Molecular Diversity最新文献

The urgent global health threat of antimicrobial resistance demands innovative therapeutic strategies. Herein, we report the design, synthesis, and biological evaluation (antibacterial and antifungal activities) of two series of alkynyl-linked aminoguanidine derivatives. A critical structure-activity relationship (SAR) was revealed: the exposure of the aminoguanidine group is paramount for activity. In vitro antibacterial and antifungal activities revealed that the imidazol-2-hydrazine series exhibited inhibition against both Gram-positive and Gram-negative bacteria, with minimum inhibitory concentration (MIC) ranging from 2 to 64 μg/mL. Among them, compound IIh exhibited a MIC of 2 μg/mL against both S. aureus CMCC 25923 and Enterococcus faecalis CMCC 29212, and also demonstrated significant antifungal activity against Candida albicans SC5314 with a MIC of 2 μg/mL. Time-kill kinetics established the rapid bactericidal nature of IIh, achieving complete eradication of E. coli and S. aureus within 1-2 h. Furthermore, IIh significantly inhibited biofilm formation and compromised bacterial membrane integrity, leading to the leakage of cytoplasmic proteins and nucleic acids. Checkerboard assays revealed a synergistic relationship between IIh and conventional antibiotics, reducing their effective MICs. As a promising candidate for combating resistant infections, IIh deserves further efficacy and safety studies.

Breast cancer, a major global health challenge, is driven by aberrant receptor tyrosine kinase (RTK) signaling via epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). This study employs a "Dynamic Scapping" workflow, integrating molecular docking, 500 ns molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations to identify natural products with potential for dual binding to EGFR (PDB: 1M17) and VEGFR (PDB: 3VHE). From ~ 20,000 natural products, virtual screening shortlisted 13 EGFR and 12 VEGFR hits, with Digitonin, Cyclamin, Vicenin-2, Glucosylorientin, and Nicotiflorin selected for EGFR, and Quercetagetin, Silychristin, Quercetin, Scutellarein, and Isorhamnetin for VEGFR, alongside references (Erlotinib, Pyrrolopyrimidine). MD simulations, conducted as single trajectories per system, revealed stable complexes (RMSD: 1.73-2.92 Å), with Digitonin, Cyclamin, and Silychristin showing binding energies (ΔG_bind: - 84.29, - 81.47, - 63.33 kcal/mol) compared to references (Erlotinib: - 43.32 kcal/mol and Pyrrolopyrimidine: - 61.63 kcal/mol). Dynamic analyses (DCCM, PCA) indicated restricted motions, while per-residue decomposition highlighted interactions with Met769 (EGFR) and Cys919 (VEGFR). The MM/GBSA calculations excluded the entropy term, potentially affecting absolute binding energies but supporting relative ranking. These computational findings suggest Digitonin, Cyclamin, and Silychristin as candidates with the potential for dual binding to EGFR and VEGFR, addressing the need for accessible treatments globally and in regions like South Africa with high incidence rates. Experimental validation is essential to confirm their functional dual modulation and inhibitory potency for breast cancer therapy.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with current therapies often limited by toxicity and resistance. Natural compounds like canthaxanthin, a carotenoid with demonstrated anticancer properties, offer a promising alternative. This study investigates canthaxanthin's therapeutic potential in NSCLC through an integrated computational and experimental approach. Network pharmacology identified 34 shared targets between canthaxanthin and NSCLC, with EGFR, SRC, and CASP3 emerging as key hubs. Molecular docking revealed strong binding affinities (- 9.0, - 7.6, and - 8.0 kcal/mol, respectively), supported by 200-ns molecular dynamics simulations demonstrating complex stability. ADMET analysis predicted favourable pharmacokinetics and low toxicity (Class 6). In-vitro validation via MTT assay showed selective cytotoxicity against A549 cells (IC₅₀ = 23.66 µg/mL) compared to normal lung cells (HEL 299; IC₅₀ = 57.77 µg/mL), outperforming 5-fluorouracil in selectivity (SI = 2.64 vs. 2.23). Pathway enrichment implicated cancer-related signaling (PI3K-AKT, MAPK) and apoptosis. Canthaxanthin's multi-target action-inhibiting EGFR proliferation, SRC migration, and activating CASP3-mediated apoptosis-suggests a polypharmacological advantage. Computational predictions aligned with experimental results, confirming dose-dependent cytotoxicity and minimal mutagenic risk. Canthaxanthin exhibits potent, selective anti-NSCLC activity through multi-target modulation, supported by robust binding stability and low toxicity. These findings highlight its potential as an adjunct or alternative therapy, particularly for resistant NSCLC. Future studies should explore in-vivo efficacy, combination regimens, and clinical translation.

