Journal of Enzyme Inhibition and Medicinal Chemistry最新文献

Herein, a novel pyrrolo[2,3-b]pyridine-based glycogen synthase kinase 3β (GSK-3β) inhibitor, S01, was rationally designed and synthesised to target Alzheimer's disease (AD). S01 inhibited GSK-3β, with an IC₅₀ of 0.35 ± 0.06 nM, and had an acceptable kinase selectivity for 24 structurally similar kinases. Western blotting assays indicated that S01 efficiently increased the expression of p-GSK-3β-Ser9 and decreased p-tau-Ser396 levels in a dose-dependent manner. In vitro cell experiments, S01 showed low cytotoxicity to SH-SY5Y cells, significantly upregulated the expression of β-catenin and neurogenesis-related biomarkers, and effectively promoted the outgrowth of differentiated neuronal neurites. Moreover, S01 substantially ameliorated dyskinesia in AlCl₃-induced zebrafish AD models at a concentration of 0.12 μM, which was more potent than Donepezil (8 μM) under identical conditions. Acute toxicity experiments further confirmed the safety of S01 in vivo. Our findings suggested that S01 is a prospective GSK-3β inhibitor and can be tested as a candidate for treating AD.

Lespedeza bicolour Turcz. is a traditional medicinal plant with a wide range of ethnomedicinal values. The main components of L. bicolour essential oil (EO) were β-pinene (15.41%), β-phellandrene (12.43%), and caryophyllene (7.79%). The EO of L. bicolour showed antioxidant activity against ABTS radical and DPPH radical with an IC₅₀ value of 0.69 ± 0.03 mg/mL and 10.44 ± 2.09 mg/mL, respectively. The FRAP antioxidant value was 81.96 ± 6.17 μmol/g. The EO had activities against acetylcholinesterase, α-glucosidase, and β-lactamase with IC₅₀ values of 309.30 ± 11.16 μg/mL, 360.47 ± 35.67 μg/mL, and 27.54 ± 1.21 μg/mL, respectively. Molecular docking showed methyl dehydroabietate docked well with all tested enzymes. Sclareol and (+)-borneol acetate showed the strongest binding affinity to α-glucosidase and β-lactamase, respectively. The present study provides a direction for searching enzyme inhibitors for three tested enzymes and shows L. bicolour EO possesses the potential to treat a series of diseases.

Aberrant expression of PLK1 and PLK4 is closely associated with tumourigenesis, and their simultaneous inhibition can effectively suppress tumour proliferation. In this study, we successfully identified peptide inhibitors (Peptides 1-5) capable of simultaneously targeting PLK1-PBD and PLK4-PB3 via pharmacophore-based virtual screening. Binding affinity analyses demonstrated that all candidate peptides exhibited nanomolar binding affinity for both targets. In vitro cancer cell growth inhibition assays revealed that these peptides could suppress the growth of cervical cancer cells. Among them, Peptide-2 showed the optimal binding affinity and anticancer cell proliferative activity (PLK1-PBD: K_d = 8.02 ± 0.16 nM; PLK4-PB3: K_d = 11.32 ± 0.19 nM; IC₅₀ = 0.44 ± 0.03). Molecular dynamics (MD) simulations further predicted that Peptide-2 could stably bind to the binding sites of both PLK1-PBD and PLK4-PB3. This study reported a novel peptide inhibitor Peptide-2 with potent dual-target inhibitory activity against PLK1-PBD/PLK4-PB3, providing a novel strategy for cancer therapy.

ER carboxylesterase 1A (CES1A) is an important metabolic enzyme involved in lipid metabolism. Targeting the CES1A is a promising approach for diseases associated with disorders of lipid metabolism therapy. In this study, screening of 26 natural lignans, three of them were found displaying potent inhibition on CES1A and high specificity over other serine hydrolases. Inhibition kinetic analyses demonstrated that Schisandrin C and Anwuligan were mixed-type inhibitors, while Magnolol acts as a competitive inhibitor. Further investigation showed that they were cell permeable and exhibited minimal cytotoxicity and mitochondrial toxicity, as well as capable of inhibiting intracellular CES1A in living cells. Further investigation found that three Schisandras decreased the number of lipid droplets (LDs) in free fatty acid (FFA)-treated HepG2 cells. Collectively, our findings suggest that Schisandrin C is a potent and highly selective inhibitor of CES1A, which can be served as a promising lead compound.

