Mitogen-activated protein kinase-interacting kinases (MNK1/2) have emerged as promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). Through scaffold-conservative optimization of an imidazo[2,1-b][1,3,4]thiadiazole core, we identified HD202A as a highly potent MNK1/2 inhibitor (IC50 = 6.1/8.1 nM) with favorable kinome selectivity within the tested kinase panel, oral bioavailability (F = 42.1%), and favorable pharmacokinetic properties. In a high-fat-diet induced MASLD mice, HD202A markedly reduced body-weight gain, hepatic triglyceride accumulation, and serum lipids while improving glucose tolerance, insulin sensitivity, and inflammatory profiles. Mechanistically, HD202A suppressed MNK-eIF4E signaling, downregulated perilipin 2 and stearoyl-coenzyme A desaturase 1, upregulated adipose triglyceride lipase and peroxisome proliferator-activated receptor gamma coactivator 1α, and enhanced mitochondrial fatty-acid oxidation and redox homeostasis. These findings validate MNK inhibition as a viable strategy for MASLD and establish HD202A as a promising lead compound for further development.

High-throughput fragment screening identifies a new small molecule scaffold that modulates TREM2 Signaling.

Background: Chrysopogon zizanioides (L.) Roberty (vetiver) is a perennial medicinal grass with deep aromatic roots traditionally used for several ailments. Its root essential oil (CZEO) is rich in phytochemicals with documented antimicrobial, anti-inflammatory, and antioxidant activities. Although its anticancer potential remains underexplored, the complex phytochemical profile of CZEO positions it as a promising multi-target therapy, particularly for colorectal (CRC) and lung cancers where resistance and pathway redundancy often limit conventional treatments. Therefore, this study aimed to investigate the phytochemical composition and antiproliferative activity of CZEO from Qatar against colorectal (HCT-116) and lung (A549) cancer cells and to elucidate its molecular targets and mechanisms of action in CRC and lung cancer using network pharmacology and in silico approaches. Methods: CZEO was extracted by steam distillation and characterized using GC–MS. In vitro proliferation assays with HCT-116 colorectal and A549 lung cancer cells were conducted using the Alamar Blue assay. The ten most abundant phytochemicals identified by GC–MS were assessed for drug-likeness and ADMET properties and further analyzed through network pharmacology, molecular docking, and molecular dynamics (MD) simulations to elucidate the molecular targets and mechanisms underlying CZEO’s anticancer activity. Results: GC-MS profiling identified 40 compounds, predominantly sesquiterpenoids (93%), including khusimol, β-eudesmol, α-vetivone, and rosifoliol. CZEO inhibited cancer cell viability in a dose-dependent manner, with IC50 values of 62.95 ± 2.19 µg/mL for HCT-116 and 167.82 ± 6.51 µg/mL for A549 cells, demonstrating greater potency against colorectal cancer. CZEO did not affect the growth of normal human neonatal fibroblasts (HDFn), suggesting potential selectivity for cancerous cells. ADMET predictions indicated favorable pharmacokinetics and low toxicity of CZEO’s top 10 abundant compounds (TACs). Network pharmacology revealed 373 and 394 overlapping gene targets between TACs and lung and colorectal cancer, respectively. The overlapping genes were used to construct a protein–protein interaction (PPI) network to identify hub genes. STAT3 and AKT1 consistently emerged as common top-scoring hub genes in both cancers. Molecular docking of TACs showed strong binding affinities of rosifoliol and α-vetivone to AKT1 (−6.20 and −5.93 kcal/mol, respectively) and STAT3 (−5.19 and −5.09 kcal/mol, respectively), surpassing reference inhibitors. MD simulations confirmed stable ligand–protein interactions and structural stabilization, particularly with α-vetivone. Conclusions: CZEO from Qatar exhibits potent antiproliferative activity against colorectal and lung cancer cells, supported by a sesquiterpenoid-rich phytochemical profile. Integrative computational analyses highlight AKT1 and STAT3 as key molecular targets, with rosifoliol and α-vetivone emerging as promising lead compounds. These findings support CZEO as a natural, multi-target anticancer agent, warranting further mechanistic and in vitro and in vivo validation.

Small molecule discovery and drug development are increasingly being pursued in academic settings, expanding beyond their traditional confinement to the pharmaceutical industry. The initial steps in drug discovery typically include identification and validation of a target, screening of chemical libraries to identify modulators of target activity, and subsequent prioritization and optimization of lead compounds using in vitro systems and animal models, with emphasis on compound potency, selectivity and pharmacological properties. This review focuses on early-stage discovery of small molecules that target plasma membrane transporters on epithelial cells, including absorptive and secretory epithelia in kidney, gastrointestinal tract, lung and eye. Of the estimated 500 distinct epithelial plasma membrane transporters, fewer than a dozen are the targets of approved drugs, most of which have been in clinical use for decades. We discuss the logistics and challenges associated with small molecule discovery in an academic setting. Specific epithelial cell targets are considered, including chloride channels, solute-coupled transporters, urea transporters and aquaporins, with therapeutic implications spanning constipation and secretory diarrheas, cystic fibrosis, dry eye disease, edema, hypertension and kidney stones. We conclude by identifying unmet needs and outlining opportunities to enable next-generation pharmacological modulation of epithelial transport processes.