Lymphatic filariasis (LF) is a mosquito-transmitted parasitic disease, which is a main concern in tropical and subtropical countries. LF is the second major cause of chronic and irreversible disabilities worldwide, which include lymphoedema, hydrocele, and elephantiasis. According to the World Health Organization (WHO), an estimated 882 million individuals across 44 countries were reported to be at risk of acquiring LF. The nematode Wuchereria bancrofti is the predominant pathogen which causes LF, accounting for approximately 90% of filarial infections. The drugs albendazole (ALB), ivermectin (IVM), and diethylcarbamazine (DEC) are currently used to treat LF, but they are not effective against microfilariae and are known to have an inability to reverse chronic conditions, produce adverse reactions, and have developed drug resistance due to prolonged use. Further scientific studies are necessary to discover and characterize potential drug targets in the genome of W. bancrofti, which would facilitate the development of novel therapeutic approaches. This study employs a subtractive genomics approach to identify potential anti-filarial drug targets from the genome of W. bancrofti. Our analysis revealed 12 targets of W. bancrofti, which were found to be involved in important metabolic pathways such as combating oxidative stress, amino acid and nucleotide metabolism, folate biosynthesis, and DNA repair. This article highlights the proposed drug targets and their potential role in the development of effective drugs against W. bancrofti. We also propose beta-1,4-mannosyltransferase (WbEGH), one among the 12 identified targets, as a priority target based on its sequence similarity with human proteins. Further, structure-based virtual screening identified five potent phytochemicals (IMPPAT ID: 9,896,047, 49,777,225, 13,888,122, 89,483-03-4, and 14,605,093) having a better affinity with WbEGH. Furthermore, experimental validation of these identified phytochemicals would lead towards an effective method for controlling Lymphatic Filariasis.

Ischemic stroke is a leading cause of mortality and long-term disability worldwide, primarily driven by neuroinflammatory damage. Prostaglandin-endoperoxide synthase 2 (PTGS2), which encodes the cyclooxygenase-2 (COX-2) enzyme, plays a central role in mediating inflammatory pathways, making it a key therapeutic target in ischemic stroke. This study presents a comprehensive analysis aimed at identifying potential PTGS2 inhibitors for mitigating neuroinflammatory damage in ischemic stroke. Gene expression profiling of the GSE16561 dataset, comprising control and stroke patient samples, revealed 329 differentially expressed genes (DEGs), including PTGS2 and ZFHX3, central to neuroinflammatory and vascular remodeling pathways. Modular co-expression analysis identified distinct gene clusters associated with oxidative stress, apoptosis, and blood-brain barrier dysfunction, providing insights into molecular mechanisms underlying stroke pathology. To complement gene-level analysis, molecular clustering and feature correlation studies were performed on a dataset of compounds using PubChem and substructure descriptors. Hierarchical clustering revealed four molecular clusters, with Cluster 2 compounds (CHEMBL44468 and CHEMBL462709) showing unique features like sulfur-containing and bridged-ring systems. These descriptors were validated as contributors to molecular differentiation through t-SNE visualization and heatmap analysis. Molecular docking, dynamics, and MM-GBSA studies further highlighted the strong binding affinities of these compounds to the PTGS2 active site, supporting their potential to modulate inflammatory pathways implicated in stroke. This integrative approach, combining gene expression analysis, molecular clustering, and docking studies, underscores the potential of Cluster 2 compounds as promising candidates. This study provides a framework for advancing ischemic stroke therapeutics and targeted anti-inflammatory drug development by bridging transcriptomic insights with structural studies.

