CoMFA and CoMSIA of diverse pyrrolidine analogues as dipeptidyl peptidase IV inhibitors: active site requirements

The inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as an attractive target in the treatment of type 2 diabetes. In view of this development, a critical analysis of structural requirements of the DPP-IV inhibitors is envisioned to identify the significant features toward design of selective inhibitors. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) contour plots of pyrrolidine based analogues are used to analyze the structural requirements of a DPP-IV active site. The CoMFA model has shown a cross-validated q ² of 0.651 with a non-cross-validated r ² of 0.882 and explained 70.6% variance in the activity of external test compounds. In this, the steric and electrostatic fields have respectively contributed 59.8 and 40.2%, respectively, to the explained activity of the compounds. The CoMSIA model has shown optimum predictivity (cross-validated q ² = 0.661; non-cross-validated r ² = 0.803; external test set’s predictive r ² = 0.706) with four molecular fields namely, steric, electrostatic, hydrogen bond (HB)-donor, and HB-acceptor. The contour plots of molecular fields resulting from these studies have suggested: (i) steric restriction with small electron rich substituent at 2- and 3-position of pyrrolidine ring, (ii) presence of electropositive ring linker between the pyrrolidine head and aryl tail, (iii) presence of electron-rich groups around the aryl tail moiety, and (iv) presence of sulfonamide between the ring linker and aryl tail which would increase DPP-IV binding affinity of the compounds. These findings will help in the design of structurally related/new compounds as potential DPP-IV inhibitors.     

Surface Coating Rescues Proteins from Magnetite Nanoparticle Induced Damage

The presence of magnetic nanoparticles (NPs) in physiological systems induces toxicity through its effects on mitochondrial function and reactive oxygen species (ROS) imbalance. Magnetic NP induced cytotoxicity has been elaborately evaluated for impending threats, however, a detailed investigation is lacking. It is shown that the interaction of Fe₃O₄ NPs with cytochrome c can lead to different events based on the NPs to protein ratio, the solution conditions, and the type of surface protection. At low NPs concentration, rapid binding and subsequent electron transfer are the preferred events while at higher concentration slow oxidative modification of the protein is initiated. The slow event of protein modification yields conformational disorientation, loss of stability, and formation of amyloid‐like structures with cytochrome c. The possibility that the NP induced oxidative stress and age can work in concert to compromise different aspects of cellular quality control processes is discussed. Suitable surface modifications of the NPs inhibit their direct binding to the protein molecules and minimize NP induced toxicity.     

Inelastic cross sections for pentane isomers by positron impact

ABSTRACT

This work aims at the calculation of various inelastic cross sections for three pentane isomers, namely normal pentane, isopentane and neopentane. The direct ionisation, positronium formation, total ionisation and total inelastic cross section are reported for these targets using modified spherical complex optical potential (mSCOP) and complex scattering potential-ionisation contribution (CSP-ic) method. The cross sections are computed for a wide energy range from their respective thresholds to 5?keV. We have also attempted to probe the isomeric effect in the inelastic scattering of positrons from the pentane isomers. The cross sections for the three isomers were found to overlap for the entire comparative energy range except at the peak region. Hence, in general no appreciable isomeric effect was beheld for the pentane isomers.     

Antifungal activity of multifunctional Fe3O4-Ag nanocolloids

In recent years, rapid increase has been observed in the population of microbes that are resistant to conventionally used antibiotics. Antifungal drug therapy is no exception and now resistance to many of the antifungal agents in use has emerged. Therefore, there is an inevitable and urgent medical need for antibiotics with novel antimicrobial mechanisms. Aspergillus glaucus is the potential cause of fatal brain infections and hypersensitivity pneumonitis in immunocompromised patients and leads to death despite aggressive multidrug antifungal therapy. In the present article, we describe the antifungal activity of multifunctional core-shell Fe₃O₄-Ag nanocolloids against A. glaucus isolates. Controlled experiments are also carried out with Ag nanocolloids in order to understand the role of core (Fe₃O₄) in the antifungal action. The minimum inhibitory concentration (MIC) of nanocolloids is determined by the micro-dilution method. MIC of A. glaucus is 2000 μg/mL. The result is quite promising and requires further investigations in order to develop a treatment methodology against this death causing fungus in immunocompromised patients.     

