Marine Natural Products Research Articles

Discovery of Jaspamycin from marine-derived natural product based on MTA3 to inhibit hepatocellular carcinoma progression

Studies have underscored the pivotal role of metastasis-associated protein 3 (MTA3) as a cancer regulator, yet its potential as a drug target across cancers necessitates comprehensive evaluation. In this study, we analyzed MTA3 expression profiles to ascertain its diagnostic and prognostic value in pan-cancers, probing associations with genetic variations and immunological characteristics. Notably, liver hepatocellular carcinoma (LIHC) exhibited the most significant correlation with MTA3. By transfection of siRNA, interference of MTA3 affected HepG2 and Hepa1-6 cell viability and migration. Through drug screening and drug-likeness evaluation among marine-derived natural products, Jaspamycin was identified as a potential hepatocellular carcinoma treatment by targeting MTA3. By applying in vitro and in vivo experiment, the inhibitory effects of Jaspamycin on hepatocellular carcinoma viability, migration, and tumor progression were observed. To assess the potential of MTA3 as an anticancer drug target, MTA3 overexpression plasmid was transfected together with Jaspamycin treatment, and observed that MTA3 upregulation counteracted the inhibitory effects of Jaspamycin on hepatocarcinoma cell proliferation and migration, underscoring the efficacy of MTA3 as a drug target in hepatocellular carcinoma drug screening. This study highlights the clinical significance of MTA3 in pan-cancer, particularly in hepatocellular carcinoma. Additionally, it identifies Jaspamycin, a marine-derived compound with promising pharmacological properties, as an effective inhibitor of MTA3 activity, suggesting its potential for hepatocellular carcinoma treatment.

Exploring marine natural products for identifying putative candidates as EBNA1 inhibitors: An insight from molecular docking, molecular dynamics, and DFT computations

Epstein-Barr virus (EBV), namely a DNA neoplasm virus, is liable for over 1 % of malignant neoplasms involving Hodgkin's and Burkitt's lymphoma as well as ventral cancer. Despite the crucial role of EBV in carcinoma evolution, no treatment has been discovered yet against EBV. Epstein-Barr nuclear antigen 1 (EBNA1), the EBV-encoded latent protein, is produced in all EBV-linked neoplasms and is the only latent protein in these cancer types. EBNA1 protein has multiple roles in the upkeep, reproduction, and EBV genome separation and can thus act as an attractive therapeutic target for treating EBV-related malignancies. In the past few decades, attempts have been made to develop specialized EBNA1 inhibitors to reduce EBNA1 expression or obstruct EBNA1-relied processes, but none has been approved yet. Marine natural products (MNPs) have garnered significant interest as potential sources of antiviral drug candidates. In seeking potent drug candidates to inhibit EBV reproduction, an MNP database containing >14,000 compounds was mined to hunt putative EBNA1 inhibitors using docking computations and molecular dynamics simulations (MDS). On the basis of binding energy (ΔGbinding) estimations over 200 ns MDS, UMHMNP351444649 and UMHMNP134128179 revealed a greater binding affinity towards EBNA1 compared to KWG, with ΔGbinding values of −35.6, −33.3, and −32.4 kcal/mol, respectively. Structural and energetical investigations of UMHMNP351444649 and UMHMNP134128179 complexed with EBNA1 were inspected, unveiling the great constancy of these inhibitors within the EBNA1 binding site. Moreover, the identified MNPs demonstrated favorable physicochemical and medicinal chemistry characteristics. Finally, density functional theory calculations were executed, and the results assured the outcomes obtained from docking computations and MDS. These findings proposed UMHMNP351444649 and UMHMNP134128179 as potential anti-EBV drug candidates that warrant further in-vitro and in-vivo assays.

Bioactives from marine resources as natural health products: A review.