Interleukin-23 (IL-23) is a key driver of chronic inflammatory diseases, yet current therapies rely on costly monoclonal antibodies. This study aims to identify small-molecule IL-23 inhibitors using an in silico approach that mimics antibody interactions. The structure of IL-23 and the monoclonal antibody Risankizumab was reconstructed using homology modeling and deep learning. Key binding sites were characterized and used to generate 3D pharmacophore models, which guided virtual screening of compounds from DrugBank and ZINC12 databases. Top candidates were evaluated via ADMET filtering, molecular docking, molecular dynamics simulations and MM/GBSA binding free energy calculations. ZINC20572287 (r3-7) demonstrated stable binding within the IL-23p19 pocket and maintained strong hydrogen bonding over a 600 ns simulation. In contrast, no potent IL-12p40 inhibitors were identified. These findings suggest r3-7 as a promising scaffold for developing cost-effective IL-23-targeted therapeutics.

Obesity-induced insulin resistance impairs glucose tolerance and β-cell function, significantly contributing to the pathogenesis of type 2 diabetes (T2D). Protein kinase A (PKA), being one of the key effector molecules of the cyclic AMP (cAMP) pathway, increases insulin secretion via membrane activity, gene expression, and exocytosis of insulin granules. The previous studies were limited to either target cAMP analogs as PKA agonist or mostly flavonoids using In vivo and In vitro studies (Hameed in Int J Biol Macromol 119:149-156, 2018;Shahab in Biomed Pharmacother 177, 2024;Hameed in Eur J Pharmacol 820:245-255, 2018;Hameed in Eur J Pharmacol 858, 2019;Hafizur in Med Chem Res 27:1408-1418, 2018;). To speed up the process, this study aimed to identify potential PKA activators as therapeutic agents for restoring β-cell function in Type 2 Diabetes (T2D) using a multistage virtual screening approach. In the initial phase, a ligand-based pharmacophore model was constructed to screen an in-house small molecule database for potential PKA agonists. By targeting the essential pharmacophoric features necessary for interaction with the cyclic nucleotide-binding (CNB) domain of PKA, the goal was to identify compounds with strong binding affinities and therapeutic promise. To gain deeper insights into the molecular mechanisms of PKA activation and evaluate key interactions and dynamic stability, a subset of promising hits was subjected to all-atom molecular dynamics simulations. Simulations showed significant conformational changes in PKA complexes, with average backbone root mean square deviations (RMSD) of 0.37 ± 0.15 nm for Comp-03, 0.53 ± 0.18 nm for Comp-11, 0.31 ± 0.06 nm for Comp-17, 0.28 ± 0.03 nm for Comp-38, and 0.48 ± 0.13 nm for Comp-41. The N3A motif showed consistent fluctuations, suggesting increased flexibility. Binding free energy calculations showed binding free energies (ΔGbind) for cAMP, Comp-03, Comp-17, Comp-38, and Comp-41, with ΔGbind values of - 62.87 ± 10.04, - 68.57 ± 12.77, - 78.13 ± 16.36, - 62.67 ± 13.06, and - 80.87 ± 10.45 kcal/mol, respectively. To further probe the conformational stability of these complexes, multidimensional scaling and free energy profiling were carried out. This exhaustive research study, involving examination of stability dynamics, deviation patterns, interaction networks, conformational changes, and energy profiles, provides profound understanding about mechanisms that activate PKA. The findings highlight several promising lead compounds, notably Comp-03, Comp-17, Comp-38, and Comp-41, which exhibit superior potential to activate PKA compared to cAMP. These findings lay a strong foundation for the development of novel PKA activators as potential therapeutic agents for managing T2D.

