Molecular Diversity最新文献

Breast cancer is one of the leading reasons of mortality due to cancer globally. Estrogen receptor-positive (ER +) breast cancer being a significant subtype. The therapeutic potential of Vitamin D₃ in cancer treatment has gained attention due to its ability to modulate key molecular targets and signaling pathways. This study investigates the anticancer mechanisms of Vitamin D₃ in MCF-7 breast cancer cells using network pharmacology and omics technology approach. Utilizing protein-protein interaction (PPI) networks, we identified several critical protein targets involved in breast cancer progression, including ESR1, ESR2, PGR, IGF1R, and KDR. Pathway enrichment analyses highlighted Vitamin D₃'s impact on pivotal signaling pathways such as the PI3K/Akt pathway, estrogen receptor signaling, and apoptosis regulation. In vitro studies showed that Vitamin D₃ significantly inhibited cell proliferation in MCF-7 cells. It also induced apoptosis and disrupted mitochondrial function. Flow cytometry analysis demonstrated a dose-dependent increase in apoptotic cell death and S-phase cell cycle arrest. Confocal imaging and mitochondrial membrane potential assays further supported the findings, indicating mitochondrial dysfunction and chromatin condensation. Additionally, gene expression analysis in breast invasive carcinoma tissues confirmed the relevance of ESR1 and PGR in hormone receptor-positive breast cancer. Histopathological studies on DMBA-induced mammary carcinoma revealed Vitamin D₃'s protective effects, reducing tumor malignancy severity through anti-proliferative and pro-apoptotic actions. These findings provide strong evidence for Vitamin D₃'s potential as a multi-targeted therapeutic agent in breast cancer, suggesting further investigation into its clinical applications and combination strategies with existing therapies as an adjunct or alternative in the treatment.

Staphylococcus aureus is an opportunistic microorganism which can cause minor skin infections and also serious diseases, and its increasing antibiotic resistance necessitates further discovery of new targets and inhibitors for antibacterials. The transmembrane protein LcpA_SA that plays an essential role in the synthesis of cell wall in S. aureus has been identified as a potential drug target. In this study, we performed virtual screening of chemical compound libraries to establish their binding with target protein and molecular docking among other studies which led to identification of hit compounds with good binding affinity towards LcpA_SA domain and involvement of key amino acid residues in the intermolecular interactions. All molecules showed satisfactory drug-likeness properties such as ADME and non-carcinogenicity. 500 ns molecular dynamics (MD) simulations using Amber18 was performed on all molecular systems to explain the mechanism of LcpA_SA extracellular domain function and reveal potential hit molecules to bind the enzyme. Based on the post-MD data analysis; such as RMSD, RMSF, SASA, intermolecular hydrogen bonds, clustering analysis, anisotropic network model-based normal mode analysis and mechanical stiffness, and essential dynamics seven molecules were finally selected as hit compounds to bind LcpA_SA. Steered MD was employed to study the unbinding of the hit molecules.

Given the prevalence and significance of flavanones, we present a regio- and chemoselective approach for the synthesis of flavanone isosteres. This method is facilitated by the synergistic effects of hydrogen bonding and solvent interactions. Notably, this novel multicomponent reaction employs commercially available starting materials, operates without the need for catalysts, and achieves high levels of regio- and chemoselectivity under mild conditions. The protocol exhibits excellent tolerance for complex substrates, including those derived from Linagliptin and Cholesterol. Furthermore, this robust synthetic method not only surpasses the limitations of traditional approaches but also aligns with the principles of green chemistry.

Acetylcholinesterase inhibitors (AChEIs) are essential in the treatment of neurodegenerative disorders like Alzheimer's disease, as they prevent the breakdown of acetylcholine, thereby enhancing cognitive function. This review provides a comprehensive analysis of the structural motifs and mechanisms governing AChEI pharmacological activity, with a focus on medicinal chemistry strategies to enhance potency, selectivity, and pharmacokinetic properties. Beginning with the physiological role of acetylcholinesterase in neurological disorders, the review explores the historical evolution of AChEIs and highlights key structural interactions with catalytic, peripheral anionic, and allosteric binding sites. Advances in computational modeling, virtual screening, and structure-based drug design are discussed, alongside emerging approaches, such as multi-target-directed ligands and prodrugs. Additionally, the significance of natural products and drug repurposing in identifying novel AChEI scaffolds is emphasized, contributing to chemical diversity and innovation in drug discovery. By integrating computational tools, expansive chemical libraries, and innovative design strategies, this review identifies promising directions for developing effective AChEIs. These advancements hold great potential in addressing the multifaceted nature of neurodegenerative diseases and improving therapeutic interventions.

Cancer cells can hijack receptor-interacting protein kinase 1 (RIPK1) and exploit its scaffolding function to orchestrate pro-survival signaling and fuel immunosuppressive program. Accordingly, targeting RIPK1 for elimination has emerged as a promising anti-cancer strategy. Based on the RIPK1 inhibitor 4 previously reported by our group, we employed proteolysis targeting chimera (PROTAC) technology and designed a series of RIPK1 degraders. Structure-activity relationship (SAR) study revealed three types of ligands for E3 ligase - cereblon (CRBN), von Hippel-Lindau (VHL) and inhibitor of apoptosis protein (IAP) - demonstrated varied efficacy in RIPK1 degradation of human and mouse cells. The VHL-based compound 18 exhibited potent RIPK1 degradation activity in both human and mouse cellular scenarios. Further biological evaluation confirmed that compound 18 potently induced RIPK1 degradation of I2.1 cells with a DC₅₀ value of 274.4 nM and maintained long-term and dramatic RIPK1 degradation within 72 h. This study provided important insights into future development of RIPK1-PORTACs, and compound 18 was a promising RIPK1 degrader candidate.