The oceans are a rich source of a myriad of structurally different and unique natural products that are mainly found in invertebrates with potential applications in different disciplines. Microbial infection and cancer are the leading causes of death worldwide. Discovery of new sources of therapy for microbial infections is an urgent requirement due to the emergence of pathogenic microorganisms that are resistant to existing therapies. Marine bioactives have demonstrated to be promising sources for the discovery and development of novel antimicrobial and anticancer compounds. Several marine compounds are confirmed to have antibacterial effects and most marine-based antifungal compounds are cytotoxic. Numerous antitumor marine natural products, derived mainly from sponges or molluscs, and also bryozoans and cyanobacteria, exhibit potent antimitotic activity. In addition, marine biodiversity offers some possible leads or new drugs to treat human immunodeficiency virus (HIV). A majority of marine derived drugs are currently in clinical trials or under preclinical evaluation. Furthermore, marine-based drugs, approved by the US Food and Drug Administration (FDA) are available in the market. This review summarizes the sources, mechanisms of action and potential utilization of marine natural products such as peptides, alkaloids, polyketides, polyphenols, terpenoids and sterols as antifungal, antibacterial, antiviral, and anticancer compounds. Significance Statement Utilization of marine bioactives as natural health products leads to crucial advancement in providing dietary supplements, nutraceuticals, functional foods and pharmaceuticals. Their myriad of application promotes health and plays a role in disease risk reduction. Therapeutic potential of potent compounds from marine organisms and use of their bioactives have promising medicinal value for preventing ailments and advancing pharmaceutical and nutraceutical industries. Their utilization benefits human health globally and contributes to the conservation of marine ecosystem in a transformative / sustainable approach.

Chemical profiling of fungal metabolites via the OSMAC approach: Novel identification of Brianthein W from an endophytic fungus, Hypomontagnella monticulosa Zg15SU

In the previous report, we reported that Hypomontagnella monticulosa originating from the rhizome of Zingiber griffithii was known to produce a marine-derived natural product. An OSMAC-based approach was designed by modifying the nutritional composition of the growth medium to investigate any possible new metabolites produced by the strain. The culture filtrate and biomass were conditioned through the use of three basal media, namely, Czapek-dox, potato dextrose, and Wickersham broth medium. GC-MS and multivariate analysis was performed to distinguish the chemicals and determine their composition in the tested extracts. Antimicrobial activity was tested against selected human pathogenic microbes using the disk-diffusion method. The MeOH extract of both culture filtrate and biomass from different fermentation media revealed that the majority of identified compounds (n=40) were found in Wickerham medium (n=23), which is later termed as MeOH-Wi. The chemical composition of MeOH-Wi was fatty acids (21.74%), followed by terpenoids (17.38%), cyclosiloxane (13.04%), aldehydes (13.04%), alkenes (8.7%), hydrocarbons (8.7%), esters (8.7%), alkaloids (4.35%), and an unclassified compound, the 9,9-Dimethyl-3,7-diazabicyclo[3.3.1]nonane. The numerous chemical compounds in MeOH-Wi corresponded with its antimicrobial activities against Micrococcus luteus NBRC 13867 (±11 mm), Candida maltosa NBRC 1977 (±9 mm), and Escherichia coli JM 109 (±5 mm) which were higher than the other tested extracts. Further purification using HPLC RP-C18 using NP-SiO2/n-Hex–EtOAc (10:2) to yield compound (1). Compound (1) was determined as an analog of briarian W—a diterpene mostly found in marine sponge, Briareum spp.—as a pure compound in the MeOH extract of H. monticulosa based on the 1D and 2D NMR analysis. The anticancer activity (IC50) of compound (1) was 0.077, 0.080, and 0.102 µg/mL against the growth of HCT-116, NBT-T2, and Panc-1, respectively. As far as we are aware, this is the first report on finding a briarian diterpene that originates from an endophytic fungus, especially by H. monticulosa.

Recent Advances in Marine-Derived Nanoformulation for the Management of Glioblastoma.

