Drug Design, Discovery and Therapy
Redefining Anthraquinone-based Anticancer Drug Design through Subtle Chemical Modifications
Anthraquinones are well known for their wide spectrum of pharmacological properties. Anthraquinone antibiotics such as doxorubicin daunorubicin epirubicin and mitoxantrone have long been used in the clinical management of various tumors. However their use is limited due to their toxicity effects especially cardiomyopathy despite their pronounced therapeutic effects. In recent years medicinal chemists have explored the possibility of modifying the anthraquinone ring appended with structurally diverse functionality in order to develop better chemotherapeutic agents with fewer adverse effects. The fused polycyclic structure of anthraquinone offers rigidity planarity and aromaticity which helps in double helix DNA intercalation disruption of G4 DNA and inhibition of topoisomerase-II enzyme of cancer cells making them suitable pharmacophore for anticancer drug discovery. Incorporation of suitable functional groups such as amino hydroxyl and their derivatives into anthraquinone rings can improve their interactions with biological targets involved in cancer progression. These subtle structural changes produce newer anthraquinone derivatives with improved anticancer properties increased potency selectivity and reduced toxicity and can overcome multi-drug resistance. On the other hand the molecular hybrids of the anthraquinone derivatives have been reported to act on multiple targets in cancer cells as seen in the case of clinical candidates like alectinib midostaurin tucatinib belinostat and dacinostat. Molecular hybrid has given a new direction for anticancer drug development which can produce bifunctional drug candidates with reduced toxicity. This review summarizes different structural modifications that have been made to the anthraquinone ring in the last decade with the aim of bringing out potent yet toxicity-free anticancer agents.
Molecular Dynamics (MD) Simulation of GPR87-LPA Binding: Therapeutic Implications for Targeted Cancer Treatment
GPR87 is an orphan G-protein-coupled receptor (GPCR) that represents a potential molecular target for developing novel drugs aimed at treating squamous cell carcinomas (SCCs) or adenocarcinomas of the lungs and bladder.
The present study aims to identify potential LPA analogues as inhibitors of the GPR87 protein through computational screening. To achieve this the human GPR87 structure was modeled using template-based tools (Phyre2 and SWISS-MODEL) iterative threading (I-TASSER) and neural network-based de novo prediction (AlphaFold2). The modeled structures were then validated by assessing their quality against template structures using Verify-3D ProSA and ERRAT servers.
We conducted a comprehensive structural and functional analysis of the target protein using various computational tools. Several computational techniques were employed to explore the structural and functional characteristics of the target with LPA selected as the initial pharmacological candidate. A library of 2605 LPA analogues was screened against orphan GPR87 through in-silico docking analysis to identify higher-affinity and more selective potential drugs.
Molecular dynamics (MD) simulations were performed to track structural changes and convergence during the simulations. Key metrics including the root mean square fluctuation (RMSF) of Cα-atoms radius of gyration and RMSD of backbone atoms were calculated for both the apo-form and the LPA-GPR87 complex structures. These studies on structure-based drug targeting could pave the way for the development of specific inhibitors for the treatment of squamous cell carcinomas.
These findings may contribute to the design and development of new therapeutic compounds targeting GPR87 for the treatment of SCC.
A Path to the Formation Mechanism of Propolis Nanoparticles, their Cytotoxicity on 3T3 Fibroblasts, Metastatic Murine B16F10 Cells, and their In vivo Irritability in Animals
Natural products such as propolis are an important source of biologically active compounds with the potential to treat health disorders. Propolis is a well-known waxy resin recognized for its antimicrobial immunomodulatory and cytotoxic effects.
In this study we aimed to clarify the formation mechanism of propolis nanoparticles from the perspective of their stability and chemical composition. By evaluating the light absorption behaviour of the nanoparticles formed in different media and quantifying the polyphenols we show that they are superficially hydrophobic nanoparticles with the capacity to encapsulate some polar compounds.
Biological activity was evaluated by in vitro cell viability performed on NIH/3T3 fibroblasts incubated with 10 100 and 1000 μg/mL of propolis nanoparticles for 48 hours.
The results show that nanoparticles are cytocompatible with a proliferation effect. In contrast the results of the viability of metastatic murine B16F10 cells indicate that a dose with a concentration of 5 µg/mL in the cell culture media is sufficient to stop the abnormal cell growth having an antitumor effect. This effect might be related to the flavonoids present in the propolis nanoparticles. In vivo dermal irritability tests on New Zealand rabbits show that propolis nanoparticles' aqueous dissolution was non-irritant.
