QbD Design, Formulation, Optimization and Evaluation of Trans-Tympanic Reverse Gelatination Gel of Norfloxacin: Investigating Gene-Gene Interactions to Enhance Therapeutic Efficacy.

Traditional otic drug delivery methods lack controlled release capabilities, making reverse gelatination gels a promising alternative. Reverse gelatination gels are colloidal systems that transition from a sol to a gel phase at the target site, providing controlled drug release over an extended period. Thermosensitive norfloxacin reverse gelatination gels were developed using a Quality by Design (QbD)-based optimization approach. The formulations were evaluated for their in vitro release profile, rheological behavior, visual appearance, pH, gelling time, and sol-gel transition temperature. The results show that the gelation temperatures of the formulations ranged from 33 to 37 °C, with gelling durations between 35 and 90 s. The drug content in the formulations was uniform, with entrapment efficiency ranging from 55% to 95%. Among the formulations, F10 exhibited the most favorable properties and was selected for a stability study lasting 60 days. Ex-vivo release data demonstrate that the F10 formulation achieved 95.6percentage of drug release at 360 min. This study successfully developed thermosensitive norfloxacin reverse gelatination gels using a QbD-based optimization approach. The selected formulation, F10, exhibited desirable properties in terms of gelling temperature, drug content, and release profile. These gels hold potential for the controlled delivery of norfloxacin in the treatment of ear infections.

Understanding the interaction between α-1-acid glycoprotein (AGP) and potential Cu/Zn metallo-drugs of benzimidazole derived organic motifs: A multi-spectroscopic and molecular docking study.

Drug-binding and interactions with plasma proteins strongly affect their efficiency of delivery, hence considered as a key factor in determining the overall pharmacological action. Alpha-1-acid glycoprotein (AGP), a second most abundant plasma protein in blood circulation, has unique drug binding ability and involved in the transportation of various compounds. Here, we have investigated the mechanism of interaction between AGP and potential Cu/Zn metallo-drugs of benzimidazole derived organic motifs (CuL2 and ZnL2, where L is Schiff base ligand) by applying integrated spectroscopic, biophysical techniques and computational molecular docking analyses. We found that both the metallo-drugs (CuL2 and ZnL2) were bound at the central cavity of AGP interacting with the residues of lobe I, lobe II as well as lobe III. The binding of metallo-drugs to AGP occurs in 1:1 M ratios. Hydrogen bonding, electrostatic and hydrophobic interactions played a significant role in stabilizing the AGP-metallo-drug complexes. Binding affinities of both the metallo-drugs towards AGP at 298 K were of the order of 104-105 M-1, corresponding to Gibbs free energy of stabilization of approximately -5.50 to -6.62 kcal mol-1. Furthermore, the spectroscopic investigation by circular dichroism and synchronous fluorescence analyses suggest conformational changes in AGP upon the binding of metallic compounds.

Evaluation of pyrazolopyrimidine derivatives as microtubule affinity regulating kinase 4 inhibitors: Towards therapeutic management of Alzheimer's disease.

Microtubule affinity regulating kinase 4 (MARK4) plays essential role in the tau-assisted regulation of microtubule dynamics. Over expression of MARK4 causes early phosphorylation of Ser262 of tau protein which is essential for microtubule binding. Hyperphosphorylation of tau protein causes the formation of paired helical fragments and neurofibrillary tangles, the hallmarks of Alzheimer's disease. Targeting the modulation of MARK4 activity is an effective strategy for therapeutic intervention of Alzheimer's and other MARK4 associated neurodegenerative diseases. Having role of pyrazolopyrimidine derivatives in the therapeutic management of neurodegenerative diseases, we have tried to estimate their binding affinity with the MARK4. We performed in silico screening of 59 pyrazolopyrimidine derivatives against MARK4 and obtained a few best possible inhibitors. Molecular docking-based interaction analysis suggested five potential leads that were further analyzed using molecular dynamics simulations, MM/PBSA, principal component analysis and graph theory based dynamic network analysis to observe structural changes caused due to ligand binding. All these computational analyses suggested that compounds with PubChem IDs: 91895678, 91895679, 91895692, 91145515 and 90794095 may be further exploited to address Alzheimer's and other neurodegenerative diseases.Communicated by Ramaswamy H. Sarma.

Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy.

Sphingosine kinase 1 (SphK1) has recently gained attention as a potential drug target for its association with cancer and other inflammatory diseases. Here, we have investigated the binding affinity of dietary phytochemicals viz., ursolic acid, capsaicin, DL-α tocopherol acetate, quercetin, vanillin, citral, limonin and simvastatin with the SphK1. Docking studies revealed that all these compounds bind to the SphK1 with varying affinities. Fluorescence binding and isothermal titration calorimetric measurements suggested that quercetin and capsaicin bind to SphK1 with an excellent affinity, and significantly inhibits its activity with an admirable IC50 values. The binding mechanism of quercetin was assessed by docking and molecular dynamics simulation studies for 100 ns in detail. We found that quercetin acts as a lipid substrate competitive inhibitor, and it interacts with important residues of active-site pocket through hydrogen bonds and other non-covalent interactions. Quercetin forms a stable complex with SphK1 without inducing any significant conformational changes in the protein structure. In conclusion, we infer that quercetin and capsaicin provide a chemical scaffold to develop potent and selective inhibitors of SphK1 after required modifications for the clinical management of cancer.