immunotoxicity, carcinogenicity, mutagenicity, hepatotoxicity and were at medium risk for hERG inhibition. Also they were found to be inactive for androgen receptor and aromatase. These results imply that catechin and nakinadine B may be suggested as QS modulators, which may reduce the virulence factors of drug-resistant bacteria.
... Sometimes, new biological properties of old compounds are found during screening programs, clinical trials, or practical use of drugs, which becomes a reason for a new indication of therapeutical agents and their alternative sources. For example, the sponge Amphimedon sp., as a source of manzamine type alkaloids against Trypanosoma brucei, the causal agent of human sleeping sickness (Shady et al. 2020). The reverse scenario also shows a promising approach to the previous "old compound vs. new activities" direction. ...
Indonesian marine natural products have been one of the most promising sources in the race to obtain potential drugs for cancer treatment. One of the primary producers of cytotoxic compounds is sponges. However, there are still limited sources of comprehensive reviews related to the relationship between the structure of isolated compounds and their cytotoxic activity. This review remarks the attempt to provide a preliminary guidance from the perspective of structure-activity relationship and its participation on marine natural products research. This guidance is segregated by the compound's classes and their cytotoxic targets to obtain and organized a reliable summary of inter-study of the isolated compounds and their cytotoxicity. Structure-activity relationship is well-known for its ability to tune the bioactivity of a specific compound, especially on synthetic organic chemistry and in silico study but rarely used on natural product chemistry. The present review is intended to narrow down the endless possibilities of cytotoxicity by giving a predictable structure-activity relationship for active compounds. In addition, bioactive framework leads were selected by uncovering a noticeable structure-activity relationship with the intervention of cytotoxic agents from natural sources, especially Indonesian marine sponge.
Graphical abstract:
... Marine sponges are considered great reservoirs for potent antiviral chemicals [10][11][12][13]. Among them, Amphimedon sp. is a rich source of potential drugs, with diverse chemical constituents exhibiting a wide range of pharmacological activities [14,15]. We previously studied the antiviral potential of Amphimedon sp., and our results indicated that Amphimedon sp. ...
Since December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and serious health problems worldwide. In this study, we investigated 14 natural compounds isolated from Amphimedon sp. via a molecular docking study, to examine their ability to act as anti-COVID-19 agents. Moreover, the pharmacokinetic properties of the most promising compounds were studied. The docking study showed that virtually screened compounds were effective against the new coronavirus via dual inhibition of SARS-CoV-2 RdRp and the 3CL main protease. In particular, nakinadine B (1), 20-hepacosenoic acid (11) and amphimedoside C (12) were the most promising compounds, as they demonstrated good interactions with the pockets of both enzymes. Based on the analysis of the molecular docking results, compounds 1 and 12 were selected for molecular dynamics simulation studies. Our results showed Amphimedon sp. to be a rich source for anti-COVID-19 metabolites.
The total ethanol extract and its derived ethyl acetate fraction of the soft coral Nephthea mollis displayed remarkable in-vitro anti-trypanosomal potential against Trypanosoma brucei with IC 50 value of 6.4 and 3.7 (µg/ml, 72 h respectively. Consequently, the total ethanol extract was subjected to LC-HR-ESI-MS metabolomic profiling to discover the constituents that possibly underlie their bioactivities. Therefore, thirty-three secondary metabolites were characterized, among them, sesquiterpenes and diterpenes were found to prevail. In silico modeling was carried out on the dereplicated compounds to provide an insight into their anti-trypanosomal mechanism of action with docking study on ornithine decarboxylase (ORD) which illustrated that five of the dereplicated compounds (2-deoxy-12-ethoxy-7- O -methyl lemnacarnol, Nephthenol, 4 α - O -acetyl-selin-11-en, Eudesma-4,7(11)-diene-8 β -ol, and Chabrolidione A) have the highest affinity to the ornithine decarboxylase enzyme. These results highlight the valuable chemical profile of Nephthea mollis as a lead source for anti-trypanosomal natural products.
Background:
From time immemorial, natural products have been used for the treatment of various diseases. Various natural products, their semisynthetic derivatives, and synthetic analogs have been explored for their anti-infective properties. One such group of natural compounds that have been widely explored is manzamine alkaloids. Manzamine alkaloids are complex natural compounds consisting of a β-carboline nucleus attached to a pentacyclic ring system that was first isolated from a marine sponge during the 1980s.
Objective:
The review aims to provide a critical overview of the anti-infective potential of manzamine alkaloids.
Method:
A comprehensive and exhaustive review of the literature on manzamine alkaloids consisting of their isolation, anti-infective properties, and mechanism of action is presented.
Results:
Various manzamine alkaloids have been isolated and found to exhibit potent anti-infective activities like antibacterial, antimalarial, antiviral, antifungal, antileishmanial, among others. These manzamine alkaloids exhibit their anti-infective activity by inhibiting targets like GSK-3β and MtSK.