According to the results obtained from this study reducing the size of raw propolis down to nanoparticles and dispersing them in water solvents enhance its positive effects. The superficially hydrophobic propolis nanoparticles encapsulate active compounds such as polyphenols and flavonoids which also confirms their ability to generate selective effects on the cells depending on their nature.
Identification of Flavonoid-based Hypoxia-inducible Factor-2 Alpha Inhibitors for the Treatment of Breast Cancer– In silico and In vitro Evidence
Breast cancer (BC) is a common malignancy that poses a serious threat to women's health. The hypoxic tumor microenvironment in BC promotes drug resistance making hypoxia-targeted therapies crucial. Targeting hypoxia-inducible factors (HIFs) particularly HIF-2α has emerged as a promising approach to inhibit tumor growth and improve response to chemotherapy and radiotherapy. However further research is required to fully understand the role of HIF-2α to develop more effective treatments for BC.
The aim of this study is to identify phytochemicals that target HIF-2α and evaluate their effects on the MCF-7 breast cancer cell line under hypoxic conditions.
Molecular docking identified phytochemicals targeting HIF-2α with high-affinity compounds undergoing stability evaluation via GROMACS molecular dynamics simulations. ADMET and toxicity assessments were performed using SwissADME and ProTox-3.0. In vitro assays on hypoxic MCF-7 cells examined cell viability and gene expression. The expression of HIF-2α-regulated genes (VEGFA CCND1 GLUT1) was analyzed by using qRT-PCR.
Molecular docking revealed that naringin (-8.2 Kcal/mol) and morin (-7.1 Kcal/mol) showed better binding affinity than the standard drug belzutifan (-7.7 Kcal/mol). Dynamic simulations including RMSD RMSF H-bond interactions Rg SASA and PE confirmed their strong binding potential. Morin in particular demonstrated more H-bond interactions and met Lipinski's Rule of Five making it a promising candidate for in vitro studies. It reduced cell viability with an IC50 of 118 µM and significantly downregulated HIF-2α-associated genes.
Morin demonstrated promising anti-cancer activity under hypoxic conditions by inhibiting HIF-2α in the hypoxia signaling pathway.
Retraction Notice to "Anti-proliferative, Morphological and Molecular Docking Studies of New Thiophene Derivatives and their Strategy in Ionic Liquids Immobilized Reactions"
Gut Microbiota and the Gut-liver Axis in Hepatocellular Carcinoma: A Comprehensive Review of Pathogenesis and Therapeutic Strategies
Hepatocellular carcinoma (HCC) is among the most prevalent and fatal cancers globally. The gut-liver axis involving intricate interactions between gut microbiota and the liver has emerged as a critical pathway in HCC development. This review comprehensively examines the molecular mechanisms by which gut microbiota contribute to hepatocarcinogenesis. It discusses factors that either protect against or promote HCC such as bacterial translocation and explores the biological processes that drive carcinogenesis while addressing clinical and pathophysiological complexities. Special attention is given to the role of toll-like receptors (TLRs) and inflammation in liver cells where microbial components trigger changes in TLR activation leading to increased inflammation and fibrosis. Additionally the review covers obesity-related HCC highlighting the impact of gut microbiota alterations on this cancer type. It critically assesses current literature on therapeutic interventions targeting gut microbiota in HCC focusing on strategies like probiotics and antibiotics that could modulate microbial composition to prevent HCC progression. The review also explores gut microbiota-derived biomarkers for early detection and monitoring of HCC and discusses personalized therapies based on individual gut-liver interactions. Finally it identifies research gaps and suggests future studies to deepen understanding of how gut microbiota can be leveraged as an adjunct therapy in HCC. Overall the review underscores the pivotal role of gut microbiota in HCC pathogenesis and treatment pointing to microbiome modulation as a promising therapeutic avenue.
Potentials of N-Acyl Hydrazones Against Colorectal Cancer: A Mini Review
Colorectal cancer (CRC) is a malignant gastrointestinal tract disorder with high occurrence and mortality index and showing an upsurge. Standard therapies for treating CRC are surgery and chemotherapy. Despite great effort in developing effective treatments the progress is limited due to its relapse and recurrence. Prognosis of metastatic CRC is always complicated. This condition can be evaded by a novel approach i.e. targeted therapy which increases the survival rate in CRC patients by blocking important pathways and acting on immune checkpoints. Drugs with N-acyl hydrazones (NAH) are currently being employed treatment of infectious diseases and disorders. NAH in combination with diverse heterocycles natural product isolates are identified as interesting CRC inhibitors under-explored. This review provides an overview of the existing CRC targeted compounds having acyl hydrazones hydrazine hydrazides moieties and their underlying mechanisms towards different CRC cell lines together with a discussion of their limitations and future trends.