Glioma is the most common and aggressive type of central nervous system tumor as categorized by the World Health Organization. Glioblastoma (GBA), in general, exhibits a grim prognosis and short life expectancy, rarely exceeding 14months. The dismal prognosis is primarily attributed to the development of chemoresistance to temozolomide, the primary therapeutic agent for GBA treatment. Hence, it becomes imperative to develop novel drugs with antitumor efficacy rooted in distinct mechanisms compared to temozolomide. The vast marine environment contains a wealth of naturally occurring compounds from the sea (known as marine-derived natural products), which hold promise for future research in the quest for new anticancer drugs. Ongoing advancements in anticancer pharmaceuticals have led to an upswing in the isolation and validation of numerous pioneering breakthroughs and improvements in anticancer therapeutics. Nonetheless, the availability of FDA-approved marine-derived anticancer drugs remains limited, owing to various challenges and constraints. Among these challenges, drug delivery is a prominent hurdle. This review delves into an alternative approach for delivering marine-derived drugs using nanotechnological formulations and their mechanism of action for treating GBA.

Chemoproteomics of Marine Natural Product Naamidine J Unveils CSE1L as a Therapeutic Target in Acute Lung Injury.

Acute lung injury is a devastating illness characterized by severe inflammation mediated by aberrant activation of macrophages, resulting in significant morbidity and mortality, highlighting the urgent need for novel pharmacological targets and drug candidates. In this study, we identified a novel target for regulating inflammation in macrophages and acute lung injury via chemical proteomics and genetics based on a marine alkaloid, naamidine J (NJ). The structures of NJ-related naamidine alkaloids were first confirmed or revised by a combination of quantum chemical calculations and X-ray diffraction analysis. NJ was found as a potential anti-inflammatory agent by screening our compound library, and CSE1L was identified by chemoproteomics as a main cellular target of NJ to inhibit inflammation in macrophages and protect against acute lung injury. Mechanistically, we demonstrated that NJ directly interacted with CSE1L on the sites of His745 and Phe903 and then inhibited the nuclear translocation and transcriptional activity of transcription factor SP1, thereby suppressing inflammation in macrophages and ameliorating acute lung injury. Taken together, these findings have uncovered a novel pharmacological target for the treatment of acute lung injury and have also provided a potential druggable pocket of CSE1L and a lead compound or an available chemical tool from marine sources for investigating CSE1L function and developing novel drug candidates against acute lung injury.

Marine Bioactives in Cancer Prevention and Treatment

The twice high incidence risk of cancer in men was the reason for over a million new cases and deaths recorded globally in 2018. The two most frequent cancer-related fatalities are lung and breast cancer. Novel therapies have been made possible by developments in immunotherapy, biology, and pharmaceutical design. Novel cancer prevention and therapy elements are being made possible by technological advancements and studies on marine natural resources. The creation of innovative anticancer medications is utilizing marine-derived natural products (MNPs). Biologically active polyketides, high molecular weight organic sugars, terpenes, bioengineered alkaloids, and marine animal peptides are some examples of these MNPs. Anticancer drugs are also developed with the help of plants, animals, invertebrates, and microbes found on land. The National Cancer Institute is exploring the potential of nutrition and food in cancer prevention despite the absence of preclinical and clinical data. Marine organisms contain bioactive compounds that have potential anticancer effects. Polyphenols, polysaccharides, and alkaloids are some of the active components found in marine species. Polyphenols, found in edible seaweeds like Palmaria palmata, can lower cancer cell division and proliferation, while polysaccharides trigger the innate immune system, causing apoptosis in pancreatic islet cancer and human leukemia cells. Alkaloids, derived from marine sources, can inhibit cancer cell development. Peptides, found in various plant species, have shown cytotoxic effects on several human cell lines, including pancreatic, breast, lung, and bladder cancers. Marine drug approval faces challenges like the possibility of a resurgence of different metabolites due to environmental conditions and limited lead compound availability.

Antifouling activity of Malaysian green seaweed Ulva lactuca and its isolated non-polar compound