Conclusion:
This present review with structure-activity relationship study of manzamine alkaloids for their anti-infective activity will be useful for further development of semisynthetic manzamine analogs as potent anti-infective agents with better therapeutic potential and reduced toxicity.
Marine species are known as rich sources of metabolites involved mainly in the pharmaceutical industry. This study aimed to evaluate the effect of biologically active compounds in the marine sponge on the SARS-CoV-2 RNA-dependent-RNA polymerase protein (RdRp) using the in-silico method. A total of 51 marine compounds were checked for their possible interaction with SARS-CoV-2 RdRp using Maestro interface for molecular docking, molecular dynamic (MD) simulation, and MM/GBSA method to estimate compounds binding affinities. Among the 51 compounds screened in this study, two (mycalamide A, and nakinadine B) exhibited the lowest docking energy and best interaction. Among these compounds, mycalamide A was identified as a potent inhibitor of SARS-CoV-2 RdRp that showed the best and stable interaction during molecular dynamic simulation, with residues (Asp760 and Asp761) found in the catalytic domain of RdRp. The analysis through MM/GBSA for molecular dynamic simulation results revealed binding energy −59.7 ± 7.18 for Mycalamide A and −56 ± 10.55 for Nakinadine B. These results elucidate the possible use of mycalamide A for treating coronavirus disease.
Communicated by Ramaswamy H. Sarma
Cancer is a hazard life-threatening disease, which affect huge population worldwide. Marine actinomycetes are considered as promising source for potential chemotherapeutic agents. In our study, we carried out metabolic profiling for Nocardia sp. UR 86 and Nocardiopsis sp. UR 92 that were cultivated from the Red Sea sponge Amphimedon sp. to investigate their chemical diversity using different media conditions. The crude culture extracts were subjected to high-resolution mass spectrometry (HRMS) analysis. The chemical profiles of the different extracts of Nocardia sp. UR 86 and Nocardiopsis sp. UR 92 revealed their richness in diverse metabolites and consequently twenty compounds (1–20) were annotated. Moreover, the obtained extracts of the differently cultivated Nocardia sp. UR 86 and Nocardiopsis sp. UR 92 were investigated against three cell lines HepG2, MCF-7 and CACO2 and revealed the targeted cytotoxicity of Nocardia sp. and Nocardiopsis sp. metabolites against the three cell lines.
Marine sponges are a very attractive and rich source in the production of novel bioactive compounds. The sponges exhibit a wide range of pharmacological activities. The genus Amphimedon consists of various species, such as viridis, compressa, complanata, and terpenensis, along with a handful of undescribed species. The Amphimedon genus is a rich source of secondary metabolites containing diverse chemical classes, including alkaloids, ceramides, cerebrososides, and terpenes, with various valuable biological activities. This review covers the literature from January 1983 until January 2018 and provides a complete survey of all the compounds isolated from the genus Amphimedon and the associated microbiota, along with their corresponding biological activities, whenever applicable.
The antitrypanosomally active crude extract of the sponge Hyrtios sp. was subjected to metabolomic analysis using liquid chromatography coupled with high resolution electrospray ionization mass spectrometry (LC–HR-ESIMS) for dereplication purposes. As a result, a new alkaloid, hyrtiodoline A (1), along with other four known compounds (2–5) were reported. The structures of compounds 1–5 were determined by spectroscopic analyses, including 1D and 2D nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HRESI-MS) experiments, as well as comparison to the literature. We further investigated the antitrypanosomal activity of the five compounds, where compound 1 exhibited the most potent antitrypanosomal activity, with a half-maximal inhibitory concentration (IC50) value of 7.48 µM after 72 h.
Introduction
Marine sponge‐associated actinomycetes are potent sources of bioactive natural products of pharmaceutical significance. They also contributed to the discovery of several clinically relevant antimicrobials.
Objective
To apply the non‐targeted metabolomics approach in chemical profiling of the sponge‐derived bacterium Rhodococcus sp. UA13, formerly recovered from the Red Sea sponge Callyspongia aff. Implexa, along with testing for the anti‐infective potential of its different fractions.
Methodology
Metabolomic analysis of the crude extract was carried out using liquid chromatography with high resolution electrospray ionisation mass spectrometry (LC‐HR‐ESI‐MS) for dereplication purposes. Besides, the three major fractions (ethyl acetate, methanol, and n‐butanol) obtained by chromatographic fractionation of the crude extract were evaluated for their anti‐infective properties.
