Tyrosinase, a metalloenzyme containing a dicopper cofactor, plays a central role in synthesizing melanin from tyrosine. Many studies have aimed to identify small-molecule inhibitors of tyrosinase for pharmaceutical, cosmetic, and agricultural purposes. In this study, we report that hydroxamic acid is a potent metal-binding group for interacting with dicopper atoms, thereby inhibiting tyrosinase. Hydroxamate-containing molecules, including anticancer drugs targeting histone deacetylase, vorinostat and panobinostat, significantly inhibited mushroom tyrosinase, with inhibitory constants in the submicromolar range. Of the tested molecules, benzohydroxamic acid was the most potent. Its inhibitory constant of 7 nM indicates that benzohydroxamic acid is one of the most potent tyrosinase inhibitors. Results from differential scanning fluorimetry revealed that direct binding mediates inhibition. The enzyme kinetics were studied to assess the inhibitory mechanism of the hydroxamate-containing molecules. Experiments with B16F10 cell lysates confirmed that the new inhibitors are inhibitory against mammalian tyrosinase. Docking simulation data revealed intermolecular contacts between hydroxamate-containing molecules and tyrosinase.

Background/Objectives: Propranolol HCl (PPH), a nonselective beta-adrenergic receptor blocker, is employed as an anti-hypertensive, anti-anginal, anti-arrhythmic, and anti-migraine agent. Given its utility in chronic conditions, developing a sustained-release dosage form becomes imperative to optimize therapeutic outcomes while enhancing patient adherence and minimizing side effects. In this study, we employed a widely adopted matrix-based system to develop PPH sustained-release (PPH-SR) matrix tablets, ensuring the uniform dispersion of the drug within the polymeric matrix to regulate its release rate. Methods: Utilizing cellulose-based polymers, specifically HPMC K100M and ethyl cellulose (EC), as matrix formers, nine different formulations were prepared at varying drug-to-polymer ratios. We employed a wet granulation method, followed by compression of the dried granules, to fabricate round-shaped biconvex PPH-SR tablets. Results: Among these different formulations, formulation 2 (F2), comprising 40 mg PPH and 50 mg HPMC K100M (along with other excipients), showed excellent flowability, as evidenced by Carr’s index and angle of repose values of 12.50 and 28.50, respectively. Additionally, the mechanical properties of F2 tablets showed a hardness of 12.34 ± 0.91 KP, an average weight of 200.45 ± 1.87 mg, with a friability of 0.20%, and a content uniformity of 98.36%. Moreover, in vitro release characteristics of F2 tablets demonstrated a sustained-release behavior, with 94.3 ± 10.2% drug release over 24 h. A comparative analysis with marketed tablets yielded similarity and dissimilarity factors of 64 and 8, respectively. Furthermore, the release profile of F2 exhibited a high degree of linearity with the Korsmeyer–Peppas model (R² of 0.977), showcasing its reliability and predictability. Conclusions: In essence, this in-house developed PPH sustained-release formulation can improve patient adherence, reduce side effects, and improve therapeutic outcomes. These results align with our objective of enhancing the therapeutic efficacy of PPH and affirm the broader relevance of innovative formulation strategies in addressing the challenges of chronic disease management.

The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42‐residue form of the amyloid‐β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability. Extracted cholesterol interacts with Aβ42 and accelerates its on‐membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates Aβ42 aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes resulted in three major AD‐related events. First, free cholesterol catalyzes the assembly of Aβ42 in aggregates, which is the mechanism by which physiologically important Aβ42 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane‐bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD. image

Diabetes mellitus (DM) is a metabolic disorder characterized by persistent hyperglycemia, which results from either insufficient insulin production by pancreatic β-cells (Type I diabetes) or impaired cellular insulin responsiveness (Type II diabetes). This study aimed to qualitatively and quantitatively assess the phytochemical constituents, antioxidant potential, and both in vitro and in vivo hypoglycemic effects of specific parts of four medicinal plants, employing solvents of differing polarity; ethanol and water. The selected species included Artocarpus heterophyllus Lam., Dendrocalamus hamiltoni, Fagopyrum megacarpum H. Hara., and Urtica parviflora Roxb. Results indicated that A. heterophyllus and F. megacarpum exhibited superior total phenolic content (TPC) and total flavonoid content (TFC), correlating with significant free radical scavenging activity. In vitro analysis revealed potent α-amylase inhibitory activity of the ethanolic and aqueous extracts of F. megacarpum, with half-maximal inhibitory concentrations (IC50) of 0.136 mg/ml and 0.168 mg/ml, respectively. These findings suggest that the bioactivity of these extracts, particularly those of F. megacarpum, may be largely ascribed to their rich phenolic profiles, which confer both antioxidant and hypoglycemic properties. Given that diabetes management primarily focuses on hyperglycemia control, the concurrent mitigation of oxidative stress induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS) is critical in preserving β-cell function and limiting disease progression. Thus, the present study demonstrates that plant-derived antioxidants with robust free radical scavenging activity can also serve as effective hypoglycemic agents. Moreover, the potent α-amylase inhibition observed in F. megacarpum extracts may be mediated through both antioxidant-dependent and other mechanistic pathways, underscoring their potential as natural therapeutic agents for diabetes management. Further research, including the isolation and characterization of bioactive compounds and molecular docking analyses, is warranted to develop efficacious plant-based antidiabetic therapeutics.

The structures predicted by AlphaFold can provide unprecedented opportunities for docking screens; however, experimentally validated examples of using the apo-form are limited. This study reports novel chemotype inhibitors targeting the leucine-rich repeat kinase 2 (LRRK2) kinase domain through a docking screen using one of the ensemble structures starting from the template deposited by AlphaFold2. The MODELLER software generated the ensemble. The conformer that showed the best early enrichment of true positives with the mixture of known ligands and their property-matched decoys was selected. The docking screen against approximately 1.3 million small molecules and enzyme-based assays with the LRRK2 kinase domain followed. We selected 17 molecules, excluding those similar to all known kinase inhibitors. Combined with analogs-by-catalog, ten new small molecules with Ki values below 15 μM were discovered, including one sub-μM inhibitor. To test selectivity, enzyme assays with a mutant and six additional kinases, including known off-targets of existing LRRK2 inhibitors, were performed using three inhibitors. The data suggest that the novelty in chemical structure may be insufficient for providing selectivity. Our approach is generally applicable to cases where information on known binders is available but experimental structure is not.