Marine natural products especially seaweeds have gained much attention to combat biofouling. Ulva lactuca was determined for its antifouling activity and characterized the isolated non-polar metabolite involved. The methanolic crude extract (MCE) of U. lactuca was screened using crystal violet assay against biofilm-forming bacteria Pseudomonas aeruginosa and was further tested on laboratory and field tests. Then, it was fractionated and isolated using Liquid-Liquid Fractionation (LLE) and Column Chromatography (CC). The isolated compound was characterized using Liquid Chromatography-Mass Spectrometry (LC-MS), Nuclear Magnetic Resonance (NMR), and Fourier Transform-Infrared Spectroscopy (FTIR). The current study showed that the growth of biofilm produced by P. aeruginosa was inhibited by MCE at concentrations of 0.0156 mg/mL. The laboratory test indicated UL5% demonstrated a higher bacterial reduction of bacterial colonies with 1.903 × 106 CFU/mL better than blank paint. According to the field test, crude panels of UL5% were successful in reducing the settlement of fouling organisms due to less macrofouler growth compared to blank paint. The isolated compound A4 was identified as hexadecanoic acid (C16H32O2) through NMR with a molecular mass of 256 g/mol detected using LC-MS. The characterization through FTIR obtained functional groups consisting of CH3, CH2, C=O, and OH. Therefore, U. lactuca produced hexadecanoic acid as one of the promising compounds from the seaweed group as an eco-friendly antifouling agent.

Harnessing marine natural products to inhibit PAD4 triple mutant: A structure-based virtual screening approach for rheumatoid arthritis therapy

Peptidylarginine deiminase type4 (PAD4) is a pivotal pro-inflammatory protein within the human immune system, intricately involved in both inflammatory processes and immune responses. Its role extends to the generation of diverse immune cell types, including T cells, B cells, natural killer cells, and dendritic cells. PAD4 has recently garnered attention due to its association with a spectrum of inflammatory and autoimmune disorders, notably rheumatoid arthritis (RA). Mutations in the PAD4 gene, leading to the conversion of arginine to citrulline, have emerged as significant factors in the pathogenesis of RA and related conditions. As a calcium-dependent enzyme, PAD4 is central to the citrullination process, a crucial post-translational modification implicated in disease pathophysiology. Its critical role in autoimmune disorders and inflammation makes PAD4 a prime candidate for therapeutic intervention in RA. Inhibiting PAD4 presents a promising avenue for mitigating inflammatory responses and curtailing joint degradation and impairment. To explore its therapeutic potential, a structure-based virtual screening (SBVS) approach was employed, harnessing an array of marine natural products (MNPs) sourced from databases such as CMNPD, MNPD, and Seaweed. Notably, MNPD10752, CMNPD12680, and CMNPD2751 emerged as potential hit molecules, exhibiting adherence to essential pharmacokinetic properties and favorable toxicity profiles. Quantum mechanics studies using density functional theory (DFT) calculations revealed the inhibitory potential of these identified natural products. Further structural elucidation through molecular dynamics simulations (MDS) and principal component-based free energy landscape (FEL) analysis shed light on the stability of MNP-bound PAD4 complexes. In conclusion, this computational study serves as a stepping stone for further experimental evaluation, aiming to explore the potential of MNPs in addressing PAD4-related human pathologies.

Promoting sustainability through eco-friendly synthesis of marine natural products

Promoting sustainability through eco-friendly synthesis of marine natural products

Marine Bioactive Molecules as Inhibitors of the Janus Kinases: A Comparative Molecular Docking and Molecular Dynamics Simulation Approach.

A treasure trove of naturally occurring biomolecules can be obtained from sea living organisms to be used as potential antioxidant and anti-inflammatory agents. These bioactive molecules can target signaling molecules involved in the severity of chronic autoimmune diseases such as rheumatoid arthritis (RA). The intracellular tyrosine kinases family, Janus kinases (JAKs, includes JAK1, JAK2, and JAK3), is implicated in the pathogenesis of RA through regulating several cytokines and inflammatory processes. In the present study, we conducted molecular docking and structural analysis investigations to explore the role of a set of bioactive molecules from marine sources that can be used as JAKs' specific inhibitors. Around 200 antioxidants and anti-inflammatory molecules out of thousands of marine molecules found at the Comprehensive Marine Natural Products Database (CMNPD) website, were used in that analysis. The details of the interacting residues were compared to the recent FDA approved inhibitors tofacitinib and baricitinib for data validation. The shortlisted critical amino acids residues of our pharmacophore-based virtual screening were LYS905, GLU957, LEU959, and ASP1003 at JAK1, GLU930 and LEU932 at JAK2, and GLU905 and CYS909 of JAK3. Interestingly, marine biomolecules such as Sargachromanol G, Isopseudopterosin E, Seco-Pseudopterosin, and CID 10071610 showed specific binding and significantly higher binding energy to JAK1 active/potential sites when being compared with the approved inhibitors. In addition, Zoanthoxanthin and Fuscoside E bind to JAK2's critical residues, GLU930 and LEU932. Moreover, Phorbaketal and Fuscoside E appear to be potential candidates that can inhibit JAK3 activity. These results were validated using molecular dynamics simulation for the docked complexes, JAK1(6sm8)/SG, JAK2 (3jy9)/ZAX, and JAK3 (6pjc)/Fuscoside E, where stable and lower binding energy were found based on analyzing set of parameters, discussed below (videos are attached). A promising role of these marine bioactive molecules can be confirmed in prospective preclinical/clinical investigations using rheumatoid arthritis models.

Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Investigating the Catalytic Site of Human 15-Lipoxygenase-1 via Marine Natural Products.

Human 15-lipoxygenase-1 (15-LOX-1) is a key enzyme that possesses an important role in (neuro)inflammatory diseases. The pocket of the enzyme plays the role of a chiral catalyst, and therefore chirality could be an important component for the design of effective enzyme inhibitors. To advance our knowledge on this concept, we developed a library of the identified chiral 15-LOX-1 inhibitors and applied cheminformatic tools. Our analysis highlighted specific structural elements, which we integrated them in small molecules, and employed them as "smart" tools to effectively navigate the chemical space of previously unexplored regions. To this purpose, we utilized the marine derived natural product phosphoeleganin (PE) among with a small library of synthetic fragment derivatives, including a certain degree of stereochemical diversity. Enzyme inhibition/kinetic and molecular modelling studies has been performed in order to characterize structurally novel PE-based inhibitors, which proved to present a different type of inhibition with low micromolar potency, according to their structural features. We demonstrate that different warheads work as anchor, and either guide specific stereochemistry, or causing a time-depended inhibition. Finally, we prove that the positioning of the chiral substituents or/and the favorable stereochemistry can be crucial, as it can lead from active to completely inactive compounds.

Design, Synthesis, Molecular Docking, and in vitro Cytotoxicity Studies of Marine Natural Product Herdmanine Derivatives as Multitarget Inhibitor for EGFR and HER2 Breast Cancer Proteins

AbstractBreast cancer is a potentially deadly disease that affects millions of individuals worldwide. Therefore, it is crucial to design highly targeted therapeutic techniques with low toxicity. In this work, we synthesized natural product Herdmanine's ester derivatives and tested them against EGFR and HER2 proteins as multitargated inhibitor of breast cancer progression. Further, the newly synthesized compounds were evaluated for cytotoxicity against breast cancer cell lines MCF‐7, MDA‐MB‐231 and MDA‐MB‐157 and the biocompatibility towards NIH 3T3 cells. Higher toxicity and positive viability profiles of Herdmanine derivatives indicate their potential use for further exploration in breast cancer application.

Marine Microorganism Molecules as Potential Anti-Inflammatory Therapeutics.

The marine environment represents a formidable source of biodiversity, is still largely unexplored, and has high pharmacological potential. Indeed, several bioactive marine natural products (MNPs), including immunomodulators, have been identified in the past decades. Here, we review how this reservoir of bioactive molecules could be mobilized to develop novel anti-inflammatory compounds specially produced by or derived from marine microorganisms. After a detailed description of the MNPs exerting immunomodulatory potential and their biological target, we will briefly discuss the challenges associated with discovering anti-inflammatory compounds from marine microorganisms.

GC-MS Analysis of Chemical Constituents in Water and Methanol Crude Extracts of Red Sea Soft Coral Xenia macrospiculata Gohar, 1940

