Glutamine: fructose-6-phosphate amidotransferase (GFAT): homology modelling and designing of new inhibitors using pharmacophore and docking based hierarchical virtual screening protocol

Glutamine: fructose-6-phosphate amidotransferase (GFAT), also termed GFPT1 and GFAT1, catalyzes the first committed step of the hexosamine biosynthesis pathway in mammals and consequently plays an important role in type 2 diabetes. In the present study, a combination of pharmacophore modelling, homology modelling, and molecular docking analysis was performed to design new glutamine competitive inhibitors of human GFAT, and to investigate important interaction details of inhibitor molecules. A pharmacophore model of GFAT inhibitors was developed, subsequently validated, and utilized for the screening by the PHASE database to identify new molecules. Afterwards, homology modelling was performed to construct the glutamine-binding site of the GFAT protein. The modelled active site was utilized to dock the studied molecules to investigate important receptor-ligand interactions and to scrutinize database-screened molecules on the basis of essential interactions. This systematic in silico protocol helped us to identify new molecules that would be explored for the treatment of type 2 diabetes and its complications.     

ESR EVIDENCE OF AN ELECTRON TRANSFER BETWEEN ARYLPHOSPHINES AND ARYLNITROSO COMPOUNDS

Abstract

Electron transfer between arylphosphines and arylnitroso compounds gives rise to the formation of free radicals which have been characterized by esr     

Petra,Osiris, and Molinspiration Together as a Guide in Drug Design: Predictions and Correlation Structure/Antibacterial Activity Relationships of New N-Sulfonyl Monocyclic β-Lactams

We report in this article the design and calculated molecular properties of 18 new mono-cyclic β-lactams 4–21, on the basis of one hypothetical antibacterial pharmacophore structure designed to interact with both of Gram-positive bacteria and Gram-negative bacteria. The in vitro biological evaluation of these compounds allowed us to point out new potential non-nucleoside hits, with MIC values in the range of 2–8 μg/mL active against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. A correlation structure/antibacterial activities relationship of these monocyclic β-lactams is described.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

Microbial Screening of Copolymers of N‐Vinylimidazole with Phenacyl Methacrylate: Synthesis and Monomer Reactivity Ratios

N‐vinylimidazole (VIM), and phenacyl methacrylate (PAMA) copolymerized with different feed ratios using 1,4‐dioxane as a solvent and α,α'‐azobisisobutyronitrile (AIBN) as an initiator at 60°C. Structure and composition of copolymers for a wide range of monomer feed were determined by elemental analysis (content of N for VIM‐units) and by Fourier transform infrared spectroscopy through recorded analytical absorption bands for VIM (670 cm^?1 for C‐N of imidazole ring) and PAMA (1730 cm^?1 for C?O of ester group) units, respectively. Monomer reactivity ratios for VIM (M₁)‐PAMA (M₂) pair were determined by the application of conventional linearization methods such as Fineman‐Ross (F‐R) and Kelen‐Tüdös (KT) and a nonlinear error invariable model method using a computer program RREVM. The molecular weights (_w and _n) and polydispersity indices of the polymers were determined using gel permeation chromatography (GPC). Thermal behaviors of copolymers with various compositions were investigated by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Also, the apparent thermal decomposition activation energies (ΔE_d) were calculated by Ozawa method using the SETARAM Labsys TGA thermobalance. The antibacterial and antifungal effects of polymers were also tested on various bacteria, fungi and yeast.     

Identification of potential HIV-1 integrase strand transfer inhibitors: In silico virtual screening and QM/MM docking studies

HIV-1 integrase (IN) is a retroviral enzyme that catalyses integration of the reverse-transcribed viral DNA into the host genome, which is necessary for efficient viral replication. In this study, we have performed an in silico virtual screening for the identification of potential HIV-1 IN strand transfer (ST) inhibitors. Pharmacophore modelling and atom-based 3D-QSAR studies were carried out for a series of compounds belonging to 3-Hydroxypyrimidine-2,4-diones. Based on the ligand-based pharmacophore model, we obtained a five-point pharmacophore with two hydrogen bond acceptors (A), one hydrogen bond donor (D), one hydrophobic group (H) and one aromatic ring (R) as pharmacophoric features. The pharmacophore hypothesis AADHR was used as a 3D query in a sequential virtual screening study to filter small molecule databases Maybridge, ChemBridge and Asinex. Hits matching with pharmacophore hypothesis AADHR were retrieved and passed progressively through Lipinski’s rule of five filtering, molecular docking and hierarchical clustering. The five compounds with best hits with novel and diverse chemotypes were subjected to QM/MM docking, which showed improved docking accuracy. We further performed molecular dynamics simulation and found three compounds that form stable interactions with key residues. These compounds could be used as a leads for further drug development and rational design of HIV-1 IN inhibitors.     

Theory of docking scores and its application to a customizable scoring function

In general, the docking scoring tends to have a size dependence related to the ranking of compounds. In this paper, we describe a novel method of parameter optimization for docking scores which reduce the size dependence and can efficiently discriminate active compounds from chemical databases. This method is based on a simplified theoretical model of docking scores which enables us to utilize large amounts of data of known active and inactive compounds for a particular target without requiring large computational resources or a complicated procedure. This method is useful for making scoring functions for the identification of novel scaffolds using the knowledge of active compounds for a particular target or a customized scoring function for an interesting family of drug targets.     

Palladium-catalyzed hydrodehalogenation of aryl halides using paraformaldehyde as the hydride source: high-throughput screening by paper-based colorimetric iodide sensor

Paraformaldehyde was employed as a hydride source in the palladium-catalyzed hydrodehalogenation of aryl iodides and bromides. High throughput screening using a paper-based colorimetric iodide sensor (PBCIS) showed that Pd(OAc)₂ and Cs₂CO₃ were the best catalyst and base, respectively. Aryl iodides and bromides were hydrodehalogenated to produce the reduced arenes using Pd(OAc)₂ and Pd(PPh₃)₄ catalyst. This catalytic system showed good functional group tolerance. In addition, it was found that paraformaldehyde is the hydride source and the reducing agent for the formation of palladium nanoparticles.     

Rapid determination of enantiomeric excess of α-chiral aldehydes using circular dichroism spectroscopy

A method for enantiodiscrimination of α-chiral aldehydes is reported. The method utilizes circular dichroism (CD) spectroscopy and a sensing ensemble composed of 2-(1-methylhydrazinyl) pyridine (1) and Fe(II)(TfO)₂. Aldehydes react rapidly with hydrazine (1) to form chiral imines, which form complexes with Fe(II). By monitoring the CD bands above 320 nm, one can determine the enantiomeric excess (ee) values of α-chiral aldehydes with an average absolute error of ±5%. The analysis was fast, and thus can have potential applications in high-throughput screening (HTS) of catalytic asymmetric induction.