Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Cancer Agents) - Volume 25, Issue 16, 2025

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.

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.

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.