Protein kinase CK2 is a promising therapeutic target, and this study explores 54 aurone derivatives as potential CK2 inhibitors. Activity was evaluated using luminescent and capillary electrophoresis assays, identifying 17 compounds with submicromolar activity. The most potent inhibitors shared key structural features: a benzo group on the A-ring, a hydrogen bond acceptor at the R4' position, and an additional substituent at the R3' position of the B-ring. Molecular docking revealed similar binding modes among active compounds, with interactions involving Leu45, Val53, Val66, Met163, Phe113, Lys68, and Ile174. Notably, BFO25 showed the highest activity (IC₅₀ = 3 nM at 100 μM ATP). These findings highlight aurones as promising CK2 inhibitors and emphasise the significance of specific structural features.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is crucial in regulating inflammation, apoptosis, and necroptosis. Accumulating evidence highlights RIPK1 as a promising therapeutic target for various human diseases, including neurodegenerative disorders, autoimmune diseases, and cancer. In tumour cells, RIPK1 suppresses immunogenic cell death, promotes an immunosuppressive tumour microenvironment, which facilitates immune evasion, metastatic progression, and therapeutic resistance, contributing to an immunologically cold tumour phenotype. Therefore, targeting RIPK1 represents a promising therapeutic approach to overcome immune checkpoint blockade resistance and convert tumours into an immunologically hot phenotype. In this review, we summarise the biological functions of RIPK1 and elaborate on its roles in cancer progression in terms of the tumour immune microenvironment, tumour metastasis, and chemoresistance. Furthermore, we enumerate several identified RIPK1-targeted inhibitors with potential for cancer therapy. Although RIPK1 has been proposed as a potential anticancer target, there are still great opportunities and challenges that require further investigation.

This study investigated the potential of the indirubin-3'-oxime (I3O) compound to mitigate temperature-induced male infertility in Drosophila melanogaster. Elevated temperatures significantly reduced egg-hatching rates, but I3O supplementation improved these rates, suggesting it can partially restore fertility under heat stress. Additionally, I3O was found to inhibit soluble epoxide hydrolase (sEH), an enzyme involved in the metabolism of epoxyeicosatrienoic acids, which are vital for reproductive health. I3O exhibited sEH inhibitions with an IC₅₀ value of 59.74 ± 0.41 µM. Enzyme kinetics revealed that I3O acts as a non-competitive inhibitor of sEH with a K_i value of 78.88 µM. Molecular docking showed strong interactions between I3O and key residues in the allosteric regions within the sEH enzyme, with a binding affinity of -9.2 kcal/mol. These interactions were supported by 100 ns molecular dynamics simulations, which confirmed the stability of the sEH-I3O complex.

In light of searching for new breast cancer therapies, DNA-targeted small molecules were rationally designed to simultaneously bind DNA and inhibit human dihydrofolate reductase (hDHFR). Fourteen new arylidene-hydrazinyl-1,3-thiazoles (5-18) were synthesised and their dual DNA groove binding potential and in vitro hDHFR inhibition were performed. Two compounds, 5 and 11, proved their dual efficacy. Molecular docking and molecular dynamics simulations were performed for those active derivatives to explore their mode of binding and stability of interactions inside DHFR active site. Anti-breast cancer activity was assessed for 5 and 11 on MCF-7 cells using MTX as reference. IC₅₀ measurements revealed that both compounds were more potent and selective than MTX. Cytotoxicity was examined against normal skin fibroblasts to examine safety and selectivity Moreover, mechanistic studies including apoptosis induction and wound healing were performed. Further in silico ADMET assessment was conducted to determine their eligibility as drug leads suitable for future optimisation and development.

PLK1 is essential for cell cycle regulation and proliferation, and its elevated expression in prostate cancer is associated with high tumour grade. Therefore, PLK1 inhibition is considered a promising strategy for the treatment of prostate cancer. Here, we identified five compounds (Hits 1-5) targeting the kinase domain (KD) of PLK1 using a combined virtual screening approach. Hits 1-5 all had picomolar (pM) inhibitory potency against PLK1. Notably, Hit-4 showed the strongest inhibitory activity against PLK1 (IC₅₀ = 22.61 ± 1.12 pM) and displayed high selectivity for PLK1. Meanwhile, molecular dynamics (MD) simulations revealed that the complex formed by Hit-4 and PLK1 remained stable. Importantly, Hit-4 exhibited potent inhibitory effects on the proliferation of DU-145 prostate cancer cells (IC₅₀ = 0.09 ± 0.01 nM). In conclusion, Hit-4 is a potent and highly selective antitumor candidate with therapeutic potential for prostate cancer.

Current antithrombotic therapies face dual constraints of bleeding complications and monitoring requirements. Although natural hirudin provides targeted thrombin inhibition, its clinical adoption is hindered by sourcing limitations. This study developed a recombinant hirudin variant HMg (rHMg) with enhanced anticoagulant activity through genetic engineering and established cost-effective large-scale production methods. The synthesised HMg gene was expressed in E. coli BL21 via a pET vector plasmid, followed by nickel-affinity purification. Systematic evaluations demonstrated rHMg's antithrombin activity of 9573 ATU/mg, dose-dependent prolongation of APTT/PT/TT. It has superior thrombin inhibition with the IC₅₀ and K_i values were 2.8 and 0.323 nM respectively compared to FDA approved drug bivalirudin (p < 0.001). The high-yield prokaryotic expression of rHMg with enhanced anticoagulant efficacy provides a novel strategy for developing affordable antithrombotic drugs, showing significant potential for cardiovascular disease management.