Quercetin’s Potential Therapeutic Role in Human Colorectal Cancer: An Effective Strategy for Prevention and Treatment
Colorectal cancer (CRC) is a significant global health burden ranking third in incidence and second in mortality worldwide. The incidence of CRC continues to rise and drug resistance to conventional therapies such as 5-fluorouracil (5-FU) poses a challenge in treatment. Quercetin a naturally occurring flavonol has shown anti-carcinogenic properties and potential in sensitizing cancer cells to chemotherapy.
This review assesses recent animal and clinical studies on the impact of quercetin on CRC treatment and progression and evaluates its potential in combination with conventional therapies.
A comprehensive literature search was conducted to identify relevant studies investigating quercetin's effects on CRC. The search included both animal and clinical studies.
Quercetin has been shown to inhibit cancer progression through cell cycle arrest and apoptosis induction. It sensitizes cancer cells to chemotherapy while exhibiting protective effects on normal cells. In CRC quercetin has demonstrated potential in reducing tumor growth and modulating signaling pathways involved in inflammation and immune responses.
Quercetin shows promise as a novel therapeutic agent for CRC and its combination with conventional therapies may lead to more effective treatment options and improved patient outcomes. Further research is warranted to validate these findings in clinical settings.
Chrysin Exhibits Selective Antiproliferative and Antimigratory Activities in a Wide Range of Human-derived Cervical Cancer Cell Lines
In the past few years the antiproliferative activities of chrysin (57-dihydroxyflavone) have garnered significant attention in anticancer drug discovery due to its promising ability to suppress cancer cell proliferation. However studies on its effects on cervical cancer are limited and have primarily focused on HeLa cells.
In order to better understand its therapeutic potential for cervical cancer we assessed the antiproliferative and anti-migratory effects of chrysin in a wide range of human-derived cell lines comprising C33A (human papillomavirus/HPV-negative) HeLa (HPV 18-positive) SiHa (HPV 16-positive) and CaSKi (HPV 16 and 18-positive) in comparison to a human epithelial cell line derived from spontaneously immortalized cell HaCaT.
Cell viability was determined using the MTT assay while the clonogenic assay evaluated long-term cytotoxicity. Morphological alterations were observed via light microscopy and cell death was assessed using Annexin V FITC/propidium iodide (PI) staining. Total reactive oxygen species (ROS) levels were measured by fluorescence microscopy the mitochondrial transmembrane potential was assessed using TMRE and lipid peroxidation was analyzed using DPPP. Additionally wound healing migration and cell invasion assays were conducted.
Chrysin selectively inhibited cell proliferation and induced apoptosis in every cervical cancer cell line assessed while exerting minimal effects on HaCaT cells. Additionally it triggered mitochondrial redox imbalance and significantly suppressed both migration and invasion of cervical cancer cells.
Based on these results chrysin appears to be a promising candidate as an anticancer agent for both HPV-associated and HPV-independent cervical cancers emphasizing the necessity for further exploration in subsequent studies.
Atractylenolide I Inhibits the Growth of Esophageal Cancer Cells by Inhibiting the Wnt/β-Catenin Pathway
Esophageal cancer is a highly lethal cancer with a rapidly increasing incidence and a poor prognosis. Atractylenolide I is a natural sesquiterpene lactone extracted from the rhizome of the Asteraceae plant which has a variety of pharmacological effects such as anti-inflammatory and immunomodulatory. Still its impact on esophageal cancer has not been reported. Therefore this study investigated the in vitro and in vivo effects of Atractylenolide I on the growth and proliferation of esophageal cancer and explored its possible mechanisms.
To evaluate the effect of atractylenolide I on esophageal cancer cells apoptosis assay and cell cycle assay tests were performed. Atractylenolide I was used to treat esophageal cancer cells for 48 hours and flow cytometry detects apoptosis and cell cycle. The Wnt/β-catenin-related pathway proteins were then detected by Western blotting. For in vivo studies an esophageal cancer graft tumor model was established subcutaneously in BALB/c nude mice which were given Atractylenolide I treatment for 2 weeks.