CDK2 inhibition is a promising breast cancer treatment. Purines target CDK2 and are effective against breast cancer, proving a therapeutic scaffold. New purine-based compounds, 5a-5j were synthesized using chloro-amine coupling and phenacylation in a two-step procedure, characterized, and tested for anticancer activity. The highest yield (82%), without column purification or a costly catalyst like Pd/Cu, was achieved with concentrated HCl. The synthesis and site-selective substitution at the purine ring's C-2 position were confirmed by ¹H NMR, ¹³C NMR, IR, MS, and HMBC spectroscopy. In the NCI-60 study, compounds 5e and 5f inhibited growth of MDA-MB-231 cells by 93% and 91%, respectively. In addition, compound 5f exhibited higher cytotoxicity against MDA-MB-231 and MDA-MB-468, with IC_50s of 0.19 and 0.72 µM, respectively (triple-negative breast cancer). Furthermore, 5f demonstrated higher selective cytotoxicity against MDA-MB-231 and MDA-MB-468 than the Vero (non-cancerous) cell line, with selectivity indexes of 460.63 and 121.55, respectively. Compared to the reference (IC₅₀ = 0.79 µM), 5f demonstrated a greater affinity against CDK2 with a lower IC₅₀ of 0.47 µM, confirming its anticancer potential. Moreover, higher docking score of 5f than standard shows that the purine derivative acted via inhibition of CDK2.

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains a critical global health challenge due to rising drug resistance and the pathogen's ability to persist in hostile host environments. Identifying novel molecular targets that underlie Mtb's unique survival mechanisms is essential for developing more effective therapies. In this study, we developed an integrative computational pipeline combining genome-scale metabolic modeling, flux balance analysis (FBA), comparative genomics, and network-based prioritization to uncover metabolic vulnerabilities specific to Mtb. Comparative analysis with the reductively evolved Mycobacterium leprae revealed significant differences in pathways involved in pantothenate biosynthesis (PanB), peptidoglycan synthesis (GlmU), and branched-chain amino acid metabolism (IlvN). These targets were prioritized based on gene essentiality, dormancy-associated expression, druggability, and absence of human homologs to maximize therapeutic selectivity. Molecular docking, followed by MM-GBSA binding free energy calculations, identified high-affinity ligands from LifeChemicals and ChEMBL libraries interacting strongly with active-site residues. Molecular dynamics simulations were performed to further validate target engagement and ligand retention, revealing stable conformational behavior and persistent protein-ligand interactions across 300 ns. Similarly, metabolite flux analysis and pathway enrichment highlighted adaptive rewiring in glycine, serine, pyruvate, and nitrogen metabolism, reflecting Mtb's persistence strategies under host-imposed stress. This study provides a robust, generalizable pipeline for pathogen-specific drug target and ligand discovery and supports the rational development of new therapies against drug-resistant tuberculosis.

Monkeypox (Mpox), an emerging global health threat, necessitates the development of effective antiviral agents. In our study, we selected the Mpox virus methyltransferase VP39 (MTase) protein due to its role in viral replication and immune evasion. The MTase protein is essential in Mpox and is associated with similar replication mechanisms in other viruses like COVID-19, making it a broad-spectrum target for antiviral therapy. We screened the ZINC20 in-stock compounds against the MTase protein, utilizing molecular docking, accompanied by pharmacokinetic analysis to assess their binding affinity and drug-like properties, and conducted molecular dynamic simulations to observe the stability and conformational changes of the protein-ligand complexes over time. The docking results revealed that the highest binding energy was exhibited by ZINC257233856, with a value of - 7.68 kcal/mol, indicating a strong interaction with the MTase protein followed by the other compounds. All the compounds selected for the study showed consistently acceptable safety profiles. Molecular dynamics simulations demonstrated that the selected compounds, specifically ZINC257233856, showed significant stability within the MTase binding pocket. Additionally, solvation thermodynamics were investigated using Grid Inhomogeneous Solvation Theory (GIST), revealing key hydration patterns and thermodynamic hotspots that further support the binding stability of top-ranked inhibitors. Thus, our study demonstrates the promising potential of selected compounds as therapeutic options against Mpox. Our findings lay a foundational basis for further clinical investigation and the development of effective treatments.