Pharmacophore mapping of the crucial mediators of acetylcholinesterase and butyrylcholinesterase dual inhibition in Alzheimer's disease

Optimization and re-optimization of bioactive molecules using in silico methods have found application in the design of more active ones. Herein, we applied a pharmacophore modeling approach to screen potent dual inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) aimed at Alzheimer's disease (AD) treatment. The investigation entails molecular dynamics simulation, docking, pharmacophore modeling, drug-like screening, and binding energy analysis. We prepared a pharmacophore model from approved inhibitors of AChE and BuChE to predict the crucial moieties required for optimum molecular interaction with these proteins. The obtained pharmacophore model, used for database screening via some critical criteria, showed 229 hit molecules. Further analyses showed 42 likely dual inhibitors of AChE/BuChE with drug-like and pharmacokinetics properties the same as the approved cholinesterase inhibitors. Finally, we identified 14 dual molecules with improved potentials over the existing inhibitors and simulated ZINC92385797 bound to human AChE and BuChE structure after noticing that these 14 molecules are similar. The selected compound maintained relative stability at the active sites of both proteins over 120 ns simulation. Our integrated protocols showed the pertinent recipes of anti-AD drug design through the in silico pipeline.

Graphical abstract

     

Molecular docking,ADME/Tox prediction,and in vitro study of the cell growth inhibitory activity of five β-carboline alkaloids

Structural Chemistry - In a continuing effort to find new cytotoxic, antitumor, and less toxic agents from β-carbolines derivatives, using experimental and computational studies, five...     

A silica fiber coated with a ZnO-graphene oxide nanocomposite with high specific surface for use in solid phase microextraction of the antiepileptic drugs diazepam and oxazepam

A novel ZnO-graphene oxide nanocomposite was prepared and is shown to be a viable coating on fused silica fibers for use in solid phase microextraction (SPME) of diazepam and oxazepam from urine, this followed by thermal desorption and gas chromatographic quantitation using a flame ionization detector. A central composite design was used to optimize extraction time, salt percentage, sample pH and desorption time. Limits of detection are 0.5 μg·L^?1 for diazepam and 1.0 μg·L^?1 for oxazepam. Repeatability and reproducibility for one fiber (n?=?4), expressed as the relative standard deviation at a concentration of 50 μg·L^?1, are 8.3 and 11.3% for diazepam, and 6.7 and 10.1% for oxazepam. The fiber-to-fiber reproducibility is <17.6%. The calibration plots are linear in the 5.0–1000 μg·L^?1 diazepam concentration range, and from 1.0–1000 μg·L^?1 in case of oxazepam. The fiber for SPME has high chemical and thermal stability (even at 280 °C) after 50 extractions, and does not suffer from a reduction in the sorption capacity.

Open image in new window

Graphical abstract A hydrothermal method was introduced for preparation of ZnO- GO nano composite on a fused silica fiber as solid phase microextraction with high mechanical, chemical stability and long service life

     

Reaction of sulphur dioxide with chlorocarbonyls of ruthenium,rhodium and iridium

Summary The reactions of SO₂ with chlorocarbonyls of rhodium and iridium ([M(CO)₂Cl₂]^– and ruthenium ([Ru(CO)_2–Cl₂]_n) ions were studied. Addition of either the Ph₄As⁺ cation or the nitrogen-donor ligands 2,2-bipyridine (bipy),o-phenylenediamine (opd), 1,10-phenanthroline (phen), 2,2,6,2-terpyridine (terpy) or 6,7-dihydro-1,4-di(2-pyridyl)-5H-cyclopenta {d}-pyridazine (5-dppn) to the SO_2– treated chlorocarbonyl solutions resulted in the formation of various complexes according to the nature of metal and ligand. The products have been characterized by physicochemical methods.     

RP-HPLC Method for the Quantitation of Glabridin in Yashti-madhu (Glycyrrhiza glabra)

A reverse phase high performance liquid chromatographic method is developed for the quantitation of glabridin in Glycyrrhiza glabra, using C₁₈ column with acetonitrile-water containing 2% AcOH (70:30) as an eluent. Glabridin is detected by UV absorption at 280 nm after separation by the chromatographic system. Good linearity was obtained in the working range of the concentration (0.01–0.1 mg mL^?1), with correlation coefficients 0.999. Limit of detection and limit of quantitation were 0.0195 and 0.065 mg mL^?1. The method was validated under ICH guidelines. The described method can be utilized for routine analysis (assays and stability tests) of G. glabra extracts and Ayurvedic medicine based on Yashti-madhu.     

Varying the metal/metal ratio in related Cu–Ca complexes

We demonstrate with the help of structural determinations and spectroscopic data that the nuclearity of Cu–Ca complexes derived from compartmental Schiff base ligands does not depend on the ionic radius of calcium. The main factors governing these reactions are the different affinities of the calcium ions for the anionic species present in solution: the tetradentate O₂O₂ coordination site of the ligand and the nitrato ions. Because these affinities do vary upon going from calcium to lanthanide ions, it is not possible to use the template effect of the trinuclear Cu–Ca–Cu complexes in order to prepare the corresponding Cu–Ln–Cu complexes.     

Synthesis of polyfunctionally substituted heteroaromatic compounds via benzotriazolyl chalcones with antimicrobial and antifungal activities

The utility of both 3‐(1‐benzotriazolyl) chalcone derivatives 3a‐c and 2‐(1‐benzotriazolyl)‐1,4‐pentadien‐3‐one (18) in the synthesis of some new 2‐(1H)‐pyridone, pyridine, pyrazole and isoxazole derivatives is reported. Antimicrobial and antifungal screening of some selected examples from the synthesized products were carried out. The structure of the newly synthesized compounds was elucidated by elemental analysis, ir, ¹H and ¹³C nmr investigations.     

Synthesis of pH‐responsive magnetic yolk–shell nanoparticles: A comparison between conventional etching and new deswelling approaches

Iron oxide (Fe₃O₄) magnetic nanoparticles as movable cores were used to synthesize yolk–shell nanoparticles with pH‐responsive shell composed of ethylene glycol dimethacrylate (EGDMA)‐crosslinked poly(acrylic acid) (PAA) via two different routes. In the first more common route, Fe₃O₄ nanoparticles were coated with silica layer via the Stöber process to yield Fe₃O₄@SiO₂ core–shell nanoparticles, subsequently used as seeds in the distillation precipitation copolymerization of AA and EGDMA to yield Fe₃O₄@SiO₂@P(AA‐EGDMA). The silica layer was selectively removed through alkali etching to yield Fe₃O₄@air@P(AA‐EGDMA). In the second route, Fe₃O₄ nanoparticles without any stabilization were used as seeds in the distillation precipitation copolymerization of AA and EGDMA to yield Fe₃O₄@P(AA‐EGDMA) core–shell nanoparticles. The nanoparticles were subsequently dispersed in acidic medium of pH = 2. Yolk–shell Fe₃O₄@air@P(AA‐EGDMA) nanoparticles were formed through deswelling of crosslinked PAA because of protonation of carboxyl groups at low pH values. Various techniques were utilized to investigate the characteristics of the synthesized core–shell nanoparticles. Formation of yolk–shell nanostructure was observed for both synthesis routes, namely etching of silica layer and deswelling approaches, from vibrating sample magnetometry and transmission electron microscopy results. Both types of nanoparticles showed pH‐responsive behaviour, i.e. decrease in absorption with increase in pH, as examined using UV–visible spectroscopy.