Molecular Diversity最新文献

Lung cancer is the world's top ranked cancer, with non-small cell lung cancer accounting for over 80% of lung cancer, so it is an urgent need to find new treatment strategies for non-small cell lung cancer. Celastrol is one of the effective active ingredients in the plant Tripterygium wilfordii Hook. f., and research has found that celastrol has an inhibitory effect on non-small cell lung cancer. However, the significant toxic side effect of celastrol limits its clinical application. In this study, 9 novel celastrol derivatives were developed using PROTAC technology. Cell viability testing displayed that some compounds exhibited higher antiproliferative activity in cancer cells, and had lower toxicity to normal cells. Among them, compound MX-108 (11c) showed a high inhibitory activity with an IC₅₀ value of 0.66 ± 0.07 μM against human non-small cell lung cancer NCI-H358 cells. The DIA-based quantitative proteomics and western blot analyses had confirmed that compound MX-108 could effectively degrade RAB9A protein in NCI-H358 cells. Compound MX-108 could downregulate the phosphorylation level of Akt and upregulate the expression of cleaved caspase 3. Molecular docking predicted that celastrol had a high binding ability with RAB9A protein. Furthermore, compound MX-108 could effectively inhibit tumor growth in xenografts model of NCI-H358 cells. This study provides new ideas for the development of novel celastrol derivatives to treat cancer.

Penicillin-binding protein 4 (PBP4) is essential in imparting significant β-lactam antibiotics resistance in Staphylococcus aureus (S. aureus) and the mutation R200L in PBP4 is linked to β-lactam non-susceptibility in natural strains, complicating treatment options. Therefore, discovering novel therapeutics against the mutant PBP4 is crucial, and natural compounds from lichen have found relevance in this regard. The aim of our study was to identify novel inhibitors against the R200L mutation by applying machine learning (ML) approach. Predictive classification models were developed using six machine learning algorithms to categorize lichen-derived compounds as either active or inactive. The models were evaluated using ROC curves, confusion matrices, and relevant statistical parameters. Among these, the Extra Trees algorithm showed superior predictive accuracy at 81%. The model identified 115 potentially active compounds from lichen, which were further evaluated for drug-likeness and structural similarity to β-lactam antibiotics. The top 23 compounds, showing similarity to β-lactam drug, were subjected to molecular docking. Among the top 10 compounds, two compounds, Barbatolic acid and Orcinyl lecanorate, displayed promising results in 200 ns molecular dynamics (MD) simulations and MM-PBSA analysis, exhibiting better docking score compare to reference compound. Additionally, DFT calculations revealed negative binding energies and smaller HOMO-LUMO gaps for both compounds. The obtained results prove the utility of ML in screening natural compounds, and provide novel opportunities for the design of antimicrobial compounds in the future.

The p53 Y220C mutation, a prevalent structural variant in human cancers, compromises DNA binding and tumor suppressor functions by destabilizing the protein structure. Leveraging a combined approach of structure-based virtual screening, molecular dynamics simulations, and in vitro assays, we have identified C8, a racemic compound with an indole core and α, β-unsaturated carbonyl groups, as a covalent stabilizer for p53 Y220C. Protein thermal shift and homogeneous time-resolved fluorescence assays confirmed that C8 and its analogs selectively bind to p53 Y220C and restore its DNA binding ability. Subsequent molecular dynamics simulations and structure-activity relationship analyses showed that both enantiomers of C8 form covalent bonds with Cys124 and Cys220, stabilizing the mutant structure. C8 and its analogs emerge as promising lead candidates for restoring the Y220C mutant's transcriptional function, highlights the potential of this scaffold for further optimization into p53 Y220C-targeted therapeutics.

The low efficacy and toxicity of traditional chemotherapy, led by drug resistance of targeted anticancer therapies, have mandated the exploration and development of anticancer molecules. In this league, hybrid drugs, owing to their peculiar multitargeted functionality and structural diversity, could serve as vital leads in this quest for drug discovery. They are plausibly found to offer added advantages considering the improved efficacy, low toxicity, and improved patient compliance. Among numerous heterocycles explored, pyrimidine derivatives epitomize as a valuable resource for the hybrid drug development due to their validated efficacy and versatility. The present review discusses the role of pyrimidine, a diversified pharmacophore in drug development and concepts of hybrid drugs. The study covers the recent advancements in pyrimidine-based hybrid pharmacophores. It delves further into the challenges in hybrid drug development and ongoing research in hybrid drug discovery. Furthermore, the challenges faced in developing hybrid molecules, such as their design and optimization complexities, bioavailability and pharmacokinetics issues, target identification and validation, and off-target effects, are discussed.

