Chemical Biology & Drug Design最新文献

Mitragyna diversifolia is commonly used to cure diarrhoea in the Bandarban region. However, the impact of anti-inflammatory properties and underlying material basis remains unexplored. This study aimed to determine the anti-inflammatory and antidiabetic potential of metabolites from M. diversifolia. The results indicated that 2,4-di-tert-bylphenol (8), cryptotanshinone (9), and dihydrotanshinone I (10) not only effectively inhibited LPS-induced NO production but also demonstrated potential antidiabetic activities by promoting glucose uptake. Network pharmacological analysis, molecular docking, and molecular dynamics simulation revealed that AKT1 was a crucial target for the anti-inflammatory and antidiabetic effects of M. diversifolia. At the same time, molecular docking analysis showed that compounds 8, 9, and 10 possessed superior binding capacities with AKT1 (−7.3, −11.9, and −11.7 kcal/mol, respectively). Collectively, this study preliminarily clarified the possible material basis and mechanism of M. diversifolia to prevent inflammation and diabetes. Further research is needed to determine the in vivo conditions of compounds 8, 9, and 10, particularly with regard to their safety and efficacy.

Astrocytes play a central role in maintaining synaptic homeostasis, regulating neurotransmitter clearance, and supporting neuronal function, all of which are integral to cognition. In Alzheimer's brain, astrocytic dysfunction contributes significantly to the rapid progression of the disease pathology. Aβ deposition induces oxidative alterations in the astrocytic glutamate transporter EAAT2, leading to impaired glutamate uptake and elevated extracellular glutamate levels, which drive excitotoxicity. This disruption adversely impacts synaptic plasticity, neuronal survival, and cognitive integrity, highlighting the pivotal role of astrocytes in the early phases of AD. Restoration of EAAT2 function is critical to mitigating disease progression and preserving cognitive function. Through in silico analyses, three potential allosteric modulators of EAAT2 were identified. These compounds were further tested on Aβ-intoxicated primary neuronal-astrocyte mixed cultures, with their efficacy evaluated via immunoblotting for EAAT2 expression, in vitro glutamate assays for functional assessment, and morphological analyses of astrocytes and neurons using GFAP and β-III tubulin markers. Notably, PTID and NDHP significantly enhanced EAAT2 expression and function, reducing extracellular glutamate levels and ameliorating excitotoxic damage. Moreover, these compounds demonstrated neuroprotective effects by promoting dendritic growth and branching in β-III tubulin-positive neurons. Immunocytochemical analyses further revealed an increased number of β-III tubulin and GFAP-positive cells, suggesting that PTID and NDHP not only improved neuronal integrity but also supported astrocytic resilience and functionality. The findings of the current study underscore the critical role of astrocytes in glutamate homeostasis and cognition, showcasing the therapeutic potential of EAAT2 allosteric modulators, particularly PTID and NDHP, in alleviating Aβ-induced neurotoxicity. By enhancing EAAT2 function, these modulators restore astrocytic support for synaptic health, offering a promising avenue for addressing cognitive decline in AD.

Considerable effort has been put into developing YC-1 (lificiguat), an indazole derivative with dual targets including soluble guanylate cyclase (sGC) and hypoxia-inducible factor-1 (HIF-1), as new drug molecules with increased potency. Building on our previous findings, this structure–activity relationship study focused on the substitutability of 4H-furo[3,2-b]indole derivatives. (4H-thieno[3,2-b]indol-3-yl)methanol was identified as the chemical skeleton for developing tumoricidal compounds. Notably, the chemotypes exhibited selective cytotoxicity toward cancer cell lines without affecting normal human fibroblasts. Among these compounds, (5-((3-(hydroxymethyl)-4H-thieno[3,2-b]indol-4-yl)methyl)furan-2-yl)methanol (28i) emerged as the most promising candidate, demonstrating robust antiproliferative efficacy against A498 renal carcinoma cells, with an IC₅₀ value of 21.0 nM. Moreover, 28i induced significant apoptosis in A498 cells at a concentration of 50 nM, accompanied by cell cycle arrest in the G₂/M phase. Western blot analysis of apoptosis-related proteins indicated that 28i induces mitochondrial-mediated apoptosis. Molecular docking studies on YC-1, 4H-furo[3,2-b]indole derivative A, and 28i demonstrated that compound 28i exhibited the highest docking score and possesses high potential for inhibiting HIF-1 by targeting the ARNT-dependent pathway. The structural framework of (4H-thieno[3,2-b]indol-3-yl)methanol makes it a promising candidate for cancer therapy.

