Current Medicinal Chemistry - Volume 33, Issue 3, 2026

Aspergillus fumigatus, a significant fungal pathogen, poses a threat to human health, especially in immunocompromised individuals. Addressing the need for novel antifungal strategies, this study employs virtual screening to identify potential inhibitors of Fructosamine oxidase, also known as Amadoriase II, a crucial enzyme in Aspergillus fumigatus (PDB ID: 3DJE).

Virtual screening of 81,197 triazole derivatives was subjected to computational analysis, aiming to pinpoint molecules with high binding affinity to the active site of Fructosamine oxidase. Subsequently, an in-depth ADMET analysis assessed the pharmacokinetic properties of lead compounds, ensuring their viability for further development. Molecular dynamics simulations were performed to evaluate the stability of top-ranked compounds over time.

The results unveil a subset of triazole derivatives displaying promising interactions, suggesting their potential as inhibitors for further investigation.

This approach contributes to the development of targeted antifungal agents, offering a rational starting point for experimental validation and drug development against Aspergillus fumigatus infections.

Colorectal Cancer (CRC) affects the colon and rectum part of the digestive system and is a significant global health concern, with approximately 1.1 million new cases annually. It ranks second in cancer-related deaths. Studies have shown future projections of CRC cases to enhance at a worrisome rate, estimating 3.2 million new cases and 1.6 million deaths worldwide by 2040. Studies have shown the downregulation of TMEM236 in CRC, and this study aimed to find the agonist to restore the function of TMEM236 via the drug repurposing method.

The different molecular and structural level analyses were performed to understand how the TMEM236 expression can be restored. To obtain the molecular level data, the following analyses were employed to understand the binding affinity and agonistic behaviour of the screened drugs: molecular docking, oral toxicity prediction, Molecular Dynamics (MD) simulation, Free Energy Landscape (FEL) analysis, and g_mmpbsa.

The molecular docking, oral toxicity, and molecular interaction analyses have identified db06435, db05423, and db15197 drugs from the DrugBank database to either belong to an approved or investigational class of drugs as a potential agonist for TMEM236. The MD simulation and PCA analysis had shown db05423 (ORG-317) to exhibit stable interaction with TMEM236 protein. Similar results were obtained through FEL analysis.

The downregulation of TMEM236 expression and its constant binding affinity with db05423 during MD simulation suggest that this drug may restore the diminished function and expression of TMEM236. Additionally, it could function as an agonist and can be used for CRC treatment.

Cancer remains a leading cause of mortality worldwide. Specific proteins play critical roles in cancer development, and MTH1 is one such protein. MTH1 removes the terminal phosphate groups from oxidized nucleotides like 8-oxo-dGTP and 2-OH-dATP, generated by oxidative stress in tumor cells.

These oxidized nucleotides can disrupt DNA replication and cell division. By preventing their incorporation into newly synthesized DNA, MTH1 promotes cancer cell proliferation. Developing new anticancer drugs is complex, but interdisciplinary research can significantly contribute to this endeavor. For the first time, we propose a multi-pronged approach utilizing computational chemistry, statistical analysis, machine learning, molecular dynamics simulations, and synthesis to design novel MTH1 inhibitors.

This approach underscores the power of collaboration between diverse scientific disciplines. Our research aims to identify potent MTH1 inhibitors through a synergy of these methodologies.

This comprehensive study demonstrates that computational chemistry, statistical analysis, and MD simulations can be effectively integrated. Our findings from this combined approach illustrate that our newly designed MTH1 inhibitor, Xyl-Trp, can be a promising candidate for MTH1 inhibition.

This study aimed to establish a PANoptosis related prognostic signature and identify potential prognostic markers and therapeutic targets for HCC.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The survival rate of patients with HCC remains relatively low. PANoptosis can be mediated by lncRNA to involve the pathophysiology of HCC, but the mechanism is still unclear.

TCGA and GEO hepatocellular carcinoma databases and previous research results were used to construct the PANoptosis related risk model.

