Search for potentially biased epidermal growth factor receptor (EGFR) inhibitors through pharmacophore modelling, molecular docking, and molecular dynamics (MD) simulation approaches.

Epidermal growth factor receptor (EGFR), being one of the most crucial receptor in cancer therapy, has been selected as a potential target for the present study. Ligand-based pharmacophore model (n = 30, R2=0.93 with root mean square deviation = 1.14, ΔCost = 144.27 and configuration cost = 21) was developed and validated with Fischer's randomisation (at 95% confidence), test set (n = 225, R2 pred = 0.81), external data set (n = 13, R2 pred = 0.95) and decoy set (n = 70), further the model has been used to search for novel EGFR inhibitors. The validated model was used for virtual screening of zinc database. A pool of 115,948 candidate molecules was screened through the model. Subsequently, molecules having predicted IC50<0.2 µM were selected for screening through drug-like properties filter. Based on pharmacokinetic profile (ADMET study), Lipinski's rule of five and Veber's rule, 62 molecules were shortlisted for molecular docking. Using consensus docking, five hit molecules were selected, which were further considered for molecular dynamics simulation. Additionally MM-GBSA analysis was carried which showed that affinity of hits towards the receptor of three compound mainly ZINC305, ZINC131796 and ZINC131785 were similar to the standard vanedtinib. The simulation, performed for 100 ns, revealed that two hit molecules, namely ZINC305 and ZINC131785, showing potential interactions at the ligand-binding domain of EGFR protein with good ligand-protein stability. Communicated by Ramaswamy H. Sarma.

Flavonoid-Decorated Nano-gold for Antimicrobial Therapy Against Gram-negative Bacteria Escherichia coli.

Nano-gold (Aunps) have emerged as promising options that exhibit unique features discrete from traditional materials suited for biomedical applications. Aunps were synthesized using flavonoid quercetin (Q) as reducing agent, and resultant nanoparticles were further conjugated with the flavonoid. The resultant nano-system was expected to perform a dual role as antibacterial and as antioxidant agent. Nano-gold surface plasmon peaks were recorded at 560 nm with size around 62 nm and having slim distribution pattern. Spherical particle with smooth surface was observed under TEM and AFM studies. TEM micrographs confirmed a homogeneous particle population of size around 30 nm. Quercetin association to nano-gold was corroborated through FTIR and EDAX analysis. Antioxidant nature of nano-gold prevented rapid oxidation of brilliant cresyl blue dye, in presence of sodium hypochlorite. Antimicrobial action of QuAunp was tested against Gram-negative bacteria Escherichia coli. Nano-gold designed produced a minimum inhibitory concentration of 7.6 µg/ml and minimum bactericidal concentration 10.5 µg/ml against E. coli. Further TEM analysis and membrane permeability studies revealed the impact of QuAunps on bacterial membrane leading to cell damage.

Lactoferrin-tethered betulinic acid nanoparticles promote rapid delivery and cell death in triple negative breast and laryngeal cancer cells.

Cancer management presents multifarious problems. Triple negative breast cancer (TNBC) is associated with inaccurate prognosis and limited chemotherapeutic options. Betulinic acid (BA) prevents angiogenesis and causes apoptosis of TNBC cells. NIH recommends BA for rapid access in cancer chemotherapy because of its cell-specific toxicity. BA however faces major challenges in therapeutic practices due to its limited solubility and cellular entree. We report lactoferrin (Lf) attached BA nanoparticles (Lf-BAnp) for rapid delivery in triple negative breast (MDA-MB-231) and laryngeal (HEp-2) cancer cell types. Lf association was confirmed by SDS-PAGE and FT-IR analysis. Average hydrodynamic size of Lf-BAnp was 147.7 ± 6.20 nm with ζ potential of -28.51 ± 3.52 mV. BA entrapment efficiency was 75.38 ± 2.70% and the release mechanism followed non-fickian pattern. Impact of Lf-BAnp on cell cycle and cytotoxicity of triple negative breast cancer and its metastatic site laryngeal cancer cell lines were analyzed. Lf-BAnp demonstrated strong anti-proliferative and cytotoxic effects, along with increased sub-G1 population and reduced number of cells in G1 and G2/M phases of the cell cycle, confirming reduced cell proliferation and significant cell death. Speedy intracellular entry of Lf-BAnp occurred within 30 min. Lf-BAnp design was explored for the first time as safer chemotherapeutic arsenals against complex TNBC conditions.