Machine learning (ML)-driven quantitative structure–activity relationship (QSAR) modeling has gained significant attention for predicting compound biological activity based on compounds' structural, chemical, and physical properties because of the advancement of ML techniques. However, traditional ML-QSAR models often suffer from biases due to algorithm selection and limitations in training data. Additionally, these approaches root in deducing biological activities purely from compounds' structural information and disregard their pharmacokinetic (PK) properties, a key factor contributing to the 15% failure rate in clinical trials, limiting their applicability in drug discovery. To address these challenges, we propose a guided ensemble-based ML approach that integrates a supervised data preparation strategy with an ensemble stacking method, leveraging the strengths of multiple ML algorithms. By incorporating PK properties, our approach enhances prediction reliability. Specifically, we developed two ensemble stacking models: The classification model predicts the biological activity type, “inhibition” versus “activation,” based on compound features, while the regression model predicts bioactivity values. The classification model achieved an accuracy exceeding 0.85, while the regression model attained an R² above 0.77, demonstrating superior performance over traditional QSAR models. These results highlight the potential of our approach in improving drug discovery pipelines by enhancing predictive accuracy and addressing key QSAR limitations.

Myocardial infarction (MI) is currently one of the leading causes of death worldwide, which can lead to loss of heart function and heart failure in severe cases. Danhong injection (DHI) contains two traditional Chinese medicines, Salvia miltiorrhiza (Danshen) and Carthamus tinctorius (Honghua). Previous studies have shown that DHI may play a role in the treatment of MI. However, the relevant molecular mechanisms of DHI in the treatment of MI are unclear, and the potential active compounds that play a major role in DHI also need to be identified. Network pharmacology analysis revealed overlapping genes between DHI and MI. The top 6 core targets were obtained from the PPI network, GO-BP, KEGG, and the targets mainly exist in lipid and atherosclerosis. Then, we screened the potential active compounds Beta-carotene and Tanshinone IIA in DHI, which mainly play a potential therapeutic role according to the molecular docking results. Animal experiments preliminarily verified the therapeutic effects of Beta-carotene and Tanshinone IIA in DHI on MI. The above findings provide preliminary theoretical support for further research into the treatment of MI and the development of new medicines.

Fourteen new quinoline-isoxazole hybrid compounds were synthesized through click reaction with different substituent groups on the isoxazole group. The in vitro therapeutic activeness of the synthesized hybrids had been assessed versus diverse cell lines (MCF7, SKOV3, A549, LN229), using the standard tamoxifen as a reference. According to cell viability results, the most active molecules were found to be 4b against MCF7 cells (IC₅₀ = 12.94 μM) and compound 4f in the SKOV3 cells (IC₅₀ = 17.89 μM), as well as showing no cytotoxicity on the healthy human fibroblast cell line (MRC-5). These results showed us that the new compounds were selective for cancer cell lines. As an indicator of apoptosis, a significant decrease in the level of PARP protein was observed in the MCF7 cells for 4b and in the SKOV3 cells for 4f. After analyzing PARP levels by Western blot, apoptosis levels were also investigated by flow cytometry analysis. The mechanism of the 1,3-dipolar cycloaddition reaction between acetylene and benzaldoxime derivatives was investigated using time-dependent density functional theory (TDDFT). The calculated HOMO–LUMO energy differences and the changes in frontier orbital distributions were found to be consistent with the experimentally observed variations in reaction yield. The molecular docking investigation was conducted to evaluate the binding affinities, interactions, and binding modes of novel hybrid compounds with a target receptor, EGFR kinase (PDB ID: 4G5J). Results showed that compounds 4e and 4f presented favorable binding energies compared to the reference molecule Afatinib. Molecular dynamics simulations confirmed the stable binding of compound 4f with EGFR, with the complex reaching equilibrium after ~20 ns and maintaining an average RMSD of 0.25 ± 0.05 nm throughout the 100 ns trajectory. In silico ADME results also show that all synthesized molecules obey Lipinski's rules.