The result shows that Atractylenolide I inhibited the proliferation and induced apoptosis of esophageal squamous carcinoma and adenocarcinoma cells. Further research shows that Atractylenolide I inhibited the Wnt/β-catenin signaling pathway decreased the expression of CCND1 MYC and FN1 genes and thus increased the apoptosis of esophageal cancer cells and blocked the cell cycle in G0/G1 phase hence exerting the role of inhibiting esophageal cancer cells in vivo and in vitro.
This study indicates that Atractylenolide I is an efficient lead compound for the treatment of esophageal cancer providing a theoretical basis for further clinical development and application of Atractylenolide I.
Retraction Notice to "The Natural Flavonoid Naringenin Inhibits the Cell Growth of Wilms Tumor in Children by Suppressing TLR4/NF-κB Signaling"
New Radiopharmaceutical Tracers in Breast Cancer Diagnosis and Therapy
Breast cancer (BC) remains a predominant cause of mortality among women with early diagnosis and ongoing monitoring being crucial for effective management. Integrating nuclear medicine with radiological modalities offers non-invasive anatomical and functional information enabling precise target localization and quantification. This approach guided the selection of the most appropriate personalized treatment and predicted its efficacy reducing the use of unnecessary drugs and lowering patient management costs. Since 2020 significant breakthroughs have been made in the development of radiopharmaceuticals which are different in importantly targeting agents and radionuclides with a focus on their efficacy in preclinical studies. This review accentuates the central role of radiopharmaceuticals in recent advancements for both imaging and therapeutic applications in BC. We discussed various receptor-targeted radiopharmaceutical therapy (RPT) agents currently utilized in clinical and preclinical settings with their chemical structures along with the challenges faced in their implementation including angiotensin II type 1 receptor (AT1 receptor) integrins αvβ3 chemokine receptor (CXCR4) and trophoblast cell-surface antigen-2 (TROP2) cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and epithelial cell adhesion molecule (EpCAM)-targeted epidermal growth factor receptor (EGFR) vascular endothelial growth factor receptor (VEGFR) fibroblast activation protein inhibitor (FAPI) and mucin 1 (MUC1). While numerous promising RPT agents were still in preclinical stages this review underscored the potential of tailored radiopharmaceuticals to enhance BC diagnosis and treatment providing novel avenues for personalized medicine.
Unveiling the Therapeutic Potential of Trigonelline: A Promising Approach in Cancer Prevention and Treatment
With the development of herbal medicine more and more chemical extracts isolated from natural herbs are being used to treat cancer and herbal monomers play an important role in treating tumors. There is no doubt that these substances have a powerful ability to address the growing incidence of cancer. Among them Trigonelline due to its anti-tumor hypoglycemic hypolipidemic antioxidant and aphrodisiac properties has been comprehensively studied for its therapeutic potential. However there is a lack of a complete and specific review of Trigonelline research. Regarding the information mentioned before this paper summarizes and describes the literature related to the response mechanisms and therapeutic potential of Trigonelline. This review describes the effects of Trigonelline in inhibiting tumor growth and metastasis reducing the toxicity of chemotherapeutic agents decreasing oxidative stress increasing the sensitivity type of chemotherapeutic agents and reversing drug resistance. On account of the merits of low cost safety and efficacy and few toxic side effects Trigonelline has the potential to become a new and valuable drug. Furthermore the in-depth study of this natural substance is yet to be further developed. In addition by exploiting it more extensively it is expected to be an effective addition to cancer treatment. We can expect that in the future more and more herbal extracts can be used in clinical practice to prolong the survival and improve the quality of life of patients.
From Bench to Bioactivity: Pyranopyrazole Synthesis, Anticancer, Antimicrobial Efficacy, DFT, Molecular Docking, and Molecular Dynamic Insights
Heterocyclic compounds are prevalent in nature and essential to life. The synthesis and application of medium-sized ring heterocyclic compounds have gained prominence. Pyranopyrazole is one such compound that has a significant impact on biological and medicinal chemistry. It has attracted interest in agrochemical research due to its fungicidal bactericidal and herbicidal properties. Additionally it exhibits various biological activities including anti-inflammatory analgesic antidiabetic antimicrobial anticancer and antimalarial effects. Furthermore it has been explored for its potential in treating SARS-CoV-2.
