Chemical Biology & Drug Design最新文献

Immunotherapy holds promise for thyroid cancer (TC) treatment. In the context of our previous findings that artesunate (ART) could inhibit the migration and invasion of TC cells through phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), this study was engineered to investigate whether ART regulates the tumor microenvironment in TC. THP-1 cells were differentiated into M0 macrophages by the induction of 100 ng/mL of phorbol 12-myristate 13-acetate and transfected as needed. M0 macrophages were treated with different concentrations of ART (10 and 20 μM) for 24 h. The co-culture of macrophages and TC cells was conducted. Flow cytometry and enzyme-linked immunosorbent assay were used to identify M2 macrophages. The viability, migration, and invasion of TC cells were detected by cell counting kit-8, wound healing, and transwell assays. The mRNA or protein expressions of examined genes were measured by quantitative real-time polymerase chain reaction or Western blot. In co-cultured macrophages, protein expressions of CD206, CD163, and Arginase-1, as well as the secretion of IL-10 and CCL18, were promoted, but phosphatase and tensin homolog (PTEN) mRNA expression was inhibited, which were reversed by different concentrations of ART. In the co-culture system, 20 μM of ART downregulated mRNA expressions of CD206, CD163, and Arginase-1 in macrophages and diminished viability, migration, invasion, as well as ratios of p-PI3K/PI3K and p-Akt/Akt in TC cells, which were offset by PTEN deletion in macrophages. Collectively, ART suppresses the migration and invasion of TC cells via inhibiting the PI3K/Akt pathway by PTEN upregulation-blocked M2 polarization of tumor-associated macrophages.

1-Deoxy-D-xylulose-5-phosphate reductoisomerase (IspC) is a key enzyme in the MEP pathway, essential for many bacteria, human pathogens, and plants, thus being an attractive drug target. Fosmidomycin, a potent IspC inhibitor with hydroxamate metal-binding pharmacophores (MBPs), has entered clinical trials for malaria but is hampered by pharmacokinetic and toxicity issues of the hydroxamate fragment. This has led to increased interest in non-hydroxamate inhibitors. This review focuses on the crystal structure and active-site binding mode of IspC, and the structural types, inhibitory activities, and structure–activity relationships of non-hydroxamate IspC inhibitors. Early attempts to design such inhibitors involved direct removal or replacement of the hydroxamate MBPs, with varying results. Lipophilic inhibitors, bisubstrate inhibitors, and those developed for herbicidal applications have shown promise. However, challenges remain due to the sensitivity of the enzyme active site to ligand interactions. Future research could draw from other metalloenzyme studies to develop novel and efficient non-hydroxamate IspC inhibitors.

Cdc2-like kinase 4 (Clk4), a key member of the CMGC kinase family, plays a crucial role in alternative splicing, which profoundly influences various physiological processes, including cellular signaling, proliferation, and survival. Its involvement in these vital functions has positioned Clk4 as an important target for therapeutic intervention in a range of diseases, such as neurodegenerative disorders, viral and parasitic infections, and cancer. This review highlights recent advancements in Clk4 inhibitors, covering both natural, and synthetic compounds. It further examines the core scaffolds and essential functional groups of Clk4 small-molecule inhibitors, emphasizing the most promising chemical structures. Additionally, the review explores the structure–activity relationships (SARs) and molecular binding modes of existing Clk4 inhibitors, offering insights and strategies for the development of novel Clk4-targeted drugs. This review highlights recent advancements in small molecule inhibitors targeting Clk4, emphasizing their potential in treating cancers and neurodegenerative diseases. It explores SARs, binding modes, and challenges in developing selective Clk4 inhibitors, offering insights for future therapeutic strategies.

Twelve thiazole-pyrazole analogues 4, 6, and 8 were synthesized by introducing various pyrazole systems into the core, 2-((4-acetylphenyl)amino)-4-methylthiazole (2), through many synthetic approaches. The density functional theory (DFT) study of the synthesized analogues revealed coincided configurations of their highest occupied and lowest unoccupied molecular orbitals (HOMO and LUMO), except for the nitro derivatives, in which the intramolecular charge-transfer (CT) may be denoted as π → π* and n → π*. In addition, the in vitro antiproliferative efficacy towards some cancer cell lines was examined (Panc-1, HT-29, MCF-7) and the non-cancerous (WI-38), using Dasatinib (Reference). The analogues 4c and 4d demonstrated the most potent anticancer effect, particularly against Panc-1 and MCF-7 cells. Moreover, the antiviral activity against H5N1, using a plaque reduction assay, showed that analogue 6a exhibited the most potent antiviral activity (100% inhibition and TC₅₀ = 61 μg/μL), comparable to the reference drug amantadine (TC₅₀ = 72 μg/μL, 100% inhibition). Furthermore, the molecular docking disclosed that the analogues exhibited a range of interactions, such as H-bonding and π-π stacking, with binding affinities between −4.8558 and − 8.3673 kcal/mol. Additionally, the SwissADME predictions indicated that the synthesized analogues possess promising drug-like characteristics, but analogues 4a–d and 8c demonstrated inadequate solubility and bioavailability, which restricts their use as viable oral medications.