WGX-50, a previously reported drug candidate for Alzheimer's disease, is derived from Zanthoxylum bungeanum Maxim commonly called Sichuan pepper. Its pharmacological actions for the long run benefit of human health have been extensively investigated. However, in terms of its anti-aging effect, it totally remains unexplored. In this work, WGX-50 was first reported to promote healthy aging in Caenorhabditis elegans with insights from drug target prediction and molecular dynamics simulations. Further investigations have experimentally demonstrated that: Firstly, both daf-16 and skn-1 genes are causative to WGX-50 mediated longevity. WGX-50 failed to extend lifespan upon depletion of these genes in transgenic worms. Their orthologs Foxo1 and Nrf2 were also activated even in D-galactose (D-gal) induced aging and Zmpste24^−/− progeria mice intestines. Secondly, WGX-50 inhibits IIS signaling via downregulating daf-2, and activating daf-16 and skn-1 genes, which thus enable downstream pro-longevity effectors increasing stress resistance and promoting healthier aging. WGX-50 increased expression levels of sod-3, ctl-1, gst-7/8/12/33, gsto-1, and heat shock protein genes such as hsp-12.2, hsp-90, F44E5.4/0.5, T05E11.9 and their inducer hsf-1. In addition, the accumulation of lipofuscin, fat, and reactive oxygen species levels with age was decreased significantly upon WGX-50 supplementation without physiological impairments. Thirdly, in progeria, D-gal and naturally aged mice, WGX-50 is incapable of inducing aging. Senescent genes and SASP factors were not produced at higher levels in livers and small intensities. No impact was observed on key organ indices, blood biochemistry parameters, and bone histomorphometry. WGX-50 perhaps prolongs lifespan through other mechanisms such as reducing fertility, inducing dietary restriction, and improving proteostasis with lowered levels of polyQ35 aggregates. Our findings thus provide primary insights for the potential medical use of WGX-50 in anti-aging and long-term healthcare.

The number of new cancer cases and cancer-related fatalities continues to rise nowadays as a result of better lives and higher survival rates. Recent research has primarily focused on developing multi-target drug designs. A new series of fluorinated 1,3,4-oxadiazole-1,2,3-triazole hybrids was designed and synthesized with high yield utilizing the substructure approach. The newly synthesized compounds were characterized using spectral analyses, including NMR (¹H, ¹³C, and ¹⁹F), mass spectrometry (MS), and high-performance liquid chromatography (HPLC). Additionally, their in vitro anti-cancer activity was evaluated against lung cancer A549 and cervical cancer HeLa cell lines. The results indicated that a number of the synthesized hybrids showed encouraging cytotoxic effects, significantly reducing cell proliferation in comparison to the control groups. Compounds (7c), (9a), and (9b) exhibited high cytotoxicity against lung cancer cell lines, with IC₅₀ values of 19.47 to 21.65 μg/mL. Compound (7c) exhibited significant activity against lung cancer, with an IC₅₀ value of 19.47 μg/mL. Compounds (7c), (9a), and (9b) exhibited broad cytotoxic effects against the HeLa cell line, with IC₅₀ values of 17.07 μg/mL for (7c), 19.21 μg/mL for (9a), and 20.85 μg/mL for (9b). Compound (7b) outperformed the other compounds in anticancer activity against the cervical carcinoma HeLa cell line. In silico drug-like properties indicated that they could be promising molecular frameworks for further studies. The binding modes of compounds (9a) and (9b) were analyzed, revealing the most favorable poses of these compounds within the active site of the tested EGFR (PDB ID: 8SC7) through a molecular docking study. Molecular dynamics simulations of compounds (9a) and (9b) highlighted the key amino acids in the enzyme's active region and provided insight into the mechanism of enzyme interactions.