Molecular Diversity最新文献

This study investigates the potential of novel thiazole and hydroxybenzohydrazide derivatives as antitubercular agents. Using molecular docking and density functional theory (DFT) calculations, the binding affinities of these derivatives to the enoyl-acyl carrier protein reductase (InhA) enzyme of M. tb were assessed. InhA is crucial for the mycobacterial fatty acid synthase II (FAS-II) pathway, making it a prime target for drug development. QSAR analysis was employed to relate molecular descriptors to biological activity, and ADMET descriptors evaluated the pharmacokinetics and toxicity of the compounds. Experimental synthesis of the compounds and their characterization via IR and NMR spectroscopy confirmed their structures. DFT calculations revealed multiple conformers for each compound, with specific isomers showing enhanced stability and favorable binding interactions with InhA. These findings suggest that the synthesized derivatives have potential as new antitubercular agents, offering a basis for future drug development strategies against multidrug-resistant TB.

Antineoplastic drugs are becoming prevalent due to increasing cancer casualties around the globe. However, the adverse effects of these drugs are evident due to limited insight into the underlying mechanisms that result in non-specific binding and consequent off-target toxicity. The study investigates the side effects of an antineoplastic drug, Capecitabine, a prodrug converted into fluorouracil by Thymidine Phosphorylase (TP) and degrades the RNA of cancerous cells. However, its non-specific binding with Dihydropyrimidine dehydrogenase (DPD) leads to severe toxicities including leukoencephalopathy, neutropenia, neuropathy, and others. Hence, identifying natural analogs of Capecitabine with comparable attributes is crucial for minimizing its adverse effects. A thorough review of the literature revealed Capecitabine-induced toxicity. 723,878 natural compounds were screened, and drug-like mimics were identified. Their binding with TP and DPD was determined by employing molecular docking, which was validated by MD simulations evaluating conformational stability and variability. Four natural compounds showed better docking scores than the standard drug. The stability of the best hit was further validated with MD simulations. This study, hence, ushers in new perspectives on safer drug alternatives using potent natural analogs and could serve as a lead identification approach for the discovery of safer therapeutics.

AKT1, a serine/threonine kinase, is pivotal in signaling and regulating cell survival, proliferation, and metabolism. This review focuses on the structural insights and the essential features required for its active conformation. AKT belongs to the AGC kinase group and has three isoforms: AKT1, AKT2, and AKT3. AKT has three functional regions: PH domain, kinase domain, and hydrophobic motif. AKT1 activation involves intricate conformational changes, including transitions in the αC-in, DFG-in, G-loop, activation loop, and PH domain out, S-spine and R-spine formation, as well as phosphorylation at Thr 308 and Ser 473, which enable AKT1 to adopt active conformation. The analysis highlights the limitations of the AlphaFold-predicted AKT1 structure, which lacks key elements of the active state, including ATP, magnesium ion coordination, phosphatidylinositol-(1,3,4,5)-tetraphosphate, substrate peptide, and phosphorylation at Thr 308 and Ser 473. This study underscores the necessity of these features for stabilizing the kinase domain and facilitating efficient substrate phosphorylation. By consolidating structural insights and activation mechanisms, this review aims to inform the development of computational models and targeted therapeutics for AKT1 activators in diseases such as hepatic ischemia-reperfusion injury, cerebral ischemia, acute hepatic failure, subarachnoid hemorrhage, and alzheimer's disease.

Sparganii Rhizoma (SR) has demonstrated promising anticancer effects across various malignancies; however, its mechanisms in laryngeal cancer (LC) remain poorly understood. This study employs network pharmacology and molecular docking to investigate the molecular mechanisms underlying SR's therapeutic effects on LC, providing novel insights for its potential use in treatment. Active compounds and targets of SR were identified through the TCMSP and Pharmmapper databases, while LC-related targets were sourced from GEO, GeneCards, OMIM, and PharmGkb databases. A Venn diagram generated from these datasets highlighted 58 overlapping targets. The STRING database and Cytoscape 3.9.1 software facilitated the construction of a protein-protein interaction network for these targets, and R language analysis revealed 15 core targets. GO and KEGG enrichment analyses, conducted with the ''clusterProfiler'' package, identified relevant biological processes, cellular components, and molecular functions associated with LC treatment. KEGG analysis suggested SR primarily regulates pathways such as TNF, IL-17, and P53. Molecular docking confirmed SR's ability to bind effectively to the 15 core targets. Molecular dynamics simulations further validated stable protein-ligand interactions for MAPK1, GSK3B, and MAPK14. Core target validation across transcriptional, translational, and immune infiltration levels was performed using GEPIA, HPA, cBioPortal, and TIMER databases. In conclusion, network pharmacology, molecular docking, and dynamics simulations provided insights into SR's mechanism in LC treatment, forming a theoretical basis for further investigation of its therapeutic potential.

