Current Issue : April-June Volume : 2026 Issue Number : 2 Articles : 5 Articles
The human Ccr4–Not complex is a central regulator of post-transcriptional gene regulation, impacting on translation and mRNA degradation. In mRNA degradation, Ccr4–Not participates in the shortening of the mRNA poly(A)-tail via two catalytic subunits. The Caf1 nuclease is encoded by the highly similar paralogues CNOT7 or CNOT8. In addition to its poly(A)-specific ribonuclease activity, this subunit also provides a structural role by binding Ccr4, the second catalytic nuclease subunit encoded by the paralogues CNOT6 or CNOT6L. To facilitate investigations into the roles of the Caf1 subunit, and to complement genetic tools, we set out to identify inhibitors of the enzymatic activity of Caf1/CNOT7. To this end, we screened a library of 10,880 chemically diverse, drug-like compounds using a fluorescence-based biochemical assay. This effort led to the discovery of 15 inhibitors of Caf1/CNOT7 with biochemical IC50 values below 25 μM. Molecular docking was performed to explore potential binding modes of these compounds. The compounds reported here may be useful to differentiate between catalytic and non-catalytic roles of Caf1/CNOT7. In addition, they may be valuable starting points for the development of more potent inhibitors of the Caf1/CNOT7 poly(A)-selective ribonuclease....
Antibodies against low-molecular-weight compounds exhibit cross-reactivities (CRs) with their structural analogs, varying by orders of magnitude for different substances. This variability limits the informativeness of antibody applications as analytical reagents and for other aims when samples contain several members of the same family, their derivatives, or partial degradation products. Therefore, there is a demand to find some criteria for understanding the relationships between the structural characteristics of antigens of a given chemical class and their immunochemical activity. This study presents an experimental and theoretical investigation of the properties of a monoclonal antibody (MAb) against the S-stereoisomer of gatifloxacin, a member of the widely used (fluoro)quinolone (FQ) family of antibiotics, characterized by high structural diversity. The aim was to determine FQs that form complexes with MAb and suggest a methodology to predict their CRs in silico. For this, the interaction of MAb with 26 FQs was studied using the enzymelinked immunosorbent assay and presented as CR values to the target antigen. The most pronounced CRs were observed for lomefloxacin, sarafloxacin, and ciprofloxacin. Molecular dynamics (MD) simulations were performed to identify differences in analyte interactions at the MAb antigen-binding site, which determines binding affinity. It has been shown that molecular docking fails to discriminate cross-reactive from non-cross-reactive compounds because FQs have similar cores. Therefore, advanced analysis ofMDtrajectories was carried out. It allowed for clarification of the dynamic features of analyte–antibody interactions responsible for binding. It was shown by the dynamical network analysis that the sum of betweenness centrality between a node corresponding to the quinolone ring and nodes representing MAb amino acids is higher for cross-reactive haptens. The found regularities can be transferred to other analyte–antibody systems as a binary classifier that discriminates cross-reactive and non-cross-reactive compounds....
Zika virus (ZIKV) caused Zika outbreaks and continues to post threats to public health. ZIKV infection may cause congenital abnormalities during pregnancy and neurological manifestations in adults. The recurrent public health threat of Zika in various geographical areas demonstrates a need for the development of effective therapeutics. Currently, there are no approved therapies for Zika. ZIKV is a single-stranded, positive-sense RNA virus, whose genome encodes three structural proteins and seven non-structural proteins. The surface envelope (E) protein is essential for host–cell recognition and viral entry; therefore, inhibition of E-mediated viral entry is a key strategy underlying antiviral treatments. Here, molecular docking-based virtual screening was used to screen small-molecule compound libraries to identify potential ZIKV entry inhibitors. Among the compounds identified, Pyrimidine-Der1 exhibited efficient inhibition of reporter ZIKV infection. The microscale thermophoresis assay confirmed its binding with the ZIKV E protein. This compound has effective inhibition of authentic ZIKV infection in a plaque inhibition assay against R103451, PAN2016, and FLR human strains (IC50: ~3–5 μM). Additionally, it efficiently inhibited ZIKV infection at viral entry and fusion steps of the virus life cycle in a time-of-addition assay. Overall, Pyrimidine-Der1 is a promising ZIKV entry inhibitor, warranting further optimization and evaluation....
Endometrial cancer is one of the most common gynecological cancers, with new global cases of approximately 420,000 new cases and 98,000 global deaths annually. Emerging evidence suggests that the EP2 receptor plays a critical role in tumor progression, angiogenesis, and immune evasion. Withanolides, a class of naturally occurring compounds, possess anticancer activity; however, the effect of the EP2 receptor in endometrial cancer remains largely unexplored. This study aims to explore the interaction between withanolides and the EP2 receptor using molecular docking techniques, with PF-04418948 as the reference antagonist. A select number of these ligands, with anticancer activity, were evaluated for their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties, and those with favorable drug-like properties, low toxicity profile, and no more than one Lipinski’s rule violation were docked to EP2 (PDB ID: 7CX2). Molecular docking studies revealed three ligands, (Pubchem 161671, 265237, and 21679027) with significantly higher binding affinity scores compared to that of the reference compound. Pubchem 161671 showed the highest binding affinity at −12.6 kcal/mol. Post-dock analysis revealed interactions with key amino acids, VAL89, LEU298, SER305, and MET31, which are essential for the antagonist activity of the EP2 receptor enzyme. Significant interaction with critical amino acid residues suggested potential inhibition of EP2 receptor activity, offering a potential therapeutic approach for treating endometrial cancer. Overall, this study proffers a deeper understanding of the potential of withanolides as leads for EP2 targeted therapy in endometrial cancer....
Background: The Ames test, a biological assay employing various strains of Salmonella typhimurium, serves as a cornerstone in genetic toxicology for evaluating the mutagenic and potentially carcinogenic properties of chemical compounds. However, experimental testing is resource-intensive and time-consuming for screening the vast chemical space of existing and novel drug candidates in pharmaceutical development. Methods: To address this limitation, we have developed the Ames Mutagenicity Predictor web application, which predicts mutagenic activity in the Ames test for given structural formulas across a comprehensive panel of different bacterial strains. The application utilizes advanced structure–activity relationship (SAR) models generated by PASS (Prediction of Activity Spectra for Substances) v2024 software. The training set comprised 3250 compounds with experimentally determined mutagenicity across 69 different strains, compiled from peer-reviewed literature and established databases, and 4285 non-mutagenic compounds from the WWAD as negative examples. Results: Leave-one-out cross-validation (LOOCV) of the 69 strain-specific models yielded an average Invariant Accuracy of Prediction (IAP) of about 0.944, and for the unspecified mutagenicity, a value of 0.962 was obtained. Conclusions: These validated models have been integrated into a freely accessible web application Ames Mutagenicity Predictor that enables users to input compound structures through multiple formats: a built-in chemical editor, SMILES notation, or compound name search. The application generates comprehensive reports detailing the predicted probability of positive Ames test results for each individual strain, providing researchers with detailed mutagenicity profiles....
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