Molecular Diversity最新文献

Xanthenone fused spiro-pyrrolidine oxindoles were conveniently synthesized in good yields with high regio- and diastereoselectivity from a multicomponent synthesis involving tetrahydroxanthenones, α-amino acids, and isatins via an azomethine ylide based [3 + 2] cycloaddition process. We utilized tetrahydroxanthenone as a dipolarophile for the first time in the [3 + 2] cycloaddition of decarboxylated azomethine ylide. The relative configuration of the spirocycloadduct was determined by single-crystal X-ray diffraction analysis.

Phosphoinositide 3-kinases (PI3Ks) phosphorylate phosphoinositides on the membrane, which act as secondary signals for various cellular processes. PI3Kα, a heterodimer of the p110α catalytic subunit and the p85α regulatory subunit, is activated by growth factor receptors or mutations. Among these mutations, E545K present in the helical domain is strongly associated with cancer, and is known to disrupt interactions between the regulatory and catalytic subunits, leading to its constitutive activation. However, while the mutation's role in disrupting autoinhibition is well documented, the molecular mechanisms linking this mutation in the helical domain to the structural changes in the kinase domain remain poorly understood. This study aims to understand the conformational events triggered by the E545K mutation, elucidate how these changes propagate from the helical domain to the kinase domain, and identify crucial residues involved in the activation process. Molecular dynamics (MD) simulations combined with Markov state modeling (MSM) were employed to explore the conformational landscapes of both the wild-type and mutant systems. Structural and energetic analyses, including Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, revealed that the E545K mutation significantly reduces the binding affinity between the regulatory and catalytic subunits. The mutation was found to induce a sliding motion of the regulatory subunit along the catalytic subunit, leading to the disruption of key salt-bridges between these domains. This disruption releases the inhibitory effect of the regulatory subunit, resulting in increased domain motion, particularly in the adaptor-binding domain (ABD). Enhanced flexibility in the ABD, helical, and C2 domains facilitates the rearrangement of the two lobes of kinase domain, thereby promoting activation. Additionally, the mutation appears to enhance PI3Kα's membrane affinity via the Ras-binding domain (RBD). Network analysis helped to identify key residues that may involve in allosteric signaling pathways, providing insights into the communication between domains. Druggable pockets in the metastable states were predicted followed by its docking with a PI3K inhibitor library. Docking studies revealed the crucial residues that may be participating in inhibitor binding. The identification of residues and regions involved in activation mechanisms using MSM helped to reveal the conformational events and the knowledge on probable allosteric pockets, which may be helpful in designing better therapeutics.

Antineoplastic drugs are becoming prevalent due to increasing cancer casualties around the globe. However, the adverse effects of these drugs are evident due to limited insight into the underlying mechanisms that result in non-specific binding and consequent off-target toxicity. The study investigates the side effects of an antineoplastic drug, Capecitabine, a prodrug converted into fluorouracil by Thymidine Phosphorylase (TP) and degrades the RNA of cancerous cells. However, its non-specific binding with Dihydropyrimidine dehydrogenase (DPD) leads to severe toxicities including leukoencephalopathy, neutropenia, neuropathy, and others. Hence, identifying natural analogs of Capecitabine with comparable attributes is crucial for minimizing its adverse effects. A thorough review of the literature revealed Capecitabine-induced toxicity. 723,878 natural compounds were screened, and drug-like mimics were identified. Their binding with TP and DPD was determined by employing molecular docking, which was validated by MD simulations evaluating conformational stability and variability. Four natural compounds showed better docking scores than the standard drug. The stability of the best hit was further validated with MD simulations. This study, hence, ushers in new perspectives on safer drug alternatives using potent natural analogs and could serve as a lead identification approach for the discovery of safer therapeutics.

