Khair Bux

Valsartan (Val)—a lipophilic non-peptide angiotensin II type 1 receptor antagonist—is highly effective against hypertension and displaying limited solubility in water (3.08 μg/mL), thereby resulting in low oral bioavailability (23%). The limited water solubility of antihypertensive drugs can pose a challenge, particularly for rapid and precise administration. Herein, we synthesize and characterize valsartan-containing silver nanoparticles (Val-AgNPs) using Mangifera indica leaf extracts. The physicochemical, structural, thermal, and pharmacological properties of these nano-conjugates were established through various analytical and structural tools. The spectral shifts in both UV-visible and FTIR analyses indicate a successful interaction between the valsartan molecule and the silver nanoparticles. The resulting nano-conjugates are spherical and within the size range of 30–60 nm as revealed in scanning electron-EDS and atomic force micrographs. The log-normal distribution of valsartan-loaded nanoparticles, with a size range of 30 to 60 nm and a mode of 54 nm, indicates a narrow, monodisperse, and highly uniform particle size distribution. This is a favorable characteristic for drug delivery systems, as it leads to enhanced bioavailability and a consistent performance. Dynamic Light Scattering (DLS) analysis of the Val-AgNPs indicates a polydisperse sample with a tendency toward aggregation, resulting in larger effective sizes in the suspension compared to individual nanoparticles. The accompanying decrease in zeta potential (to −19.5 mV) and conductivity further supports the idea that the surface chemistry and stability of the nanoparticles changed after conjugation. Differential scanning calorimetry (DSC) demonstrated the melting onset of the valsartan component at 113.99 °C. The size-dependent densification of the silver nanoparticles at 286.24 °C correspond to a size range of 40–60 nm, showing a significant melting point depression compared to bulk silver due to nanoscale effects. The shift in Rf for pure valsartan to Val-AgNPs suggests that the interaction with the AgNPs alters the compound’s overall polarity and/or its interaction with the stationary phase, complimented in HPTLC and HPLC analysis. The stability and offloading behavior of Val-AgNPs was observed at pH 6–10 and in 40% and 80% MeOH. In addition, Val-AgNPs did not reveal hemolysis or significant alterations in blood cell indices, confirming the safety of the nano-conjugates for biological application. In conclusion, these findings provide a comprehensive characterization of Val-AgNPs, highlighting their potential for improved drug delivery applications.

Context Glioblastoma (GBM), well known as grade 4 tumors due to its progressive malignant features such as vascular proliferation and necrosis, is the most aggressive form of primary brain tumor found in adults. Mutations and amplifications in the vascular endothelial growth factor receptor (VEGFR) contribute to almost 25% of GBM tumors. And thus, VEGFR has been declared the primary target in glioblastoma therapeutic strategies. However, many studies have been previously reported that include GBM as global therapeutics challenge, but they lack the molecular level insights that could help in understanding the biological function of a therapeutically important protein playing a major role in the disease and design the best strategies to develop the potential drugs. Methods Therefore, to the best of our knowledge, the present study is the first time of kind, which involves multi-in silico approaches to predict the inhibition potential of withanolides from Withania coagulan against VEGFR. The study is actually based on determining the mode of action of five isolates: withanolide J, withaperuvin, 27-hydroxywithanolide I, coagule E, and coagule E, along with their respective binding energies. Molecular docking simulations revealed primarily four ligands, withanolide J (− 7.33 kJ/mol), 27-withanolide (− 7.01 kJ/mol), ajugine, withaperuvin (− 6.89 kJ/mol), and ajugine E (− 6.39 kJ/mol), to have significant binding potencies against the protein. Ligand binding was found to enhance the confirmational stability of the protein revealed through RMSD analysis, and RMSF assessment revealed the protein residues especially from 900–1000 surrounding the binding of the protein. Structural and dynamics of the protein via dynamics cross-correlation movement (DCCM) and principal component analysis (PCA) in both the unbound form and complexed with most potent ligand, withanolide J, reveal the ligand binding affecting the entire conformational integrity of the protein stabilized by hydrogen bonds and electrostatic attractions. Free energy of binding estimations by means of molecular mechanics Poisson-Boltzmann surface area (MMPBSA) method further revealed the withanolide J to have maximum binding potency of the all ligands. Withanolide J in final was also found to have suitable molecular characterizations to cross the blood–brain barrier (BBB +) and reasonable human intestinal absorption ability determined by ADMET profiling via admetSAR tools. Graphical abstract

