Molecular Diversity最新文献

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.

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.

Telomerase, a reverse transcriptase implicated in replicative immortality of cancers, remains a challenging target for therapeutic intervention due to its structural complexity and the absence of clinically approved small-molecule inhibitors. In this study, we explored drug repurposing as a pragmatic approach to address this gap, leveraging FDA-approved drugs to accelerate the identification of potential telomerase inhibitors. Using a structure-based drug discovery framework, we screened the DrugBank database through a previously validated pharmacophore model for the FVYL pocket in the hTERT thumb domain, the established binding site of BIBR1532. This was followed by molecular docking, pharmacokinetic filtering, and molecular dynamics (MD) simulations to evaluate the stability of protein-ligand complexes. Binding free energy calculations (MM-PBSA and MM-GBSA) were employed for cross-validation, identifying five promising candidates. Experimental validation using the Telomerase Repeat Amplification Protocol (TRAP) assay confirmed the inhibitory potential of Raltitrexed, showing significant inhibition with IC₅₀ 8.899 µM in comparison to control. Decomposition analysis and Structure-Activity Relationship (SAR) studies further offered insights into the binding mechanism, reinforcing the utility of the FVYL pocket as a druggable site. Raltitrexed's dual mechanism of action, targeting both telomerase and thymidylate synthase, underscores its potential as a versatile anticancer agent, suitable for combination therapies or standalone treatment. As the top lead, Raltitrexed demonstrates the potential of repurposed drugs in telomerase-targeted therapies, offering a time and cost-effective strategy for advancing its clinical development. The study also provides a robust framework for future drug development, addressing challenges in targeting telomerase for anticancer therapy.

Epigenetic regulation intricately governs cellular mechanisms, including proliferation, death, differentiation, and cell cycle orchestration. One such target, Enhancer of zeste homolog 2 (EZH2), is essential for epigenetic regulation. EZH2 trimethylates histone H3 lys27 (H3K27me3), inhibiting target gene transcription and promoting chromatin condensation, thereby initiating tumorigenesis, thus a potentially plausible target to disrupt cancer progression. In this virtual screening study, we utilized two large, open-source natural product libraries, NPASS and LOTUS, to search for potential natural product scaffolds capable of EZH2 inhibition. The merged library was filtered through increasingly rigorous criteria at each stage, including Medchem-based rule filters, 2D Tanimoto similarity, sequential rounds of docking, rescoring via ML-based functions, and binding pose visualization, funneling down to the most promising candidates for further pharmacokinetics and toxicological profiles. The best hits were analyzed for their binding stability through molecular dynamics simulation and their binding free energy estimations. Exploratory chemical analysis was conducted to understand the similarity of hits with known EZH2 chemical space. This comprehensive workflow identified one potential inhibitor, LTS0131784, which exhibited favorable pharmacokinetic toxicity profiling with binding stability and free energy better than the FDA-approved EZH2 inhibitor, Tazemetostat. Furthermore, the plausible binding mechanism was also elucidated by analyzing the per residue-free decomposition of the simulated trajectories, which indicated the involvement of the LTS0131784 with the key residues TYR:111, TRP:521, CYS:560, ASN:585, and SER:561.

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.

Thirty-two tetrahydrothiopyran derivatives were synthesized, and their acaricidal activities against Psoroptes cuniculi were evaluated in vitro. The results showed that eight compounds exhibited higher acaricidal activity than ivermectin when evaluated by mass concentration, while six compounds showed superior activity when assessed by molar concentration. Compound b10 showed the lowest LC₅₀ value [62.3 µg/mL (0.12 mM)] and LT₅₀ value (2.2 h at 4.5 mM), far lower than ivermectin [LC₅₀ = 223.3 µg/mL (0.26 mM), LT₅₀ = 8.7 h]. Structure-activity relationship (SAR) analysis showed that the presence of the sulfone structure is crucial for activity, while the types and positions of substituents on the benzene rings are two main factors affecting the activity. Molecular docking results demonstrated that compounds a10, b9, b10 and b11 exhibited good affinity with the AChE protein, along with potential binding modes, suggesting AChE as a promising acaricidal drug target. Overall, these results suggest that tetrahydrothiopyran derivatives, particularly their sulfone derivatives have great potential for the development of novel acaricides.