This study investigates the potential of novel thiazole and hydroxybenzohydrazide derivatives as antitubercular agents. Using molecular docking and density functional theory (DFT) calculations, the binding affinities of these derivatives to the enoyl-acyl carrier protein reductase (InhA) enzyme of M. tb were assessed. InhA is crucial for the mycobacterial fatty acid synthase II (FAS-II) pathway, making it a prime target for drug development. QSAR analysis was employed to relate molecular descriptors to biological activity, and ADMET descriptors evaluated the pharmacokinetics and toxicity of the compounds. Experimental synthesis of the compounds and their characterization via IR and NMR spectroscopy confirmed their structures. DFT calculations revealed multiple conformers for each compound, with specific isomers showing enhanced stability and favorable binding interactions with InhA. These findings suggest that the synthesized derivatives have potential as new antitubercular agents, offering a basis for future drug development strategies against multidrug-resistant TB.

Herpes Simplex Virus 2 (HSV-2) infection is a global concern, affecting around 500 million individuals worldwide and being the leading cause of genital ulcers. Although several HSV vaccine candidates have been tested in humans, as of right now, neither HSV type has a licenced vaccination available. This study utilized reverse vaccinology to conduct an extensive analysis of the entire genome of HSV-2 where glycoprotein-D was chosen for T-cell epitope predictions. Through an immunoinformatic approach, we identified 2 novel CD8 + and 8 CD4 + T-cell epitopes overlapped within conformational B-cell epitopes, which hold promise as potent vaccine candidates. These epitopes were highly immunogenic and non-toxic, and also showed significant population coverage all over the world. Notably, the predicted epitopes demonstrated cross-reactivity with HSV-1, with the majority exhibiting over 80% conservation within glycoprotein-D. In addition, the designed vaccines' physicochemical properties revealed that these vaccines are non-toxic and non-allergenic, exhibited highly antigenic properties and had the potential to interact with immune receptors effectively. Furthermore, molecular docking studies with human immune receptors, specifically TLR2, demonstrated robust interactions, supported by molecular dynamics simulations indicating stable binding and dynamics. Finally, via codon optimization and in silico cloning, the vaccine candidates were successfully expressed in Escherichia coli, demonstrating feasibility for large-scale production. Computational immune response modelling following varied dosages suggested that the immunogenic constructs could elicit significant immune responses. In conclusion, this study presents promising vaccine candidates against HSV-2, utilizing a rational design approach. However, experimental validation is necessary before advancing to clinical trials.

A series of novel dual-action statin conjugates, which exhibit both triglyceride and cholesterol lowering activities, have been systematically designed, synthesized, and subjected to comprehensive pharmacological evaluation. All the target compounds were characterized by ¹HNMR, ¹³CNMR, and HRMS. Biological evaluation demonstrated that the majority of the synthesized compounds exhibited significant lipid-lowering and cholesterol-reducing activities. In particular, ligand 8a demonstrated significant potency, resulting in a marked reduction in cholesterol and triglyceride levels in a dose-dependent manner. Its minimum response has lowered 2.778 mmol/L (cholesterol level) and 0.699 mmol/L (triglycerides level), surpassing the positive control. For the preliminary assessment of the safety of the target compound, the ADMETlab 2.0 predictive software was utilized. Data show that compared to the combination of drugs used clinically, the safety of the target compounds may be improved. These findings suggest that compound 8a holds promise as a potential candidate for the treatment of hyperlipidemia.

Sparganii Rhizoma (SR) has demonstrated promising anticancer effects across various malignancies; however, its mechanisms in laryngeal cancer (LC) remain poorly understood. This study employs network pharmacology and molecular docking to investigate the molecular mechanisms underlying SR's therapeutic effects on LC, providing novel insights for its potential use in treatment. Active compounds and targets of SR were identified through the TCMSP and Pharmmapper databases, while LC-related targets were sourced from GEO, GeneCards, OMIM, and PharmGkb databases. A Venn diagram generated from these datasets highlighted 58 overlapping targets. The STRING database and Cytoscape 3.9.1 software facilitated the construction of a protein-protein interaction network for these targets, and R language analysis revealed 15 core targets. GO and KEGG enrichment analyses, conducted with the ''clusterProfiler'' package, identified relevant biological processes, cellular components, and molecular functions associated with LC treatment. KEGG analysis suggested SR primarily regulates pathways such as TNF, IL-17, and P53. Molecular docking confirmed SR's ability to bind effectively to the 15 core targets. Molecular dynamics simulations further validated stable protein-ligand interactions for MAPK1, GSK3B, and MAPK14. Core target validation across transcriptional, translational, and immune infiltration levels was performed using GEPIA, HPA, cBioPortal, and TIMER databases. In conclusion, network pharmacology, molecular docking, and dynamics simulations provided insights into SR's mechanism in LC treatment, forming a theoretical basis for further investigation of its therapeutic potential.

