Molecular Diversity最新文献

EZH2 (Enhancer-Homozygous Protein 2), as a key epigenetic regulator, is closely associated with multiple cancers. Consequently, the design of EZH2-targeting inhibitors has become a significant focus in drug development. The application of deep learning methods in the chemical field can accelerate the process of discovering new molecules. This study utilized the SMILES sequence information of 1,202,321 small molecules from the ChEMBL29 database and the known molecular structures of 11 compounds with EZH2 inhibitory activity. A molecular generation model based on a gated recurrent unit (GRU) network and transfer learning was constructed, generating 50,000 SMILES molecular sequences. Through classification prediction by an ECFP4-SVM model, 37,802 effective and novel molecular structures were screened. Subsequent virtual screening incorporated Lipinski's Rules, ADMET properties, and molecular docking, ultimately identifying 10 candidate compounds for 100 ns molecular dynamics simulations and density functional theory (DFT) calculations. MM-GBSA calculations revealed binding free energies ≤ - 42.3518 kcal/mol for the candidate compounds, suggesting strong interactions with EZH2. DFT calculations further characterized the electronic interaction features underlying ligand-protein binding. This study demonstrates the feasibility of a deep learning-driven computational framework for the virtual identification and prioritization of potential EZH2 inhibitor candidates.

Staphylococcus aureus, a spherical Gram-positive bacterium commonly found to coinhabit humans, can also cause minor skin infections to life-threatening conditions such as pneumonia in individuals with weakened immune systems. The bacterium has developed resistance against conventional antibiotics. This underscores the urgent need for novel therapeutic strategies that act on the cell structure and therefore integrity of the bacterium. Wall teichoic acids (WTAs) are essential anionic glycopolymers covalently anchored to the peptidoglycan layer of Gram-positive bacteria, including S. aureus and are crucial for bacterial survival. The biosynthesis of WTA occurs by a multi-step process in the cytoplasm and proceeds through membrane translocation and incorporation into the cell wall. The earliest and most essential step in this pathway is catalyzed by TarA, which transfers N-acetylglucosamine (GlcNAc) to undecaprenyl phosphate, forming the WTA precursor lipid I. TarA catalyzes the reaction that serves as the first committed step in WTA biosynthesis, without which the entire WTA polymer cannot be constructed or transported. The TarA protein domain has emerged as a promising target for drug development due to its pivotal role in cell wall biosynthesis. We obtained the S. aureus TarA three-dimensional structure from AlphaFold2, performed virtual screening on diverse compound libraries so as to establish their binding to the target protein, which led to the identification of hit compounds with good binding affinity towards TarA domain and involvement of key amino acid residue interactions. This was followed by molecular docking studies, assessment of drug likeness properties of hit compounds and molecular dynamics (MD) simulations of S. aureus TarA-hit molecule complexes using Amber18 bio-simulations package. MD trajectory analysis; root mean square deviation, root mean square fluctuation, hydrogen bonding analysis, solvent accessible surface area, principal component analysis, secondary structure analysis, clustering analysis, free energy landscape, interactive hydrogen bond matrix, binding free energies of the simulated complexes and steered MD simulations were studied. This study resulted in the identification of new hit molecules with a potential to reduce the risk of the S. aureus infections.

Chalcones are a subclass of flavonoids characterized by the presence of an α, β-unsaturated carbonyl system, and they have emerged as important scaffolds in medicinal chemistry because of their structural simplicity, ease of synthesis, and wide spectrum of pharmacological activities. They occur abundantly in nature and are reported to exhibit antioxidant, anti-inflammatory, antimicrobial, and particularly anticancer effects, making them attractive leads for therapeutic development. This review specifically highlights the most recent advances in chalcone-based anticancer research, with a focus on the structural features directly linked to enhanced cytotoxicity activity. Naturally occurring chalcones and their general pharmacological significance are briefly summarized to provide fundamental context. Classical methods, such as the Claisen-Schmidt condensation, remain the most widely used due to their simplicity and high yields, while modern catalytic, solvent-free, and green methodologies have expanded the diversity and efficiency of chalcone libraries. In parallel, structure-activity relationship (SAR) analyses are highlighted to illustrate how substituent effects, heterocyclic incorporation, and linker modifications influence activity profiles. Selected studies are discussed to demonstrate the relationship between structural design and cytotoxic responses across different cancer models. In the selected studies, aim to demonstrate how structural modifications can modulate cellular interactions, enhance therapeutic efficacy, and impact treatment outcomes across various cancer models. By integrating advances in synthesis with biological evaluation, this review emphasizes the versatility of chalcones and provides an updated framework for guiding rational design. The collective evidence underscores their promise as adaptable scaffolds for the development of next-generation anticancer agents.