Based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, this study identified long non-coding RNAs (lncRNAs) associated with PANoptosis in HCC. Univariate, LASSO-Cox, and multivariate COX analyses were employed to gradually screen prognostic lncRNAs and construct prognostic models. Further analysis was conducted on the core lncRNA-AC034229.4.

A total of 8 differentially expressed lncRNAs closely correlated with HCC prognosis were discovered. A prognostic model comprising 6 lncRNAs (AC090192.2, LINC01703, AC034229.4, AC073352.1, AC004816.1, and AL136162.1) was established demonstrating good predictive ability for prognosis. Moreover, this prognostic model exhibited close associations with tumor immune microenvironment and immune checkpoints. Subsequent investigations revealed that AC034229.4 independently influenced HCC prognosis by regulating cell cycle progression and inhibiting the immune microenvironment response. Drug sensitivity analysis indicated that AC034229.4 displayed sensitivity to various anticancer drugs as well. In addition, inhibition of AC034229.4 expression suppressed HCC migration and invasion abilities.

This study generated a novel and efficient prognostic signature model while identifying AC034229.4 as a promising diagnostic and prognostic biomarker in HCC.

Super-enhancer-associated long noncoding RNAs (SE-lncRNAs) play crucial roles in CRC pathogenesis.

RP11-803D5.4 and AC005592.2 were identified as SE-lncRNAs of interest via microarray analysis, and our study aimed to evaluate their clinical value in CRC diagnosis and prognosis assessment.

Fluorescence quantitative real-time PCR (qRT-PCR) was used to measure the expression of RP11-803D5.4 and AC005592.2 in the tissues and serum of CRC patients. Receiver operating characteristic (ROC) curves were generated to determine the predictive value of the two SE-lncRNAs. Functional assays were applied to assess the ability of RP11-803D5.4 to promote the proliferation, migration, and invasion of CRC cells.

The two SE-lncRNAs were significantly upregulated in CRC tissue and serum samples vs. corresponding controls. ROC curve analysis indicated that RP11-803D5.4 (AUC=0.842) and AC005592.2 (AUC=0.811) had a high diagnostic performance for CRC. The combination of RP11-803D5.4, AC005592.2, and CEA had an AUC of 0.946 and distinguished CRC patients and healthy controls better than SE-lncRNA alone. The serum levels of RP11-803D5.4 and AC005592.2 were strongly correlated with their tissue expression levels. The expression levels of the two SE-lncRNAs were significantly lower in postoperative samples than in preoperative samples. Furthermore, similar to the findings of previous studies on AC005592.2, high RP11-803D5.4 expression promoted the proliferation, invasion, and migration of CRC cells.

The findings suggested that RP11-803D5.4 and AC005592.2 are upregulated in CRC and are crucial promoters of CRC progression. They also suggested that they might serve as noninvasive biomarkers for diagnosing CRC.

G-quadruplexes (G4s) are non-classical high-level structures that are formed by DNA/RNA sequences and have been a promising target for developing antitumor drugs. However, it is still a challenge to find a ligand that binds to a particular G4 with selectivity. Telomeric multimeric G4s are more accessible for screening for specific ligands due to their higher-order structure compared with telomeric monomeric G4s.

In this study, the natural product berberine was found to exhibit a higher selectivity for telomeric multimeric G4 in comparison with other G4s. The mechanism of interaction between telomeric G4s and berberine was further investigated by fluorescence spectra measurements, job plot analysis, and UV titrations. We found that there are three binding sites for berberine on telomeric dimeric G-quadruplex Tel45, which are located at the 5' and 3' terminal G-quartet surfaces and the pocket between the two quadruplex units of Tel45. It was worth noting that the berberine preferred to interact within the interfacial cavity between two G4 units.

Moreover, via dynamic light scattering (DLS) and native polyacrylamide gel electrophoresis (Native-PAGE) assays, it was found that the particle size of the telomeric multimeric G4s conformation was significantly increased by the addition of berberine. In contrast, the particle sizes of Tel21 did not change significantly after the addition of berberine. An immunofluorescence assay indicated that berberine induced the formation of endogenous telomeric G4 structures along with the related telomeric DNA damage response.

This study provides a hypothetical basis for the development of natural products targeting telomeric G4 as antitumor drugs.