α-Glucosidase inhibitors (AGIs) are pharmacological agents commonly used to manage postprandial hyperglycemia associated with type 2 diabetes mellitus (T2DM). Developing novel, potent AGIs remains a significant area of research. In this study, we investigated a series of derivatives of the natural product from α-mangostin as potential AGIs. A combined experimental and computational approach was employed to characterize promising compounds with potent α-glucosidase inhibitory activity. We found that α-mangostin (AM) and its derivatives (AM1 - 3) exhibited micromolar range α-glucosidase inhibition (IC₅₀ ranging from 15.14 to 67.81 µM), surpassing the known drug acarbose (IC₅₀ of 197.09 µM). Among the derivatives, AM1 exhibited the most promising α-glucosidase inhibition, displaying competitive inhibition kinetics with a K_i value of 47.04 µM. Molecular docking and molecular dynamics (MD) simulations provided mechanistic insights into the binding interactions between AM1 and the α-glucosidase active site. AM1 was observed to form hydrogen bonds and hydrophobic interactions with key amino acid residues within the enzyme's active site. The introduction of amine groups in compound AM1 enhanced activity compared to AM, the parent compound. This study highlights the potential of α-mangostin derivatives as potent AGIs. The identified lead compound, AM1, warrants further investigation to assess its efficacy and safety in managing T2DM.

Acute respiratory distress syndrome (ARDS) is the leading cause of mortality in pathogen-mediated lung inflammation. Viral-induced cytokine release syndrome (CRS) has emerged as a global pandemic, characterized by a hyperactive immune response and excessive cytokine production causing irreversible lung injury. This study aimed to evaluate FDA-approved drugs for their potential to target hyperactive immune response and SARS-CoV-2 viral replication simultaneously. Six potential 3-CL^pro inhibitors were identified by molecular docking using MOE software, including ebastine (1), orlistat (2), atracurium besylate (3), piperaquine phosphate (4), valsartan (5), and acarbose (6), among which 1-3 binds strongly to the target protein with binding affinity of - 8.22, - 9.12, and - 7.81, kcal/mol, respectively. Additionally, all identified inhibitors except 4 revealed significant anti-viral potential, with a 50-100% reduction in SARS-CoV-2 plaques. Significant attenuation of phagocyte oxidative burst and inflammatory cytokines (IFN-γ, GM-CSF, IL-6, IL-2, IL-1β, TNF-α) demonstrated the immunomodulatory potential of these drugs. This study demonstrates the potential of pre-existing drugs to ameliorate the cytokine storm and oxidative damage with simultaneous anti-viral effects. The data provide pre-clinical support to develop these drugs as potential therapeutic agent against ARDS.

This study investigated the molecular targets and pathways modulated by pterostilbene in breast cancer using network pharmacology and in vitro analysis. The structure of chemicals of pterostilbene was retrieved from PubChem, and gene targets were predicted through Swiss Target Prediction. Human-specific targets were validated using UniProtKB and breast cancer-related targets were identified using GeneCards and BioVenn. Protein-protein interaction (PPI) networks were created using STRING and visualized using Cytoscape, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses to elucidate biological functions. Molecular docking studies using AutoDock Vina were used to assess the binding interactions of pterostilbene with key nuclear receptors (PTGS2, ESR1, EGFR, and BCL2). Molecular dynamics (MD) simulations over 200 ns in GROMACS confirmed the stability of the ESR1-pterostilbene complex and highlighted significant hydrogen bonding. ADME/T was assessed using the Protox software. In vitro cytotoxicity was assessed using the MTT assay in MCF-7 cells. Sixteen key genes, including PTGS2, ESR1, EGFR, and BCL2, were identified as key targets connecting pterostilbene to breast cancer. PPI analysis identified ESR1, EGFR, and BCL2 as central nodes in the network. Molecular docking revealed robust binding of pterostilbene (below - 8.1 kcal/mol), suggesting potential modulation of estrogen receptor signaling. MD simulations confirmed the stability of the complex with favorable structural dynamics. Toxicity analysis suggested a low risk, and MTT assays revealed selective cytotoxicity of pterostilbene toward MCF-7 breast cancer cells (IC₅₀ = 14.8 µM) with a Selectivity Index of 2.85 compared to normal HEL 299 cells. These findings highlight the potential of pterostilbene as a treatment option for breast cancer, which merits additional exploration in experimental models and human studies.