Label Free Colorimetric Biosensing Using Nanoparticles

In this review article, we discuss a class of biosensors that exploit the change in the colorimetric properties of noble metal nanoparticles in response to biomolecular binding at their surface. Several sensor fabrication techniques as well as sensor configurations are discussed with an emphasis on their strengths and limitations. We conclude by presenting the future prospects and challenges for the successful transition of this technology from the laboratory to a commercial product.     

Highly bacterial resistant silver nanoparticles: synthesis and antibacterial activities

In this article, we describe a simple one-pot rapid synthesis route to produce uniform silver nanoparticles by thermal reduction of AgNO₃ using oleylamine as reducing and capping agent. To enhance the dispersal ability of as-synthesized hydrophobic silver nanoparticles in water, while maintaining their unique properties, a facile phase transfer mechanism has been developed using biocompatible block co-polymer pluronic F-127. Formation of silver nanoparticles is confirmed by X-ray diffraction (XRD), transmission electron microscopy (TEM) and UV–vis spectroscopy. Hydrodynamic size and its distribution are obtained from dynamic light scattering (DLS). Hydrodynamic size and size distribution of as-synthesized and phase transferred silver nanoparticles are 8.2 ± 1.5 nm (σ = 18.3%) and 31.1 ± 4.5 nm (σ = 14.5%), respectively. Antimicrobial activities of hydrophilic silver nanoparticles is tested against two Gram positive (Bacillus megaterium and Staphylococcus aureus), and three Gram negative (Escherichia coli, Proteus vulgaris and Shigella sonnei) bacteria. Minimum inhibitory concentration (MIC) values obtained in the present study for the tested microorganisms are found much better than those reported for commercially available antibacterial agents.     

Synthesis, spectral and biological studies of nitrogen–sulphur donor macrocyclic ligands and their transition metals complexes

Mn(II), Co(II), Ni(II) and Cu(II) complexes have been synthesized with 22 and 24 membered tetramide macrocyclic ligands viz; 1,9,12,20-tetraaza-2,8,13,19-tetraone-5,16-dithiacyclodocosane [L¹] and 1,9,13,21-tetraaza-2,8,14,20-tetraone-5,17-dithiacyclotetracosane [L²] and characterized by elemental analysis, molar conductance, magnetic susceptibility measurements, mass, IR, electronic EPR spectral studies and electrochemical properties. The molar conductance of all the complexes in DMSO solution is corresponding to 1:2 electrolyte. Thus these complexes may be formulated as [M(L′)]Cl₂ [where M = Mn(II), Co(II), Ni(II) and Cu(II) L′ = L¹ and L²]. On the basis of spectral studies a distorted octahedral geometry has been assigned for all the complexes. The ligands and their complexes were also screened in vitro against two pathogenic fungi (F. moniliformae and R. solani) to assess their growth inhibiting potential.     

Role of a Repeated Hexapeptide Motif GIHFAP Near C-terminus in Assembly, Stability, and Activity of “HCH Dehydrochlorinase LinA”

Enzyme “hexachlorocyclohexane (HCH) dehydrochlorinase LinA” mediates first step of aerobic microbial degradation of a chlorinated insecticide γ-HCH. The archetypal LinA-type1 consists of 156 amino acids that include a directly repeated hexapeptide motif GIHFAP at positions 141–146 and 148–153. Analysis of a series of LinA mutants, containing none, one, two, or three units of this repeated motif revealed that two units, as present in wild-type LinA, are required for its optimal activity and stability. Moreover, the presence of a bend in its secondary structure due to a proline residue that precedes the distal repeated unit contributes to enhanced LinA activity.