The development of multifunctional agents has been a heated area of research for AD treatment in recent years. In this work, a series of melatonin-isatin hybrids were designed, synthesized, and evaluated as multifunctional agents for treating AD. In vitro studies indicated that most of the synthesized compounds displayed moderate to good MAO-B inhibition activities and good antioxidant activities. In particular, compounds IM-5 and IM-10 exhibited the best inhibitory activities with IC₅₀ value of 12.4 μM and 15.6 μM against MAO-B, and potent antioxidant activities with their ORAC-FL values of 4.6 and 5.2 at 5 μM, respectively. ThT assay revealed compounds IM-5 and IM-10 exhibited the optimal Aβ_1-42 self-induced aggregation inhibitory activities with the inhibition ratio of 72.8% and 69.7% at 20 μM. In addition, compounds IM-5 and IM-10 exhibited low cytotoxicities and significant neuroprotective effects on Aβ_1-42-induced and H₂O₂-induced SH-SY5Y cell injury. More importantly, compounds IM-5 and IM-10 could significantly ameliorate the memory impairment and cognition injury in scopolamine-induced mice. The SwissADME program was used to predict drug-like properties of compounds IM-5 and IM-10 which exhibited they had good pharmacokinetics and drug-likeness properties. Molecular docking study further manifested that compounds IM-5 and IM-10 showed high hMAO-B inhibitory potency. In summary, all above results revealed compounds IM-5 and IM-10 might be promising multifunctional agents for AD treatment.

Vitamin D receptor (VDR) agonists play a pivotal role in modulating immune responses and promoting melanocyte survival, making them potential candidates for vitiligo treatment. The VDR gene is integral to mediating the effects of vitamin D in the immune system, and disruptions in its structure due to missense mutations may significantly contribute to the pathogenesis of vitiligo. Missense single-nucleotide polymorphisms (SNPs) can alter the amino acid sequence of the VDR protein, potentially affecting its ligand-binding affinity and downstream signaling. Investigating these missense SNPs provides critical insights into the genetic underpinnings of vitiligo and may help identify biomarkers for early detection and precision-targeted therapies. This study explored the therapeutic potential of vitamin D analogs in vitiligo management, with a particular focus on their binding interactions and molecular efficacy. Using molecular docking and virtual screening, 24 vitamin D analogs were evaluated. Calcipotriol exhibited the highest binding affinity (-11.4 kcal/mol) and unique interactions with key residues in the VDR ligand-binding domain. Additionally, an analysis of structural variations stemming from missense mutations in the VDR gene highlighted potential impacts on receptor-ligand interactions, further emphasizing the importance of genetic factors in treatment response. These findings underscore the potential of calcipotriol to promote melanogenesis and modulate pigmentation in vitiligo. A comparative analysis identified structural variations influencing the efficacy of other analogs, such as calcitriol and tacalcitol. Although the in silico methods provided valuable insights, the study acknowledges the limitations of excluding dynamic cellular environments and emphasizes the need for experimental validation. Overall, this study enhances our understanding of VDR-targeted therapies, and calcipotriol is a promising candidate for further development in the management of vitiligo.

In previous studies, we discovered YZD-7082B, a selective estrogen receptor degrader (SERD) with excellent comprehensive properties. Here, we reported the development of an efficient multigram-scale synthetic process for YZD-7082 in 13 steps. The route featured a chiral resolution of a thiochroman intermediate with a unique cis-1,2-diaryl motif using a chiral amine and a mild reduction of amide using ZnEt₂/LiCl/(EtO)₃SiH system. This approach also overcomes the issues of high loadings of palladium catalysts and long reaction time. The developed process provided YZD-7082B with an HPLC purity of > 99.8% and ee of > 99%.