Molecular Diversity最新文献

In an attempt to develop broad-spectrum antiviral agents, we designed non-nucleoside small molecules as deubiquitinating enzyme inhibitors. The newly developed candidates are based on the quinazolinone nucleus and have been biologically evaluated as antiviral agents against four viruses: adenovirus, HSV-1, coxsackievirus, and SARS-CoV-2. Additionally, activity against papain-like protease (PL^pro), a DUB enzyme of SARS-CoV-2, was evaluated. Structure-activity association was established dependent on the obtained data. Regarding adenovirus, HSV-1, and coxsackievirus, most of the new candidates showed promising antiviral activity. Among them, compounds 8d and 8c have the highest potential, with IC₅₀ values reaching from 12.77 to 15.96 μg/mL and 16.71 to 19.58 μg/mL, respectively, compared to acyclovir's IC₅₀ of 3.45-15.97 μg/mL. However, 8c outperformed acyclovir in terms of selectivity index, with selectivity indices ranging from 19.04 to 22.31, whereas acyclovir's selectivity indices ranged from 4.77 to 22.10. While 8d had selectivity indices comparable to those of acyclovir. Interestingly, compound 8d revealed very potent activity against SARS-CoV-2, showing an IC₅₀ value of 0.948 μg/mL in comparison to IC₅₀ of 1.141 μg/mL for remdesivir. Additionally, 8d displayed a far better selectivity index than remdesivir. Furthermore, 8d showed promising inhibition of papain-like protease with an IC₅₀ of 5.056 μg/mL. In addition, the proposed binding modes and affinities of the new derivatives to papain-like protease were significant. Overall, the majority of such synthesized compounds, especially compound 8d, have shown strong antiviral activity and good safety profiles, making them promising candidates for future development in antiviral therapies.

The poor prognosis of hepatocellular carcinoma (HCC) is mainly due to its high metastatic properties. Hence, metastasis inhibition might provide a reliable strategy for HCC treatment. As its pivotal role in the tumor cell proliferation, survival and metastasis, a disintegrin and metalloproteinase 17 (ADAM17) has become an attractive target for cancer therapy. Nevertheless, the role of ADAM17 in HCC metastasis and its underlying mechanisms remain enigmatic. In the present study, we discovered a novel ADAM17 inhibitor FLF-15, with an IC₅₀ value of 10.43 nM. Further mechanistic studies showed that FLF-15 inhibits HCC migration and invasion in vitro and in vivo mainly by reducing interleukin-6 receptor (IL-6R) shedding, which inhibits IL-6 trans-signaling, while also leading to a reduction in IL-6 levels and downregulation of IL-6 classic-signaling. Furthermore, we revealed an overlapping but distinct biological effects of IL-6 classic and trans-signaling in HCC. Specifically, JAK2/STAT3 and ERK1/2 signaling can be stimulated by both IL-6 classic and trans-signaling pathway. However, AKT appears to be only activated by IL-6 trans-signaling pathway, suggesting its essential role for FLF-15 induced metastasis suppression in HCC. Taken together, our study identified FLF-15 as a novel ADAM17 inhibitor and elucidated its underlying mechanism of HCC metastasis suppression. These findings indicated FLF-15 might be a promising candidate for the development of HCC therapeutic agents.

Aristolochic acid (AA) is a naturally occurring toxin widely present in traditional herbal medicines and is well known for its nephrotoxic and carcinogenic effects. Its association with clear cell renal cell carcinoma (ccRCC) has attracted increasing attention, yet the key molecular targets and underlying mechanisms of AA-induced carcinogenesis remain poorly understood. In this study, 62 intersection genes related to both AA exposure and ccRCC were identified by integrating toxicogenomic databases with ccRCC-associated gene profiles. Transcriptomic analysis and weighted gene co-expression network analysis further narrowed this list to six critical candidates. Diagnostic models built using 13 machine learning algorithms demonstrated robust and consistent performance across multiple datasets. Immune infiltration and functional enrichment analyses suggested that several of these genes may contribute to immune remodeling and metabolic dysregulation. Among them, JAK3 stood out due to its significant upregulation, negative correlation with immunosuppressive cell subsets, and strong association with poor prognosis. Although JAK3 exhibited strong binding affinity to AA in docking analysis, molecular dynamics simulations revealed reduced conformational stability and increased flexibility in its kinase domain, suggesting ligand-induced structural perturbation and potential toxic interference. Collectively, these findings identify JAK3 as a critical toxicological target of AA in ccRCC and demonstrate the power of toxicogenomic and multi-omics integration in uncovering environment-related carcinogenic mechanisms.