Results
A variety of metabolites, mostly peptides, were characterised herein for the first time from the genus Rhodococcus. Among the tested samples, the n‐butanol fraction showed potent inhibitory activities against Staphylococcus aureus, Candida albicans, and Trypanosoma brucei brucei with IC50 values of 9.3, 6.7, and 8.7 μg/mL, respectively, whereas only the ethyl acetate fraction was active against Chlamydia trachomatis (IC50 = 18.9 μg/mL). In contrast, both fractions did not exert anti‐infective actions against Enterococcus faecalis and Leishmania major, whereas the methanol fraction was totally inactive against all the tested organisms.
Conclusion
This study showed the helpfulness of the established procedure in metabolic profiling of marine actinomycetes using liquid chromatography mass spectrometry (LC–MS) data, which aids in reducing the complex isolation steps during their chemical characterisation. The anti‐infective spectrum of their metabolites is also interestingly relevant to future drug development.
Covering: up to December 2012Actinomycetes are known for their unprecedented ability to produce novel lead compounds of clinical and pharmaceutical importance. This review focuses on the diversity, abundance and methodological approaches targeting marine sponge-associated actinomycetes. Additionally, novel qPCR data on actinomycete abundances in different sponge species and other environmental sources are presented. The natural products literature is covered, and we are here reporting on their chemical structures, their biological activities, as well as the source organisms from which they were isolated.
African trypanosomes cause human sleeping sickness and livestock trypanosomiasis in sub-Saharan Africa. We present the sequence and analysis of the 11 megabase-sized chromosomes of Trypanosoma brucei. The 26-megabase genome contains 9068 predicted genes, including approximately 900 pseudogenes and approximately 1700 T. brucei-specific genes. Large subtelomeric arrays contain an archive of 806 variant surface glycoprotein (VSG) genes used by the parasite to evade the mammalian immune system. Most VSG genes are pseudogenes, which may be used to generate expressed mosaic genes by ectopic recombination. Comparisons of the cytoskeleton and endocytic trafficking systems with those of humans and other eukaryotic organisms reveal major differences. A comparison of metabolic pathways encoded by the genomes of T. brucei, T. cruzi, and Leishmania major reveals the least overall metabolic capability in T. brucei and the greatest in L. major. Horizontal transfer of genes of bacterial origin has contributed to some of the metabolic differences in these parasites, and a number of novel potential drug targets have been identified.
Ornithine decarboxylase (ODC) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the rate-determining step in the biosynthesis of polyamines. ODC is a proven drug target to treat African sleeping sickness. The x-ray crystal structure of Trypanosoma brucei ODC in complex with d-ornithine (d-Orn), a substrate analog, and G418 (Geneticin), a weak non-competitive inhibitor, was determined to 2.5-A resolution. d-Orn forms a Schiff base with PLP, and the side chain is in a similar position to that observed for putrescine and alpha-difluoromethylornithine in previous T. brucei ODC structures. The d-Orn carboxylate is positioned on the solvent-exposed side of the active site (si face of PLP), and Gly-199, Gly-362, and His-197 are the only residues within 4.2 A of this moiety. This structure confirms predictions that the carboxylate of d-Orn binds on the si face of PLP, and it supports a model in which the carboxyl group of the substrate l-Orn would be buried on the re face of the cofactor in a pocket that includes Phe-397, Tyr-389, Lys-69 (methylene carbons), and Asp-361. Electron density for G418 was observed at the boundary between the two domains within each ODC monomer. A ten-amino acid loop region (392-401) near the 2-fold axis of the dimer interface, which contributes several residues that form the active site, is disordered in this structure. The disordering of residues in the active site provides a potential mechanism for inhibition by G418 and suggests that allosteric inhibition from this site is feasible.
Natural products have been a rich source of compounds with structural and chemical diversity for drug discovery. However, antibiotic resistance in bacteria has been reported for nearly every antibiotic once it is used in clinical practice. In the past decade, pharmaceutical companies have reduced their natural product discovery projects because of challenges, such as high costs, low return rates, and high rediscovery rates. The largely unexplored marine environment harbours substantial diversity and is a large resource to discover novel compounds with novel modes of action, which is essential for the treatment of drug-resistant bacterial infections. In this Review, we report compounds derived from marine sources that have shown in-vivo and in-vitro efficacy against drug-resistant bacteria. Analysis of the physicochemical properties of these marine natural products with activity against drug-resistant bacteria showed that 60% of the compounds have oral bioavailability potential. Their overall distribution pattern of drug characteristics agrees with the observation that marketed antibacterial drugs have a polar distribution, with a lower median calculated logP. The aim of this Review is to summarise the diversity of these marine natural products, with a special focus on analysis of drug bioavailability. Such biologically active compounds, with high degrees of bioavailability, have the potential to be developed as effective drugs against infectious diseases.