Methicillin-resistant Staphylococcus aureus (MRSA) achieves high-level resistance against β-lactam antibiotics through the expression of penicillin-binding protein 2a (PBP2a), which features a closed active site that impedes antibiotic binding. Herein, we implemented a strategy that combines drug repurposing with synergistic therapy to identify potential inhibitors targeting PBP2a's allosteric site from an FDA-approved drug database. Initially, retrospective verifications were conducted, employing different Glide docking methods (HTVS, SP, and XP) and two representative PBP2a structures. The combination of Glide SP and one representative PBP2a conformation showed the highest efficacy in identifying active compounds. The optimized parameters were then utilized to screen FDA-approved drugs, and 15 compounds were shortlisted for potential combination therapy with cefazolin, an ineffective cephalosporin against MRSA. Through biological assays—checkerboard, time-kill assays, and live/dead bacterial staining—we discovered that four compounds exhibited robust bactericidal activity (FICI < 0.5) compared to both untreated control and monotherapy with cefazolin alone. Scanning electron microscopy (SEM) confirmed that while cefazolin alone did not cause visible damage to MRSA cells, the combination treatment markedly induced cell lysis. Additional MM-GBSA studies underscored the strong binding affinity of mitoxantrone to the allosteric site. These findings introduce a combination therapy approach that potentially restores MRSA's susceptibility to β-lactam antibiotics.

Malaria is a pervasive and deadly threat to the global population, and the resources available to treat this disease are limited. There is widespread clinical resistance to the most commonly prescribed antimalarial drugs. To address this issue, we synthesized a range of 4′-pyrrolidinodiazenyl chalcones using a covalent bitherapy approach to study their potential antimalarial properties. We examined the structure–activity relationships of these compounds, which could explain their antimalarial activities. The in vitro blood stage antimalarial activity of the compounds was evaluated against the mixed-blood stage culture (ring, trophozoites and schizonts) of Plasmodium falciparum 3D7, and the 50% inhibitory concentrations (IC₅₀s) ranged from 3.3 to 22.2 μg/mL after 48 h of exposure. Compounds 11, 19, and 22 displayed pronounced IC₅₀ values of 7.6 μg/mL, 6.4 μg/mL, and 3.3 μg/mL, respectively. The in vitro cytotoxicity of the active compounds was evaluated on human-derived Mo7e cells and murine-derived BA/F3 cells. Compounds 11 and 19 were found to be noncytotoxic (> 40 μg/mL), whereas compound 22 displayed cytotoxicity at higher concentrations. Moreover, these compounds exerted negligible hemolytic effects on human RBCs at their active concentrations. Molecular docking of these compounds revealed good hydrophobic and hydrogen bonding interactions with the binding sites of Plasmodium falciparum-dihydrofolate reductase, providing a rationale for their antimalarial activity, which is consistent with the in vitro results.

The bacterial cell wall is crucial for maintaining the integrity of bacterial cells. UDP-N-acetylglucosamine 1-carboxyethylene transferase (MurA) is an important enzyme involved in bacterial cell wall synthesis. Therefore, it is an important target for antibacterial drug research. Although many MurA inhibitors have been discovered, only fosfomycin is still used as a MurA inhibitor in clinical practice. Owing to the long-term use of fosfomycin, the emergence of fosfomycin resistance is worrisome. Therefore, it is still necessary to discover new MurA inhibitors with different types of action than fosfomycin. In this study, we used AutoMolDesigner to construct a machine learning model combined with molecular docking to screen for noncovalent MurA inhibitors. We subsequently conducted the MurA inhibition activity assay and identified compound L16 (N-(3-(benzo[d]oxazol-2-yl)-4-hydroxyphenyl) carbamoyl-4-methylbenzamide) as a moderately active MurA inhibitor (IC₅₀ = 26.63 ± 1.60 μM). The compound was structurally different from other known MurA inhibitors. We used molecular dynamics simulation to reveal possible interactions between the compound and MurA. In addition, we also found that compound L16 was nontoxic to human liver cancer cells (HepG2) (IC₅₀ > 100 μM). In conclusion, through virtual screening and in vitro biological evaluation, we identified a novel structural type of MurA inhibitor which may become a candidate drug for inhibiting bacterial cell wall synthesis.

Moscatilin, a biphenyl compound derived from Dendrobium nobile, exhibits significant anti-tumor activity. However, the specific role of moscatilin in clear cell renal cell carcinoma (ccRCC) and its underlying molecular mechanisms have not been fully studied. This study aims to fill this gap by demonstrating through a series of experiments that moscatilin can effectively inhibit the proliferation and migration of ccRCC and induce its apoptosis process. More importantly, we found that moscatilin can also trigger ferroptosis in ccRCC, a process accompanied by significant increases in Fe²⁺, MDA (a lipid peroxidation product), and ROS (reactive oxygen species) levels, as well as decreases in mitochondrial membrane potential and GSH (glutathione) levels. These changes strongly suggest a key role for moscatilin in inducing ferroptosis. To further explore its underlying mechanism, we speculate that moscatilin may inhibit the phosphorylation level of the JAK–STAT signaling pathway, thereby blocking the function of the key protein SLC7A11 in the ferroptosis signaling pathway, which promotes the occurrence of ferroptosis. This discovery not only reveals a new mechanism of moscatilin in the treatment of ccRCC but also provides new ideas for the development of related drugs in the future. In summary, based on the important discovery that moscatilin can induce ferroptosis in ccRCC, we have reason to believe that moscatilin has the potential to become a new type of drug for the treatment of ccRCC.