The development of novel fungicides has still been a hot topic in the field of pesticide research. In this study, three series of new perillaldehyde hydrazide, amide and acylthiourea derivatives (3a-3n, 4a-4f, and 6a-6f) were designed and synthesized. The in vitro antifungal activity of the title compounds against seven plant pathogens was evaluated. The results displayed that several hydrazide derivatives showed significant antifungal activity. Especially, compound 3b exhibited the most potent inhibitory activity against Monilinia fructicola (EC₅₀ = 0.142 mg/L), outperforming the commercial fungicides bixafen and carbendazim. In vivo experiments further confirmed that 3b presented superior protective and curative effects on pear fruits infected by M. fructicola compared to bixafen. Mechanism studies revealed that 3b could damage the mycelial morphology and cell membrane integrity, increase cell membrane permeability, reduce mycelial dry weight and exocellular polysaccharide content, and increase intracellular ROS content of M. fructicola. Additionally, 3b exhibited significant laccase inhibitory activity (IC₅₀ = 4.87 μM), suggesting that laccase could be a key target for its antifungal action. Molecular docking studies further confirmed the strong binding affinity of 3b with the active sites of laccase. This study highlighted the potential of this perillaldehyde hydrazide derivative as a promising lead for the development of novel fungicides controlling the brown rot caused by M. fructicola.

Scrub typhus is a commonly neglected infectious febrile illness caused by an obligate intracellular bacterium known as Orientia tsutsugamushi. It is a major health problem, affecting one million people annually, and poses threat to one billion people worldwide. There is always the escalating threat posed by the development of antibiotic resistance in the forthcoming future which emphasizes on urgency of the development of vaccine against Orientia tsutsugamushi. Despite eight decades of research and development, currently there is no viable vaccine available against scrub typhus. Outer membrane protein A (OmpA) is highly conserved and immunogenic across 51 geographically diverse isolates of Orientia tsutsugamishi. The multi-epitope vaccine was constructed by integrating four B-cell, four MHC-I, and four MHC-II epitopes linked together using specific linkers. The cholera enterotoxin subunit B is linked with the vaccine construct at N-terminal as an adjuvant. The constructed vaccine is 329 amino acid long, highly antigenic, non-allergen, non-toxic, soluble and has 36.3 kDa molecular weight. The molecular docking of vaccine construct with TLR receptors showed strong binding affinity. The interactions among vaccine and TLR receptors were analyzed using PDBsum. The in silico immune simulation of constructed vaccine showed ability to trigger immune response as shown by augmentation in T-cell and B-cell population. The current study provides the way forward for controlling the febrile disease scrub typhus.

Skin melanoma remains a major global health concern, necessitating novel therapeutic strategies. Epigallocatechin gallate (EGCG), a predominant polyphenol in green tea, possesses potent antioxidant and anti-inflammatory properties that may suppress melanoma progression. Camptothecin (CPT), a topoisomerase I inhibitor, disrupts DNA replication in cancer cells, demonstrating promise in targeted melanoma therapy. This study employs a comprehensive integrative approach that combines network pharmacology (NP), molecular docking, molecular dynamics (MD) simulations, and in vitro experiments to investigate the potential synergistic anti-melanoma effects of EGCG and CPT. Network pharmacology analysis revealed a complex interaction network comprising 138 nodes and 145 edges, identifying key targets involved in melanoma pathophysiology. KEGG pathway enrichment analysis revealed significant involvement of the PI3K‒Akt signaling pathway in melanoma modulation. Molecular docking studies demonstrated strong binding affinities of camptothecin with EGFR (PDB: 3LZB), with binding energies ranging from - 8.6 to - 10.1 kcal/mol. Molecular dynamics simulations further confirmed the stability of these interactions, with minimal fluctuations observed. Experimental validation via the SRB assay in B16-F10 melanoma cells revealed potent inhibition of cell viability, particularly when EGCG and camptothecin were used in combination, indicating a potential synergistic effect. The observed synergism between EGCG and camptothecin suggests a multitargeted therapeutic approach, leveraging EGCG's antioxidant and anti-inflammatory effects alongside camptothecin's ability to inhibit DNA replication to enhance melanoma suppression. This integrative study highlights the promise of combination therapy using natural and chemotherapeutic agents, paving the way for the development of effective, targeted anticancer treatments for skin melanoma.

The interaction between olanzapine (OLZ) and human serum transferrin (Tf), both in the absence and presence of Fe³⁺, was analyzed using multispectroscopic methods, molecular docking, and molecular dynamics simulations under physiological conditions. Spectroscopic results confirmed OLZ's strong affinity for Tf, driven by static interactions complemented by minor dynamic effects. The values of the binding constants, K_a (2.48 × 10⁸, 4.73 × 10⁷_, 1.13 × 10⁷ at 296, 303 and 310 K, respectively) indicate that OLZ-Tf complex is more stable at lower temperatures. Negative thermodynamic parameter values (enthalpy, ΔH⁰ = -168.46 kJmol^-1; entropy, ΔS⁰ = -408.63 JK^-1 mol^-1; and free energy, ΔG⁰ = -47.50 kJmol^-1) suggest an exothermic and spontaneous binding process dominated by hydrogen bonding and van der Waals forces. Structural changes in Tf upon OLZ binding confirmed by spectroscopic measurements. Results of molecular docking revealed that OLZ exhibits a stronger binding affinity for apotransferrin (Fe³⁺-free Tf) than for holo-transferrin (iron-bound Tf), with preferential interaction in the N-lobe. The effect of Fe³⁺ on OLZ-Tf interactions was examined, confirming that iron modulates the binding mechanism. Molecular dynamics (MD) simulations supported these findings, showing OLZ stabilizes Tf's structure while maintaining its flexibility for transport. These results suggest that OLZ can bind to Tf and influence OLZ's bioavailability and pharmacokinetics, offering potential implications for drug design and clinical applications in altered iron homeostasis.