Periodontitis is an inflammatory periodontal disease defined by the progressive loss of tissues surrounding the tooth. Ampicillin is an antibiotic for managing and treating specific bacterial infections, including periodontitis. Periodontal pockets occur due to periodontal disease progression and act as a natural reservoir that is easily reachable for the insertion of a delivery system, and the amount of drug to be released has a major role in the efficiency of treatment of the disease. Polyelectrolyte complexes (PECs), particularly those based on chitosan and hyaluronic acid combinations, offer a promising avenue to overcome the challenges associated with drug delivery. These complexes are both biodegradable and biocompatible, making them an optimal choice for enabling targeted drug delivery. This study centers on developing and assessing the structure and dynamic attributes of a drug-PEC system encompassing ampicillin and chitosan-hyaluronic acid components, which represents a targeted drug delivery system to better alleviate the periodontitis. To achieve this goal, we conducted experiments including weight and drug content uniformity, swelling ındex, drug release %, FT-IR and SEM analyses, and atomistic molecular dynamics simulations on the drug PECs loaded with ampicillin with varying amounts of hyaluronic acid. All simulations and the experimental analysis suggested that increased HA amount resulted in an increase in drug release % and swelling index. The simulation outcomes provide insights into the nature of the drug and PEC interactions alongside transport properties such as drug diffusion coefficients. These coefficients offer valuable insights into the molecular behavior of ampicillin-PEC drug delivery systems, particularly in the context of their application in periodontitis treatment.

Amphotericin B (AMPH) is an anti-fungal drug and this study, for the first time as best of our knowledge, reports the repurposing of the Amphotericin B. The drug was found to show significant antibacterial potential revealed by antimicrobial screening, molecular docking, and mode of action analysis targeting Penicillin Binding Protein 2a (PBP 2a protein) which is target of β-lactam drugs and is involved in cell wall synthesis. Mode of action analysis showed the drug to have hydrophobic and hydrophilic interactions with both C-terminal, trans-peptidase and non-penicillin binding domain of the protein. Additionally, to evaluate the impact of ligand binding on the protein's conformational dynamics, molecular dynamics (MD) simulations were used. Comparative Dynamical flexibility (RMSF) and Dynamics Cross Correlation (DCCM) followed by MD simulations revealed the complex formation significantly effecting structural dynamics of the enzyme significantly in the non-penicillin binding domain (327–668) and slightly in trans peptidase domain. Radius of gyration assessment further showed ligand binding also decreasing over all compactness of protein. Secondary structure analysis indicated the complex formation changing the conformational integrity in non-penicillin binding domain. Hydrogen bond analysis and MMPBSA, free energy of calculations followed by MD simulations, also complemented the antimicrobial and molecular docking revelations suggesting Amphotericin B to have substantial antibacterial potential.

Bacteriocins are gaining immense importance in therapeutics since they show significant antibacterial potential. This study reports the bacteriocin KAE01 from Enterococcus faecium, along with its characterization, molecular modeling, and antibacterial potency, by targeting the matrix protein of Pseudomonas aeruginosa. The bacteriocin was purified by using ammonium sulfate precipitation and fast protein liquid chromatography (FPLC), and its molecular weight was estimated as 55 kDa by means of SDS-PAGE. The bacteriocin was found to show stability in a wide range of pH values (2.0–10.0) and temperatures (100 °C for 1 h and 121 °C for 15 min). Antimicrobial screening of the purified peptide against different strains of P. aeruginosa showed its significant antibacterial potential. Scanning electron microscopy of bacteriocin-induced bacterial cultures revealed significant changes in the cellular morphology of the pathogens. In silico molecular modeling of KAE01, followed by molecular docking of the matrix protein (qSA) of P. aeruginosa and KAE01, supported the antibacterial potency and SEM findings of this study.