Molecular Diversity最新文献

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive impairment. It seriously affects the health and quality of life of the elderly. It has a complex pathogenesis including β-amyloid (Aβ) deposition, Tau protein hyperphosphorylation, cholinergic neurotransmitter deficiency, metal ion dyshomeostasis, and oxidative stress, etc. Despite intensive research, there is still a lack of effective clinical drugs to treat or control AD progression. Natural products and their derivatives exhibit multi-target anti-AD effects, together with low toxicity and affordability, have emerged as promising lead compounds for drug discovery. This review summarizes the studies on anti-AD activities of natural products bearing γ-pyranone structure and their derivatives, and further discusses their structure-activity relationships (SARs), which provided a theoretical basis for the development of effective anti-AD drugs.

A series of flavonol derivatives containing benzothiazole were designed and synthesized. The structures of all the compounds were characterized by NMR and HRMS. The results of the activity assay showed that some of the target compounds possessed outstanding in vivo antiviral activity against the tobacco mosaic virus (TMV). Among them, the median effective concentration (EC₅₀) of L20 was 90.5 and 202.2 μg/mL for curative and protective activity against TMV, respectively, which was better than that of ningnanmycin (NNM: 252.0 and 204.2 μg/mL). The results of microcalorimetric thermophoresis (MST) and molecular docking experiments indicate that L20 binds TMV-CP more strongly than NNM; density functional theory (DFT) calculation the indicating that L20 is more chemical reactivity than NNM. In addition, malondialdehyde (MDA) and superoxide dismutase assay (SOD) activity measurements also fully confirmed that L20 stimulated the plant immune system and strengthened the plant's resistance to diseases by lowering the MDA content and increasing the SOD activity. Furthermore, the chlorophyll content test experiment found that L20 could reduce the destructive effect of viruses on chloroplasts, increase the content of chlorophyll, and promote photosynthesis. In conclusion, above experimental results suggested that flavonol derivatives containing benzothiazole could be further investigated as new plant virus antiviral drugs.

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.

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.