Parkinson’s disease (PD) is linked to α-synuclein (aS) aggregation and deposition of amyloid in the substantia nigra region of the brain tissues. Recent reports suggested that oligomeric assembly structure could be neurotoxic to neuronal cells. In the current investigation we produced two distinct classes of aS oligomers and link the protein conformation state and stability to neuronal cell toxicity. Natural oligomers (NO) enriched with alpha-helical folds are produced in storage of aS at below −20°C for 7 days. Induced oligomer (IO), often observed in the aggregation pathway of aS were made incubating the protein solution at 37°C. Natural oligomers remained stable and did not transform into β-sheet rich amyloid fiber and exhibited higher toxicity (80% cell death) compared to induced oligomers. Natural oligomers were ovular shape and the size ranged between 4-5.5 nm. It maintained significant number (∼ 60%) of residues in α-helical conformational space. However, initiation of hydrophobic zipping with beta sheet conformation was evidenced in induced oligomer (IO) and a lesser number residues (45%) remained with preference to α-helical secondary structure. Hydrophobic collapse leads the transformation of IO into thermodynamically most stable β-sheet rich amyloid fibril. Molten globule like secondary structure stabilized by H-bonding in natural oligomers caused enhanced stability and cellular toxicity compared to induced oligomer. Thus off-pathway/natural oligomers could be plausible reason of neuronal cell death and possible cause of Parkinson’s disease.

Scalp itch and beard irritation are multifactorial neurocutaneous disorders associated with microbial dysbiosis, impaired skin barrier function, inflammation, and activation of the transient receptor potential vanilloid 1 (TRPV1) ion channel, a key mediator of itch signalling and neurogenic inflammation. Although conventional therapies such as ketoconazole, zinc pyrithione, and hydrocortisone provide symptomatic relief, their long-term use is limited by adverse effects, irritation, and regulatory concerns, highlighting the need for safer steroid-free alternatives. In the present study, the molecular mechanism underlying the antipruritic potential of FERMENZA, a natural postbiotic formulation, was investigated using an integrated computational approach. LC-MS metabolite profiling identified major phytochemicals, which were subjected to molecular docking against the TRPV1 vanilloid-binding pocket, followed by 40 ns molecular dynamics simulations in a POPC lipid bilayer under physiological conditions. Among the identified metabolites, rutin exhibited the highest binding affinity (-12.76 kcal mol^-1), followed by ellagic acid (-11.83 kcal mol^-1), outperforming the reference antagonist capsazepine (-8.96 kcal mol^-1) as well as hydrocortisone (-8.06 kcal mol^-1), ketoconazole (-6.56 kcal mol^-1), and zinc pyrithione (-6.06 kcal mol^-1). Both phytochemicals formed stable hydrogen bonds and hydrophobic interactions with key residues in the TRPV1 binding pocket. Molecular dynamics simulations confirmed stable protein-ligand complexes without ligand dissociation throughout the simulation. Rutin showed the highest structural stability, reflected by the lowest backbone RMSD (3.72 ± 0.37 Å), stable radius of gyration, minimal solvent-accessible surface area fluctuations, and negligible perturbation of the surrounding POPC membrane. Overall, the findings identify rutin, followed by ellagic acid, as promising natural TRPV1 modulators and provide a molecular basis for the antipruritic activity of FERMENZA, supporting its potential as a safe, drug-free and steroid-free natural formulation for managing scalp itch and beard hypersensitivity.

Antibiotic resistance is a critical global health concern, with metallo-β-lactamases like Verona integron-encoded metallo-β-lactamase-2 (VIM-2) contributing to the breakdown of β-lactam antibiotics, including carbapenems. The increasing prevalence of VIM-2-mediated resistance highlights the urgent need for novel inhibitors. In this study, a structure-based virtual screening approach was employed to identify potential VIM-2 inhibitors from the Medicinal Fungal Secondary Metabolites and Therapeutics (MeFSAT) library. Molecular docking of 1,830 fungal-derived compounds, followed by molecular dynamics (MD) simulations, led to the identification of three promising candidates: MSID001033, MSID001081, and MSID001168. These compounds showed high docking scores and favorable interactions with the VIM-2 active site, forming stable complexes through π-π stacking, hydrogen bonding, and zinc coordination. MD simulations over 250 ns confirmed the structural stability of the complexes, supported by consistent RMSD, RMSF, and hydrogen bonding profiles. Further validation using MM-GBSA binding energy calculations, radial distribution function (RDF), salt bridge analysis, and anisotropic network model (ANM) cross-correlation reinforced their strong binding affinity. Overall, this study highlights fungal secondary metabolites as promising scaffolds for VIM-2 inhibition and demonstrates the effectiveness of integrated computational methods in accelerating early-stage antibiotic drug discovery.