Twenty-four amide compounds containing a sulfone moiety were synthesized and the antibacterial activity of the target compounds was tested. Some compounds show excellent antibacterial activity. For example, compound AC4 exhibited broad antibacterial activity with the EC₅₀ of 0.55 mg/L for Xanthomonas axonopodis pv. citr (Xac), and 0.48 mg/L for Xanthomonas oryzae pv. oryzae (Xoo). In the greenhouse, compound AC4 with a concentration of 200 mg/L had good protective activity (39.3%) and curative activity (42.2%) against bacterial leaf blight, both were superior to the commercial antibacterial thiodiazole-copper (19.2% and 31.8%) and bismerthiazol (27.4% and 23.1%). The compound AC4 can inhibit the normal growth of Xoo by inhibiting the virality factors of Xoo (motility, exopolysaccharides, and biofilms). At the same time, molecular docking results showed that compound AC4 could interact with exopolysaccharides and quorum sensing-related proteins. This result was further supported by relative gene expression analysis. In addition, the compound AC4 can also increase membrane permeability, induce intracellular reactive oxygen species (ROS) levels to rise, and cause the surface of Xoo to change. The compound AC4 can be further studied as a potential antibacterial agent and this structure will continue to be optimized.

To further explore and discover natural products-based antifungal agents, seventeen tertiary amide-oleanolic acid hybrids were designed and synthesized, and structurally confirmed by ¹H NMR, ¹³C NMR, HRMS, and melting point. Bioassay results illustrated that derivative 4 k exhibited prominent in vitro inhibitory activity against the mycelium growth of Gaeumannomyces graminis and Valsa mali with the EC₅₀ values of 41.77 and 43.96 μg/mL, respectively. Meanwhile, the structure-activity relationships were also summarized. Moreover, in vivo control efficacy demonstrated that derivative 4 k displayed remarkable curative effect (CE) against V. mali at 200 μg/mL with the value of 52.6%, evidently superior to that of the positive control carbendazim (41.5%). Besides, derivative 4 k also exhibited good CE against Botrytis cinerea at 200 μg/mL with the value of 33.0%. Scanning electron microscope analysis initially indicated that derivative 4 k may exert its antifungal effect by leading to abnormal morphology on the mycelium surface, resulting in the aberrant hypha growth.

Aberrant activation of the Wnt/β-catenin signaling pathway, primarily driven by APC mutation and AXIN degradation via Tankyrase, contributes significantly to colorectal cancer (CRC) progression and metastasis. The accumulation of β-catenin, resulting from the dysregulated ubiquitination, underscores the need for alternative therapeutic strategies targeting Tankyrase and β-catenin. This present study explores microbial metabolites as a source of novel anti-cancer agents, leveraging their unique bioactivity and structural diversity, often exhibiting superior target specificity and lower toxicity than synthetic drugs. Through a computational drug discovery pipeline, a large library of 27641 microbial metabolites was initially screened based on multiple drug-likeliness criteria, resulting in the selection of 2527 compounds. Among the screened compounds, an integrated computational workflow comprising molecular docking, molecular dynamic simulations (MDS), MM/PBSA analysis, and Principal component analysis (PCA) identified Terreustoxin I (T1) as a potential Tankyrase inhibitor. In contrast, compound 10- phenyl-[12]-cytochalasin Z16 (B1) demonstrated a strong binding affinity within the β-catenin active site. Under physiological conditions, these lead compounds were evaluated for conformational stability, binding efficacy, and dynamic behavior. Additionally, ADMET profiling, physiochemical properties, and bioactivity score predictions confirmed the identified compounds' pharmacokinetic suitability and reduced toxicity profile. In silico, cytotoxicity predictions showed significant activity against SW480 and HCT90 colorectal cell lines, with additional anti-neoplastic and anti-leukemic properties, strengthening their candidacy as effective anti-cancer agents. These findings provide a foundation for further experimental validation and development of novel CRC therapies with improved safety and efficacy potential.