HER2-positive breast cancer remains a significant clinical challenge, often exhibiting resistance to standard therapies. This study applies a comprehensive in silico approach to identify the natural compounds with potential inhibitory effects on HER2, focusing on pharmacophore modeling, virtual screening, molecular dynamics (MD) simulations, and binding affinity estimation. Initially, 24 known HER2 inhibitors from the BindingDB database were analyzed using Schrödinger's Phase module to generate a pharmacophore model, highlighting one hydrophobic (H) and three aromatic rings (RRR) features essential for HER2 binding. Screening against the Coconut Database, comprising 406,076 natural compounds, yielded 60,581 hits that matched the HRRR pharmacophore. These hits underwent a rigorous docking workflow with Glide (HTVS, SP, and XP modes), narrowing the candidates to 757 compounds with high binding affinity. Further refinement using Lipinski's rule of five produced a final set of 12 compounds exhibiting drug-like properties. 500-ns MD simulations evaluated these complexes' stability and dynamic behavior, while MM-GBSA calculations confirmed strong binding affinities dominated by van der Waals and electrostatic interactions. Compounds CNP0116178, CNP0356942, and CNP0136985 demonstrated superior binding profiles compared to the reference, marking them as lead candidates for HER2 inhibition. This study underscores the efficacy of computational methods in early-stage drug discovery and highlights promising candidates for further experimental validation and optimization. These findings offer a basis for developing targeted HER2 therapies and demonstrate the potential of natural compounds in advancing breast cancer treatment.

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.

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.

Multidrug resistance (MDR) presents a major challenge for effectiveness of chemotherapy. This study investigates the effectiveness of spiroindoline quinazolinediones in reversing MDR mediated by P-glycoprotein (P-gp) overexpression in cancer cells. A series of synthesized hybrid spiro[indoline-3,2'-quinazoline]-2,4'(3'H)-dione derivatives (compounds 5a-5l) were analyzed for their ability to enhance rhodamine 123 (Rhd123) accumulation in the MES-SA/DX5 cell line using flow cytometry. The MTT assay was also employed to evaluate the compounds' effectiveness in reversing drug resistance. Additionally, docking studies and molecular dynamics simulations were conducted to investigate the interaction of these compounds with the P-gp transporter. The Rhd123 accumulation assay in MDR cancer cells revealed that most compounds, in particular 5f, 5g, 5h, 5i, 5j, 5k, and 5l, exhibited significant potential as P-gp inhibitors. Among the tested derivatives, compounds 5g and 5l demonstrated the best effects, and increased Rhd123 accumulation up to 12.9 times compared to untreated cells. Additionally, compounds 5f through 5 l bearing methylbenzyl (5f), benzyl (5g), pentyl (5 ), p-bromobenzyl (5i), p-chlorobenzyl (5j), dichlorobenzyl (5k), and tert-butylbenzyl (5l) substituents on the isatin ring effectively restored sensitivity to doxorubicin at their non-toxic concentrations in resistant MES-SA/DX5 cells. Among these, compound 5l at 5 μM exhibited the highest inhibitory potential, and lowered doxorubicin's IC₅₀ value 10.1 times compared to control. Moreover, in silico investigation identified the potential interactions of test compounds with critical residues of P-gp involved in its efflux function. Our study suggests that the synthesized spiroindoline quinazolinediones may have high potentials as agents capable of reversing MDR in cancer cells.

The dysregulation of the cell cycle in cancer underscores the therapeutic potential of targeting WEE1 kinase, a key regulator of the G2/M checkpoint. This study harnessed artificial intelligence (AI)-driven methodologies, particularly the MORLD platform, to identify novel WEE1 inhibitors. Starting with clinically validated WEE1 inhibitors as references, we generated 20,000 structurally diverse compounds optimized for binding affinity, synthetic accessibility, and drug-likeness. A rigorous cheminformatics pipeline-comprising PAINS filtering, physicochemical property assessments, and molecular fingerprinting-refined this library to 242 promising candidates. Dimensionality reduction using UMAP and clustering via K-means enabled the prioritization of structurally unique leads. Molecular docking studies highlighted two compounds, MORLD5036 and MORLD6305, with exceptional binding affinities and interactions with key WEE1 active site residues. Molecular dynamics simulations and MM-GBSA binding free energy calculations further validated MORLD5036 as the most stable and potent inhibitor. Scaffold analysis revealed novel chemotypes distinct from existing inhibitors, enhancing potential for intellectual property. Comprehensive ADME profiling confirmed favorable pharmacokinetics, while synthetic accessibility evaluations indicated practicality for experimental validation. The identified lead compound, MORLD5036, exhibits favorable pharmacokinetics and novel chemotypes, positioning it as a potential therapeutic candidate for cancers reliant on WEE1-mediated cell cycle control. This integrated, AI-driven pipeline expedites the identification of next-generation WEE1 inhibitors, paving the way for advancements in precision oncology. Unlike traditional methods reliant on pre-existing datasets, this study leverages MORLD's reinforcement learning framework to autonomously generate inhibitors, enabling exploration of uncharted chemical space. These findings establish MORLD5036 as a computationally promising WEE1 inhibitor candidate warranting further experimental validation.