A new manzamine alkaloid, zamamidine D (1), was isolated from an Okinawan Amphimedon sp. marine sponge. The structure of zamamidine D (1) including the relative configuration was elucidated on the basis of spectroscopic data. Zamamidine D (1) is the first manzamine alkaloid possessing a 2,2′-methylenebistryptamine unit as the aromatic moiety instead of a β-carboline unit. Zamamidine D (1) showed antimicrobial activity against several bacteria and fungi. © 2017 The American Chemical Society and American Society of Pharmacognosy.
Seven cytotoxic 3-alkylpyridine alkaloids, hachijodines A-G, have been isolated from two marine sponges of the genera Xestospongia and Amphimedon. Their structures were determined on the basis of spectral data. These alkaloids are moderately cytotoxic against P388 murine leukemia cells with IC50 values of 1.0-2.3 mu g/mL.
A new compound, 8,8′-dienecyclostellettamine, was isolated from the marine sponge Amphimedon compressa. Its structure was elucidated by spectroscopic methods including 1D and 2D NMR, UV, IR, ESI-MS, MALDI-MS techniques. It is probably an important precursor of the manzamine alkoids, and also showed vigorous antibacterial activities.
Two new alkaloids, keramaphidin C (2) and keramamine C (3), have been isolated from the Okinawan marine sponge Amphimedon sp. These compounds may be plausible biogenetic precursors of manzamine C (1), which is considered to generate from coupling of keramaphidin C (2) with tryptamine and a C3 unit through keramamine C (3).
New manzamine alkaloids, zamamidine C (1), 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2), and 3,4-dihydromanzamine J N-oxide (3), have been isolated from an Okinawan marine sponge Amphimedon species. The structures and stereochemistries of 1–3 were elucidated from the spectroscopic data and chemical derivatization. Zamamidine C (1) is a new manzamine alkaloid possessing a second β-carboline ring via an ethylene unit at N-2 of manzamine D, while 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2) is the first manzamine alkaloid possessing an epoxide ring at C-10 and C-11. Zamamidine C (1) showed significant antitrypanosomal activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and antimalarial activity against Plasmodium falciparum, the causative agent of malaria in vitro.
Two new 3-alkylpyridine alkaloids, pyrinodemins E (1) and F (2), were isolated from an Okinawan marine sponge Amphimedon sp. and the structures of 1 and 2 were elucidated on the basis of spectroscopic data. Pyrinodemins E (1) and F (2) were novel 3-alkylpyridine alkaloids possessing a 4-(methoxyamino)piperidinone moiety and an indol-3-glyoxylamide moiety, respectively. Pyrinodemin E (1) showed cytotoxicity against P388 and L1210 murine leukemia cells.
Marine organisms have yielded a variety of metabolites with neuropharmacological applications. Here we describe the isolation and pharmacological characterization of four novel, neurologically active purines 1-4, isolated from Haplosclerida sponges collected in the Republic of Palau. The structures were determined by analyses of spectral and X-ray data. Compound 1 induced convulsions upon intracerebroventricular injection into mice, with a CD50 value of 2.4 nmol/mouse. Purines 2-4 were active in mouse bioassays at higher doses. The seizurogenic activity of 1 was correlated with inhibition of neuronal GABAergic transmission, with only a modest impact on excitatory signaling, in electrophysiological recordings from hippocampal neurons. Despite having a purine template structure, the inhibitory activity of 1 was not prevented by a nonselective adenosine receptor antagonist. Thus, 1 represents a novel substituted purine that elicits convulsions through its actions on inhibitory neurotransmission. These 8-oxoisoguanine analogs comprise a new family of compounds closely related in structure to endogenous neurosignaling molecules and commonly used CNS stimulants.
New manzamine alkaloids, zamamidines A (1) and B (2), have been isolated from an Okinawan marine sponge Amphimedon species. The structures and stereochemistry of 1 and 2 were elucidated from the spectroscopic data and conformational analysis. Zamamidines A (1) and B (2) are the first manzamine alkaloids possessing a second beta-carboline ring via an ethylene unit at N-2 of manzamine H and 1,2,3,4-tetrahydromanzamine B, respectively.
Two new 3-alkylpiperidine alkaloids, tetradehydrohalicyclamine A (2) and 22-hydroxyhalicyclamine A (3), have been isolated from a marine sponge Amphimedon sp. as cytotoxic constituents. Their structures were elucidated by spectroscopic analysis. Compounds 2 and 3 inhibited growth of P388 cells with IC50 values of 2.2 and 0.45 microg/mL, respectively.
Pyrinodemin A, a cytotoxic pyridine alkaloid with an isoxazolidine moiety from sponge Amphimedon sp
- M Tsuda
- K Hirano
- T Kubota
Pyrinodemins BD, potent cytotoxic bis-pyridine alkaloids from marine sponge Amphimedon sp
- K Hirano
- T Kubota
- M Tsuda
- Y Mikami
- J Kobayashi