Selective recognition of SO₄^2- from HPO₄^2--containing environments is highly challenging, as SO₄^2- and HPO₄^2- not only share similar structures and sizes, but also exhibit similarities in many characteristics such as charge density, acidity, and hydration energy. In this contribution, a post-modifiable trapezoidal cage (1a) was developed to address the selective recognition of SO₄^2- from HPO₄^2-, as well as to cope with the difficulties of trapezoidal cages in post-modification and property variation. Coupled with the newly explored [4 + 4] cyclization strategy, the synthesis efficiency of producing trapezoidal cages has also been greatly improved. Afterward, by taking advantage of the tetrahedrally deployed binding sites of the trapezoidal cage 1a, selective recognition of SO₄^2- from HPO₄^2- can be realized even in complex environments containing many other anions. Through NMR, fluorescence, nonlinear fitting analysis, and HRMS experiments, the binding affinity and binding stoichiometry of 1a + anion were extensively studied. The results demonstrate that 1a + SO₄^2- follows a 1:1 host-guest binding mode and exhibits a much higher binding affinity (K ~ 1.7 × 10⁸ M^-1) than HPO₄^2- (K = 2.6 × 10⁶ M^-1) or any other anions (K = 10⁴-10⁵ M^-1) in 5% methanol/chloroform. The selective recognition of SO₄^2- in complex environments including HPO₄^2- can provide valuable considerations for the precise design of receptors that can distinguish subtle structural differences in substrates, while the post-modification strategy may also help improve the synthesis and extendibility of other covalent cages.

Renin, an aspartyl protease enzyme, is a crucial part of the renin-angiotensin-aldosterone system (RAAS) that regulates blood pressure. However, numerous renin inhibitors, including Aliskiren, Zankiren, Enalkiren, Fasidotril, and Remikiren, are in the clinical arena of managing hypertension, but they are associated with numerous drawbacks. The important one includes modest efficacy in contrast to other antihypertensive agents, which reduces their use as monotherapy; secondly, the related side effects, including hyperkalemia and renal impairment. Thus, considering the unmet need to identify new renin inhibitors, we applied the drug repurposing technique on an 1880 US FDA-approved small molecules database. The research was achieved by performing the structure-based virtual screening (SBVD) on FDA-approved drugs, which was well supported by molecular docking, dynamics, and mechanics studies. This work identified Panobinostat as a possible lead renin inhibitor. The in vitro Elisa-based assay revealed Panobinostat has the potential to inhibit the renin enzyme at the half-maximal concentration (IC₅₀) of 201.27 nM, while standard renin inhibitor Aliskiren portrayed an IC₅₀ of 162.22 nM. The comparable potency to clinical renin inhibitors presents this HDAC inhibitor as a dual-functioning ligand. The findings are significant and well correlated with the plethora of evidence suggesting the role of HDACs in regulating RAAS and cardiovascular functions via the post-translational level modulation of chromatins' structures and functions.

Salicylic acid (SA) functions as a critical phytohormone coordinating developmental regulation and defense responses in plants. Understanding SA's regulatory roles in both homeostasis and stress adaptation necessitates advanced monitoring platforms. We designed six rhodamine probes (R1-R6) containing spirolactam or spirohydrazone bridges to systematically evaluate five-membered spiro structures for SA detection. Furthermore, through Fourier infrared experiments (FTIR) and density functional theory (DFT) calculations, we performed molecular orbital analysis to disclose the SA-responsive mechanism underlying the rhodamine ring-opening process induced by SA. Comparative analysis revealed that spirohydrazone-modified probes displayed enhanced fluorescence performance and improved molecular recognition specificity for SA. The optimized probe R2, incorporating a quinoline moiety, achieved exceptional sensing performance through synergistic hydrogen bonding and C-H…π interactions, demonstrating high selectivity, rapid response kinetics (< 30 s), and excellent sensitivity (LOD = 0.87 μM). Overall, this study successfully visualized endogenous SA distribution in living tomato root systems, establishing a novel design framework for acylhydrazone-based rhodamine sensors and elucidating the SA response mechanism through molecular dynamics simulations.