The study synthesized novel pyranopyrazole compounds and evaluated their anticancer efficacy against certain tumor cell lines (MCF-7 HeLa and PC-3) and antimicrobial activities as deduced through molecular docking studies.
A one-pot four-component reaction involving ethyl acetoacetate (1) hydrazine hydrate (2) malononitrile or ethyl cyanoacetate (3a b) and aromatic aldehydes (4a-c) in an ethanolic/piperidine solution was conducted yielding pyranopyrazoles (5a-f) in moderate to good yields.
This study involved the synthesis of novel pyranopyrazole derivatives 5a-f and the evaluation of their anticancer and antimicrobial activities. These findings indicate that compound 5f is extremely active. It is more potent than 5-fluorourcail and ofloxacin and it may also have new modes of action that are worth more research while compound 5d has the highest antimicrobial activity. Molecular docking studies help us learn more about how these chemicals interact with biological targets like the TGF-βI receptor and the choline-binding domain both of which play a key role in the growth of cancer.
A series of novel pyranopyrazole derivatives 5a-f were synthesized and analyzed using spectral data. Compound 5f stands out as a lead molecule for more study and improvement due to its low IC50 value and high binding affinity. Based on how stable it is in molecular dynamics (MD) simulations and how its anticancer properties are linked to its binding affinities it may be a strong TGF-βI receptor inhibitor.
Bacteriocins from Lactic Acid Bacteria Could Modulate the Wnt Pathway: A Possible Therapeutic Candidate for the Management of Colorectal Cancer- An In silico Study
Colorectal cancer (CRC) is a type of cancer that develops due to abnormal cell growth in the colon and rectum. Existing conventional CRC treatment strategies have side effects. Hence exploring new and advanced techniques for bacterial CRC therapy is crucial. Bacteriocins are peptides produced by bacteria including lactic acid bacteria (LAB) that have bactericidal effects. In the present study we have focused on searching for effective and safe bacteriocins from LAB as alternatives to clinical therapeutics for treating CRC leaving healthy cells unaffected.
We selected nine bacteriocin-like peptides that are effective in the human gut microbiome. These peptides were derived from LAB species using online database resources. We then conducted an in silico phylogenetic analysis of other LAB species present in the gut microbiome using the KEGG Genome database. We established the phylogenetic relationship of these LAB species with others observed in the database to determine their closeness and similarity. Further the bacteriocin-like peptides were modeled and refined to interact with the plausible target. The systematic network analysis was performed to find the highly interconnected targets involved in the Wnt target genes of CRC.
The network analysis observed that the genes CTNNB1 and LRP5 were found as hub genes to upregulate CRC. In silico protein-peptide docking between the target bacteriocins like peptides and the therapeutic targets of CRC was performed significantly our findings revealed that the peptide PE4 and PE9 (Lactacin F and Lactacin B) exhibited better binding affinity with CTNNB1. In contrast the peptides PE7 and PE9 (Doderlin and Lactacin B) revealed better binding affinity with LRP5. Furthermore we conducted molecular dynamics (MD) simulations to confirm the stability and bonding interactions of the bacteriocins derived from the LAB species.
Our findings indicate that bacteriocins (Lactacin B Lactacin F and Doderlin) may have significant potential as therapeutics for CRC.
Virtual Screening and Dynamic Simulation of Baloxavir Derivatives for Multitarget Breast Cancer Treatment
Breast cancer is a leading cause of mortality among women emphasizing the need for novel therapeutic strategies. Targeting key receptors such as ERα EGFR and HER2 is critical for improving breast cancer treatments.
This study aimed to identify potent Baloxavir derivatives with inhibitory potential against ERα EGFR and HER2 and evaluate their pharmacokinetic properties and stability through computational methods.
A library of 72 Baloxavir derivatives was screened using molecular docking with AutoDock Vina. The top 32 compounds ranked by binding affinity were further assessed for ADMET properties. AutoDock 4.2 refined the docking analysis to identify potential inhibitors. The stability of the lead compound was validated through a 100 ns molecular dynamics simulation evaluating RMSD RMSF Radius of Gyration MolSA SASA and protein-ligand interactions.
Seven compounds exhibited favorable ADMET profiles. Of these six demonstrated strong inhibitory potential against ERα and HER2 while three showed promising activity against EGFR. Molecular dynamics simulations confirmed the stability of the lead compound supporting its potential as a candidate for further development.
This computational study highlights Baloxavir derivatives as promising candidates for breast cancer therapy providing a foundation for future preclinical investigations.