Influenza A virus (IAV) remains a significant public health concern due to its annual epidemics and potential for global pandemics. Despite the availability of countermeasures such as vaccines and antiviral treatments, their effectiveness is often questioned due to the emergence of novel strains with antiviral resistance and the variable efficacy of influenza vaccines compared to other vaccines. Traditionally, influenza vaccination strategies have focused on matrix, neuraminidase, and nucleoproteins. In this study, considering the crucial roles of HA and RdRp (PA, PB1, and PB2) of Influenza A, a reverse vaccinology approach is put forth in designing a possible promising antigenic protein toward the development of vaccines against H1N1 viruses. With the development of immunoinformatics approach, one can design/construct potential candidates for vaccine formulation against IAV with the epitope segments identified based on B- and T-cell recognition linked via adjuvants like EAAAK, GPGPG, and AAY linkers. Computational assessments of physicochemical properties, antigenicity, immunogenicity, allergenicity, and toxicity predictions, conducted to evaluate the potential of designed vaccine construct, indicated high antigenicity and potential interactions with immune receptors. Molecular docking of the vaccine construct with human immune receptors (MHCI, MHCII, TLR4, TLR7, and TLR8) followed by molecular dynamics simulations demonstrated stable dynamics with strong binding affinity. The computational immune response modeling with multiple dosages suggested significant immune activation by this construct against IAV. In essence, these findings highlight the potential immune property of the vaccine construct, and put forth the need of thorough preclinical assessments in transforming this construct as a vaccine against the challenging IAV pathogens.

Recently, it has been seen that there is a rapid surge in Click Chemistry (CC) research owing to its fast, reliable, and biocompatible nature, making it an ideal tool for drug discovery. CC approach allows facile and sustainable development of complex molecules with minimal off-target products. With the rapid advancement of the CC field, its applications have significantly expanded across various domains, including biomedical, pharmaceutical, radiochemistry, nanochemistry, polymer chemistry, and microscopy. However, its applications remain most prominent in medicinal chemistry. This review initially covers the introduction and distinct types of click reactions such as copper-catalyzed azide-alkyne cycloaddition (CuAAC), strain-promoted azide-alkyne cycloaddition (SPAAC), and Diels-Alder Cycloaddition (DA), followed by the different techniques facilitating the click reactions. Among these, the CuAAC reaction is most effective and extensive CC approach widely explored for creating huge number of molecular libraries of medicinal significance due to its excellent biocompatibility, reliability, and specificity. In this review, we mainly included the synthesis and medicinal attributes of click reaction (CuAAC & SPAAC)-derived organic heterocycles from 2012-2023, particularly anticancer, antiviral, antidiabetic, and antimicrobial that will help the readers to understand the concept of CC, medicinal significance of CC-derived heterocycles, unexplored areas, challenges, and future prospects. This review will also provide a roadmap for new research directions and applications of click-derived heterocycles in medicinal chemistry.

SecA protein is a vital protein in bacterial protein transport systems and has been reported as a promising drug target in various bacteria, including the multidrug-resistant Acinetobacter baumannii for which development of novel drugs are urgently needed. To this end, the present study aims to screen natural compounds as potential inhibitors against SecA protein of this pathogen. Initially, structural modeling of SecA protein was performed to generate multiple models, which were assessed using various criteria. The most reliable model, Rank3 from AlphaFold2, was selected for molecular dynamics (MD) simulation study to obtain an energy-minimized structure. Virtual screening of this energy-minimized structure against the natural compound databases (LOTUS and CMNPD) identified five natural compounds, namely TCC, TMX, DDA, PF, and DOP with docking scores of - 9.801 kcal/mol, - 9.565 kcal/mol, - 9.092 kcal/mol, - 8.862 kcal/mol, and - 8.758 kcal/mol, respectively, which were significantly better than those of known SecA inhibitors CJ-21058 (- 3.92 kcal/mol), Pannomycin (- 3.234 kcal/mol), and Rose Bengal (- 2.608 kcal/mol). MD simulation studies confirmed the stability of protein-ligand complexes for all five compounds. Although DOP demonstrated the strongest binding energy (ΔG = - 46.93 ± 6.11 kcal/mol), it was excluded as it could cause respiratory toxicity and eye irritation. TMX, on the other hand, showed significant binding energy (ΔG = - 38.23 ± 2.97 kcal/mol), complex stability, good bioavailability, and an acceptable safety profile, indicating it as a potential inhibitor against SecA protein. Thus, our study uncovers a natural compound TMX as a potential inhibitor against a specific target protein. This can be further explored for experimental validation to develop novel drugs against the infectious diseases caused by A. baumannii/other related clinically important pathogens.