Novel quinoline-based derivatives 2a-e and 4a-j have been designed and synthesized as potential antiproliferative agents. The designed compounds were screened for their antiproliferative activity against sixty cell lines according to NCI protocol. The promising hybrids 4d-g are screened by MTT assays on three cancer cell lines: leukemia (MOLT-4), lung cancer (HOP-92), and breast cancer (T47D), with IC₅₀ values ranging from 4.982 ± 0.2 to 36.52 ± 1.46 µM compared to Staurosporine, with compound 4e being the most effective. Derivatives 4d-g were evaluated for their inhibitory activity on EGFR and BRAF^V600E. Compound 4e exhibited the highest inhibitory activities, with IC₅₀ values of 0.055 ± 0.002 μM for EGFR and 0.068 ± 0.003 μM for BRAF^V600E, compared to the reference drugs erlotinib (IC₅₀ 0.06 ± 0.002 μM) and vemurafenib (IC₅₀ 0.035 ± 0.001 μM), respectively. Cell cycle analysis of the HOP-92 manifested that pre-G1 apoptosis signaling took place after 4e treatment. Docking simulations were employed to analyze the modes and scores of compounds 4d-g with respect to EGFR and BRAF^V600E. The results revealed that compound 4e exhibited strong affinity for both EGFR and BRAF^V600E compared to the reference drugs with values of - 3.226 and - 3.474 kcal/mol, respectively.

Neuraminidase (NA) is an essential enzyme located at the outer layer of the influenza virus and plays a key role in the release of virions from infected cells. The rising incidence of global epidemics has made the urgent need for effective antiviral medications an urgent public health priority. Furthermore, the emergence of resistance caused by specific mutations in the influenza viral genome exacerbates the challenges of antiviral therapy. In view of this, this study aims to identify and analyse possible inhibitors of NA from different subtypes of influenza viruses. Initially, a thorough search was conducted in the Protein Data Bank (PDB) to gather structures of NA proteins that were attached with oseltamivir, a widely recognized inhibitor of NA. Here, 36 PDB entries were found with NA-oseltamivir complexes which were studied to evaluate the diversity and mutations present in various subtypes. Finally, N1(H1N1) protein was selected that demonstrated low IC50 value of oseltamivir with mutation H275Y. In addition, the study utilized BiMODAL generative model to generate 1000 novel molecules with comparable structures to oseltamivir. A QSAR model, based on machine learning (ML), was built utilizing the ChEMBL database to improve the selection process of candidate inhibitors. These inhibitors were subsequently analysed by molecular docking and further the best hits compounds (compound_375, compound_106 and compound_597) were appended to make a bigger molecule (compound_106-375, compound_106-597, and compound_375-597) to fit into the binding pocket of protein. Further, triplicate molecular dynamics simulations lasting 100 ns to assess their effectiveness and binding stability showed that compound_106-375 had the most stable binding with the protein. Key residues, including Asn146, Ala138, and Tyr155, form critical interactions with the ligand, contributing to its stability. The investigation was enhanced by employing principal component analysis (PCA), free energy landscape (FEL), and binding free energy calculations. The total binding free energy (G_TOTAL) of - 169.62 kcal/mol suggests that the contact between compound_106-375 and the mutant N1 (H1N1) protein is thermodynamically favourable. This approach allowed for a thorough comprehension of the binding interactions and possible effectiveness of the discovered inhibitors. Overall, these findings demonstrate that compound_106-375 exhibits favourable binding characteristics and stability. Further experimental validation is required to confirm its efficacy against the H275Y mutant neuraminidase protein and its potential to overcome influenza drug resistance. However, compound_106-375 is suggested as a promising candidate for further development as a therapeutic agent against the mutant N1 (H1N1) protein. This finding will assist in drug development and to overcome the challenges associated with drug resistance in influenza strains.

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.