Soft corals are marine invertebrates known to be a prolific source of marine natural products. The genus Xenia is a rich source of bioactive compounds including terpenoids, steroids, saturated, unsaturated and poly unsaturated fatty acids. The water and methanol solvent extracts of soft coral Xenia macrospiculata Gohar, 1940 (X. macrospiculata) were screened for the novel chemical constituents using gas chromatography–mass spectroscopy (GC-MS). In the water extracts, seventeen compounds were identified including monounsaturated fatty acids (35.29%), saturated fatty acids (23.52%) followed by unsaturated fatty acids (5.88%), poly unsaturated fatty acid (5.88%), sesquiterpenoids (5.88%), aromatic compounds (5.88%), Alcohols (5.88%), thio compounds (5.88%) and pleuromutilin derivatives (5.88%). In methanol extract thirty compounds were identified, among which 30% are the poly unsaturated fatty acids (PUFA) followed by monounsaturated fatty acids (13.33%), unsaturated fatty acids (13.33%), saturated fatty acids (13.3%), sesquiterpenoids (10%), alcohols (6.66%), oxygenated heterocyclic compounds (3.33%), steroid (3.33%), organo-fluro compounds (3.33%) and aldehyde derivatives (3.33%). The GC-MS screening of water and methanol extracts of X. macrospiculata revealed the presence of several novel bioactive compounds. Fatty acids are potential nutraceutical compounds playing vital role in preventing the risk of cardiovascular disorders and fatty liver. In addition, these compounds also showed potential antioxidant activity, antimicrobial, antineoplastic, ichthyotoxic, cytotoxic, HIV-inhibitory, anti-inflammatory activity and 5α reductase inhibitory activity.

Metagenomic mining of two Egyptian Red Sea sponges associated microbial community

The Red Sea is a promising habitat for the discovery of new bioactive marine natural products. Sponges associated microorganisms represent a wealthy source of compounds with unique chemical structures and diverse biological activities. Metagenomics is an important omics-based culture-independent technique that is used as an effective tool to get genomic and functional information on sponge symbionts. In this study, we used metagenomic analysis of two Egyptian Red Sea sponges Hyrtios erectus and Phorbas topsenti microbiomes to study the biodiversity and the biosynthetic potential of the Red Sea sponges to produce bioactive compounds. Our data revealed high biodiversity of the two sponges’ microbiota with phylum Proteobacteria as the most dominant phylum in the associated microbial community with an average of 31% and 70% respectively. The analysis also revealed high biosynthetic potential of sponge Hyrtios erectus microbiome through detecting diverse types of biosynthetic gene clusters (BGCs) with predicted cytotoxic, antibacterial and inhibitory action. Most of these BGCs were predicted to be novel as they did not show any similarity with any MIBiG database known cluster. This study highlights the importance of the microbiome of the collected Red Sea sponge Hyrtios erectus as a valuable source of new bioactive natural products.

Marine sponge-derived natural products: trends and opportunities for the decade of 2011-2020

The discovery of natural products derived from marine sources has demonstrated a consistent upward trajectory for the decade of 2011-2020, holding significant promise for the development of novel drugs and many other marine bioproducts. In recent years, the spotlight has shifted away from marine sponges (Porifera) towards marine microorganisms as the primary source of discovery. Despite reports of marine sponges spanning 20 different orders and being the subject of 769 papers between 2011 and 2020, they only contributed to 19.29% of all new compounds discovered, in contrast to 51.94% by marine microorganisms and phytoplankton. 563 new compounds were reported from marine sponge-associated microbes, more than doubling the number for the previous decade (2001-2010). It heralds a positive outlook for a sustainable resource strategy as the extraction of bioactive compounds produced by pure cultures of sponge-associated microbes could overcome supply challenges that arise with isolation from host sponges for the same compound. However, the application of novel marine natural products (MNPs) remains challenging due to the limited yield of compounds from large amounts of sponges. This review covers the literature published between 2011 and 2020, focusing on MNPs isolated from marine sponges. A total of 2603 new compounds are documented, detailing their chemical classification, biological activities, source country or geographic locations, and the taxonomic information of the source organisms, including order, family, genus, and species.

A New Renieramycin T Right-Half Analog as a Small Molecule Degrader of STAT3.