A series of novel dual-action statin conjugates, which exhibit both triglyceride and cholesterol lowering activities, have been systematically designed, synthesized, and subjected to comprehensive pharmacological evaluation. All the target compounds were characterized by ¹HNMR, ¹³CNMR, and HRMS. Biological evaluation demonstrated that the majority of the synthesized compounds exhibited significant lipid-lowering and cholesterol-reducing activities. In particular, ligand 8a demonstrated significant potency, resulting in a marked reduction in cholesterol and triglyceride levels in a dose-dependent manner. Its minimum response has lowered 2.778 mmol/L (cholesterol level) and 0.699 mmol/L (triglycerides level), surpassing the positive control. For the preliminary assessment of the safety of the target compound, the ADMETlab 2.0 predictive software was utilized. Data show that compared to the combination of drugs used clinically, the safety of the target compounds may be improved. These findings suggest that compound 8a holds promise as a potential candidate for the treatment of hyperlipidemia.

Helicobacter pylori (H. pylori, Hp) is a primary contributor to various stomach diseases, including gastritis and gastric cancer. This bacterium can colonize gastric epithelial cells, compromising their integrity and leading to the development of these conditions. While antibiotics are the mainstay of treatment for H. pylori infections, their widespread use has led to serious issues with drug resistance. High-temperature requirement A (HtrA) protein is an active serine protease secreted by H. pylori, which can destroy gastric epithelium, thus helping H. pylori to colonize gastric mucosa efficiently. In this study, we identified three compounds-Quercetin, Fisetin, and Geniposide-as potential natural compounds that might specifically interact with the HtrA protein, based on molecular docking and molecular dynamics simulations (MDs). The casein hydrolysis experiment indicated that Fisetin could inhibit the activity of HtrA in hydrolyzing casein at the concentration of 50 μM m. Additionally, our in vitro antibacterial experiments further showed that Fisetin could effectively inhibit the growth of H. pylori in a concentration-dependent manner, with an inhibition rate of 80% achieved at a concentration of 10 μM. In summary, these results suggest that Fisetin has an inhibitory effect on the growth of H. pylori, and this study may be the first to reveal its obviously inhibitory effect on HtrA protein. Our findings imply that Fisetin could be a potential candidate for further research as a therapeutic agent targeting protein HtrA, providing a new direction for the exploration of lead compounds and potential drugs against H. pylori infections.

Two new series of pyrimidinyl ethyl pyrazoles derivatives 13a-f and 14a-f were designed and synthesized to possess both anticancer effect by inhibiting BRAFV600E and anti-inflammatory effect by inhibiting JNK isoforms. The structure of the new compounds was generated from hybridization of two main moieties. The pyrimidinyl moiety from reported BRAFV600E inhibitors, and the pyrazole moiety from JNK isoforms inhibitors. The new final compounds were tested on BRAFV600E, JNK1, JNK2, and JNK3 to measure their kinases inhibitory effect. Compound 14c showed the highest activity on JNK isoforms and BRAFV600E with IC₅₀ = 0.51 μM, 0.53 μM, 1.02 μM, 0.009 μM on JNK1, JNK2, JNK3,and BRAFV600E, respectively. All final compounds were tested over four cancer cell lines related to the target enzymes. Compound 14d showed the most potent activity on all tested cell lines with IC₅₀ = 0.87 μM, 0.91, 0.42 μM and 0.63 μM on MOLT-4, K-562, SK-MEL-28, and A375 cell lines, respectively. The ability of 14d and 14c to inhibit MEK1/2 and ERK1/2 phosphorylation was performed by using western blot. The cell cycle analysis of compound 14d on A375 cell line revealed that compound 14d arrested cell growth at G0-G1 phase. Compound 14d remarkably decreased cell migration compared to control group in traditional migration test. Compounds 13a-f and 14a-f showed significant ability to inhibit nitric oxide release and PGE2 production on raw 264.7 macrophages. Compounds 13d and 14d exhibited high inhibitory effect on iNOS and COX-2 compared to COX-1. Finally, the effect of most potent compounds on TNF-alpha and IL-6 was determined.