Discovery and structure-activity relationship analyses of 1,2-diphenylethane derivatives as a new class of GPR68 antagonists and the therapeutic effect in an inflammatory bowel disease model.

Discovery of PD-L1 inhibitors featuring novel indole and pyrrolopyridine scaffolds with PD-L1 degradation activity in vivo.

Design, synthesis, and antifungal evaluation of Prp8 Intein-targeting small molecule inhibitors against Cryptococcus neoformans.

SuHeXiang Wan in the treatment of stroke: Prediction potentially active metabolites using a combination of in silico analysis and experimental viability assessment.

Deciphering phenolic-rich fractions from Caesalpinia pulcherrima (L.) with integrative metabolomic and in silico insights into efflux protein inhibition.

Integrated QSAR, molecular docking, and dynamics-based discovery of a potent selective HDAC1 inhibitor with therapeutic potential in aggressive cancers.

Design and evaluation of novel pyrimidine-based nucleoside analogs as antivirals: Identification of MCH-1623 as a potent broad-Spectrum antiviral candidate.

Plants of the genus Elatostema have long been recognized for their diverse secondary metabolites, including phenanthrenes and flavonoids, many of which exhibit notable anticancer properties. Building upon this, the present study aimed to isolate and characterized phytoconstituents from Elatostema tenuicaudatum whole plant and determine their cytotoxic activity against cancer cells. The hydro-ethanol extract of Elatostema tenuicaudatum whole plant was subjected to successive chromatographic fractionations over silica gel, yielding compound 1. The cytotoxic activity of compound 1 was evaluated against a panel of cancer cell lines (MCF-7, Hep-G2, A549, HeLa, and PC-3) using the MTT assay. Chromatographic separation and purification of hydro-ethanol extract of Elatostema tenuicaudatum whole plant led to the isolation of a novel dihydrophenanthrene compound (1), identified as 2-methoxy-5-hydroxy-9,10-dihydrophenanthrene 3-O-[β-D-glucopyranosyl-(1→6)-β-D-glucopyranoside]. The compound demonstrated substantial anti-proliferative effects across multiple human tumor lines, exhibiting particularly potent effects against MCF-7 breast cancer cells (IC50 = 11.90 ± 0.82 µM), followed by HepG2 (IC50 = 29.36 ± 2.02 µM), A549 (IC50 = 50.37 ± 3.21µM), HeLa (IC50 = 71.43 ± 4.08 µM), and PC-3 cell lines (IC50 = 88.98 ± 4.71 µM). These results not only expand the chemical database of Elatostema species but also identify a promising lead compound for further investigation in plant-derived anticancer drug development.

Antibacterial activity of peptide derivatives of dermaseptins against multidrug-resistant Klebsiella pneumoniae and Staphylococcus epidermis.

Gentianine suppresses renal cell carcinoma progression via direct interaction with KDM5B and ferroptosis activation.

Design and evaluation of DNA aptamers with "stem-loop-chain" structures for spectrum neutralization of ricin and abrin.

While Candida albicans alcohol dehydrogenase I (Adh1) conventionally functions as an alcohol dehydrogenase, this study builds upon previous work to redefine its novel role in regulating hyphal morphogenesis and elucidates the underlying mechanisms. Adh1 knockout strains exhibited hyperfilamentation, suggesting that Adh1 directly regulates true hyphal development, independent of its canonical metabolic activity. Leveraging this phenotype, a 'reverse screening strategy' identified 2-hydroxyanthraquinone (HAQ) through high-throughput screening as a potent inhibitor of biofilm formation and hyphal growth by targeting Adh1. Biochemical and structural analyses confirmed HAQ's direct binding to Adh1's F224/A254/Q257 interface. Mechanistically, affinity purification-mass spectrometry revealed Adh1 modulates the SNF1 signalling axis by accelerating SNF1 dephosphorylation via interactions with Bmh1/Ssb1 regulators, thereby inhibiting hyphal conversion. HAQ disrupted these interactions, reducing SNF1 phosphorylation levels in an Adh1-dependent manner. This work establishes Adh1 as both an endogenous SNF1 pathway suppressor and an exogenous drug target, while demonstrating the efficacy of phenotype-driven discovery pipelines. The findings provide a novel antifungal strategy targeting virulence-regulating metabolic enzymes and validate HAQ as a lead compound for therapeutic development against C. albicans pathogenicity.

Design, synthesis, and biological evaluation of novel steroidal selenosemicarbazone derivatives as potent antitumor agents.

From virtual screening to functional discovery: Apigenin ameliorates acute pancreatitis by targeting HINT2 to regulate the mitochondrial acetylome.

Cumambrin A from Chrysanthemum boreale attenuates inflammation and oxidative stress through TRIF-dependent signaling inhibition and Nrf2/HO-1 pathway activation.

Multifunctional hydroquinone-1,2,3-triazole hybrids: Synthesis, biological evaluation, molecular docking, ADMET profiling, and in silico mechanistic insights as potential therapeutic agents.