Constitutive activation of STAT3 contributes to tumor development and metastasis, making it a promising target for cancer therapy. (1R,4R,5S)-10-hydroxy-9-methoxy-8,11-dimethyl-3-(naphthalen-2-ylmethyl)-1,2,3,4,5,6-hexahydro-1,5-epiminobenzo[d]azocine-4-carbonitrile, DH_31, a new derivative of the marine natural product Renieramycin T, showed potent activity against H292 and H460 cells, with IC50 values of 5.54 ± 1.04 µM and 2.9 ± 0.58 µM, respectively. Structure-activity relationship (SAR) analysis suggests that adding a naphthalene ring with methyl linkers to ring C and a hydroxyl group to ring E enhances the cytotoxic effect of DH_31. At 1-2.5 µM, DH_31 significantly inhibited EMT phenotypes such as migration, and sensitized cells to anoikis. Consistent with the upregulation of ZO1 and the downregulation of Snail, Slug, N-cadherin, and Vimentin at both mRNA and protein levels, in silico prediction identified STAT3 as a target, validated by protein analysis showing that DH_31 significantly decreases STAT3 levels through ubiquitin-proteasomal degradation. Immunofluorescence and Western blot analysis confirmed that DH_31 significantly decreased STAT3 and EMT markers. Additionally, molecular docking suggests a covalent interaction between the cyano group of DH_31 and Cys-468 in the DNA-binding domain of STAT3 (binding affinity = -7.630 kcal/mol), leading to destabilization thereafter. In conclusion, DH_31, a novel RT derivative, demonstrates potential as a STAT3-targeting drug that significantly contribute to understanding of the development of new targeted therapy.

Identification of Novel PBP2B Protein Inhibitors against Streptococcus pneumoniae in Marine Natural Products using an In-Silico Approach

Background: The aim of this research is to identify marine natural compounds derived from green, red, and brown algae that might possibly inhibit the Penicillin-Binding Proteins (PBPs) protein, which is responsible for the development of antibiotic resistance in Streptococcus pneumoniae (mutated resistant 5204-PBP2B strain). We obtained this by using virtual screening and molecular docking. In AutoDock Vina and the Schrodinger suite software, we screened a library of marine natural chemicals and discovered four intriguing candidates that had strong binding affinities to the active region of the PBPs protein. Based on our findings, four naturally occurring marine chemicals show great promise as new inhibitors of S. pneumoniae 5204-PBP2B protein. These discoveries reveal important new information on the potential application of marine natural products as a source of new drugs to combat antibiotic resistance in Streptococcus pneumoniae and other bacterial infections. Methods: The 3318 compounds in the Comprehensive Marine Natural Products Database (CMNPD) derived from green algae (293 compounds), brown algae (1212 compounds) and red algae (1813 compounds) were taken into consideration for this study. Through virtual screening and molecular docking investigations, we found the optimum compounds for the Penicillin-Binding Proteins (PBPs) protein in Streptococcus pneumoniae. Utilizing AutoDock Vina and Schrodinger Suite software, the 5204-PBP2B protein selected for this investigation was examined. The structure and binding interaction have been displayed using PyMOL software. Results: Through virtual screening and molecular docking investigations for the 5204-PBP2B protein in Streptococcus pneumoniae, we were able to identify four marine natural products that are present in brown algae from the Comprehensive Marine Natural Products Database. Conclusion: The study has indicated that the main cause of bacterial resistance to antibiotics is 5204-PBP2B in S. pneumoniae. This study's methodology has been shown to be effective in identifying four strong inhibitors of the CMNPD. In this work, potent molecules from CMNPD compounds were screened using the 3D structure of mutated resistant 5204 strain, named 5204- PBP2B (PDB ID: 2WAE) of S. pneumoniae. Out of 3318 compounds that showed strong interactions with PBP2B, docking studies revealed that four of the compounds were inhibitory for the protein and could be used to treat PBP2B. These four marine products were selected as a result of our earlier research on Klebsiella pneumonia’s New Delhi metallo-β-lactamase-1 (NDM-1) protein. This study thus reveals the importance of marine natural products for improving the drug development process, as well as the ability of four marine products generated from brown algae to inhibit both the NDM-1 protein of Klebsiella pneumoniae and the 5204-PBP2B protein in Streptococcus pneumoniae. It is also possible to expand this approach by investigating how different receptor inhibitors interact in a lab setting. Potential inhibitors can be discovered by evaluating the biological activity of the drugs and applying virtual screening and molecular docking techniques.