DNA gyrase and topoisomerase IV enzymes are promising candidates for dual targeting with novel antibacterial agents, lowering the risk of bacterial resistance development. A new series of methylene disalicylic acid/1,3,4-oxadiazole hybrids (5a-l) was developed as dual DNA gyrase and topoisomerase IV inhibitors with antibacterial activity. The structures of the novel compounds were validated using ¹H NMR, ¹³C NMR, and elemental microanalysis. Compounds 5a-l were tested for their inhibitory effect against E. coli DNA gyrase. Compounds 5g, 5h, 5j, and 5l exhibited the highest inhibitory activity against E. coli DNA gyrase, with IC₅₀ values ranging from 164 to 179 nM. Compound 5h has the highest potency as an E. coli DNA gyrase inhibitor with an IC₅₀ value of 164 nM, representing an enhanced potency compared to reference novobiocin. Compounds 5g, 5h, 5j, and 5l were tested against S. aureus DNA gyrase, E. coli, and S. aureus topoisomerase IV. The findings indicated that 5g, 5h, 5j, and 5l activities on DNA gyrase from S. aureus were predominantly less effective than those on E. coli gyrase, with IC₅₀ values ranging from 44 to 56 nM. Compound 5h was the most efficient inhibitor of E. coli and S. aureus topoisomerase IV. Compound 5h showed significant antibacterial effectiveness against the multi-drug resistant (MDR) VRE-12201 and MRSA (EMRSA-15) strains, outperforming the reference drugs vancomycin and amoxicillin. This study used molecular docking to analyze compound 5h with E. coli DNA gyrase B. ADME analysis highlighted enhanced lipophilicity, making it a promising candidate for further optimization as a Gyrase B inhibitor.

Plant-parasitic nematode (PPNs) infections threaten global crop protection and result in substantial annual losses to agriculture worldwide. However, only a limited number of nematicides are currently available, and drug resistance is becoming a more significant concern. Therefore, there is an urgent need to develop new, highly effective, and environmentally friendly nematicides. This study designed and synthesized forty-two novel fluopyram analogues containing five-membered heterocyclic molecules via a "Ring Replacement" strategy. Results from the nematicidal activity testing showed that all the target compounds showed certain activity against Caenorhabditis elegans. Notably, compound 21r demonstrated an LC₅₀ value of 1.83 mg/L, which is significantly lower than that of the commercial nematicide, tioxazafen, but slightly higher than that of the SDHI nematicide, fluopyram. Enzymatic assays and molecular docking studies identified nematode SDH as the probable molecular target. An ecological and environmental risk assessment was also conducted on the target compound 21r. However, the long-term toxic effects of these compounds on aquatic life remain to be further explored. The study indicates that the thiophene moiety, a five-membered heterocyclic ring system, holds significant potential for developing novel SDHI nematicides. The results provide critical mechanistic insights and lay the groundwork for the development of novel nematicides, which will contribute to improving crop protection strategies in agriculture.

Cyclin-dependent kinase 12 (CDK12), a key regulator of cell-cycle-linked transcriptional programs, has gained increasing attention as a driver of tumorigenesis and a promising therapeutic vulnerability across diverse malignancies. In this study, we combined pan-cancer multi-omics profiling with a computational screen of a Vietnamese medicinal herbs compound library to identify candidate inhibitors targeting both wild-type CDK12 and its drug-resistant C1039F variant. Transcriptomic and proteomic analyses of TCGA and GTEx datasets revealed significant CDK12 overexpression in 14 tumor types compared with matched normal tissues. Overall survival comparisons further indicated that elevated CDK12 expression predicts markedly poorer outcomes in different renal cancer types and glioma, whereas genomic profiling identified ovarian cancer as the malignancy with the highest frequency of CDK12 alterations. Immune deconvolution analyses showed strong associations between CDK12 expression and infiltration by endothelial cells and natural killer T cells, suggesting a link between CDK12 dysregulation and tumor immune evasion. Complementing the multi-omics investigation, molecular docking, molecular dynamics simulations, and MM/PBSA free-energy calculations were conducted to evaluate the binding profiles of natural compounds derived from Vietnamese medicinal plants against both CDK12 variants. Several phytochemicals including 2,3-Diepicastasterone from Phaseolus vulgaris (- 131.038 ± 23.572 kcal/mol), as well as compounds from Eurycoma longifolia and Oryza sativa-exhibited highly favorable binding affinities and stable interaction dynamics, highlighting them as promising scaffolds for CDK12 inhibitor development. Collectively, our findings establish CDK12 as a robust biomarker for cancer diagnosis, prognosis, and immune modulation, while highlighting natural-product-based scaffolds as promising leads for next-generation CDK12 inhibitors targeting both wild-type and resistant variants, potentially synergizing with emerging immuno-oncology strategies.

Rheumatoid arthritis (RA) is a severe autoimmune disease characterized by dysregulated functions of multiple immune cells such as phagocytes, lymphocytes, and dendritic cells. Bruton's tyrosine kinase (BTK) and FMS-like tyrosine kinase 3 (FLT3) play critical roles in RA pathogenesis, regulating B-cell survival, myeloid cell differentiation, and dendritic cell activation. Starting from the lead compound CC-292, a series of novel 5-fluoro-aminopyrimidine derivatives were designed and synthesized as dual BTK/FLT3 inhibitors for potential RA therapy. Our in vitro screening revealed that compounds 7a, 7b, and 7c are potent dual inhibitors, demonstrating potent activity with IC₅₀ values in the low nanomolar range. Among them, 7b demonstrated particularly strong dual-target activity (BTK IC₅₀ = 18 nM; FLT3 IC₅₀ = 10 nM), along with high plasma stability and hepatic microsomal metabolic stability. In collagen-induced arthritis model, 7b administration produced dose-dependent reductions in joint swelling and significantly mitigated cartilage degradation and bone erosion, as confirmed by histopathological evaluation. Acute toxicity tests revealed no obvious adverse effects at a dose of 1000 mg/kg, indicating a promising safety profile. This work presents not only a promising lead compound but also a strategic framework for developing next-generation RA therapies.