Modeling of Human Prokineticin Receptors: Interactions with Novel Small-Molecule Binders and Potential Off-Target Drugs

The Prokineticin receptor (PKR) 1 and 2 subtypes are novel members of family A GPCRs, which exhibit an unusually high degree of sequence similarity. Prokineticins (PKs), their cognate ligands, are small secreted proteins of ∼80 amino acids; however, non-peptidic low-molecular weight antagonists have also been identified. PKs and their receptors play important roles under various physiological conditions such as maintaining circadian rhythm and pain perception, as well as regulating angiogenesis and modulating immunity. Identifying binding sites for known antagonists and for additional potential binders will facilitate studying and regulating these novel receptors. Blocking PKRs may serve as a therapeutic tool for various diseases, including acute pain, inflammation and cancer.Ligand-based pharmacophore models were derived from known antagonists, and virtual screening performed on the DrugBank dataset identified potential human PKR (hPKR) ligands with novel scaffolds. Interestingly, these included several HIV protease inhibitors for which endothelial cell dysfunction is a documented side effect. Our results suggest that the side effects might be due to inhibition of the PKR signaling pathway. Docking of known binders to a 3D homology model of hPKR1 is in agreement with the well-established canonical TM-bundle binding site of family A GPCRs. Furthermore, the docking results highlight residues that may form specific contacts with the ligands. These contacts provide structural explanation for the importance of several chemical features that were obtained from the structure-activity analysis of known binders. With the exception of a single loop residue that might be perused in the future for obtaining subtype-specific regulation, the results suggest an identical TM-bundle binding site for hPKR1 and hPKR2. In addition, analysis of the intracellular regions highlights variable regions that may provide subtype specificity

STRUCTURAL AND MORPHOLOGICAL-STUDIES OF ELECTRODEPOSITED AMORPHOUS-SILICON THIN-FILMS

Amorphous silicon thin films obtained from hydrofluosilicic acid using the electrodeposition method are analysed for structure and morphology. The chemical nature of the films is discussed using the data from IR spectroscopy. The electrical resistivity of these films is very high, of the order of 10(12)-10(13) OMEGA cm, under the present experimental conditions. X-ray diffraction spectra revealed that the films are not crystalline in nature. At low concentrations of the electrolyte, scanning electron microscopy photographs exhibited some microstructure with crystalline order of about 100 angstrom, At high concentrations, the structure of the films changed widely to be homogeneous

VIBRATIONAL-MODES IN ELECTRODEPOSITED AMORPHOUS-SILICON - FT-IR ANALYSIS

Infrared spectra of 13 samples of amorphous silicon bonded with hydrogen, fluorine and carbon, prepared by electrodeposition using a mixture of ethylene glycol and fluosilicic acid were analysed in the wave number region 4000-400 cm-1 with a Fourier transform infrared spectrometer. Strong absorption peaks were observed at 1000 cm-1 due to the SiF(x) stretching mode. Small peaks were seen around 2300 and 640 cm-1 due to SiH stretching and wagging modes of absorption. The number of bonded hydrogen atoms in the film deposited at 0.05 M, 50 mA cm-2 was calculated to be 6.2579 x 10(21) and 1.2302 x 10(20) atm cm-3 using integrated absorption of the CH and SiH stretching modes, respectively. The absorption coefficient around the SiF(x) stretch region was found to vary from 1300-2500 cm-1 as the molarity of the electrolyte was increased. Binding energy shifts in X-ray photoelectron spectrum were used as a cross check to confirm the silicon bonding with carbon, hydrogen, oxygen and fluorine atoms. The absence of columnar growth in SEM photographs indicates no polysilane formation in the films

Surface properties of electrodeposited a-Si:C:H:F thin films by x-ray photoelectron spectroscopy

Surface properties of amorphous silicon thin films containing hydrogen, flourine and carbon obtained from hydrofluosilicic acid and ethylene glycol using the electrodeposition method are reported as a function of current density and deposition time. The Si2p core level X-ray photoelectron spectra exhibited binding-energy shifts corresponding to SiFx (x = 1-4), SiC, Si-H and Si-O-2 type bond formations. The shifts in 1s spectra of fluorine, carbon x and oxygen confirmed the presence of fluorine, carbon and oxygen in bonded form. Theoretical binding-energy shifts calculated from Pauling's electronegativity values were in close agreement with the measured values. The relative concentration values of C/Si estimated in these films were found to be larger than those of F/Si and O/Si. The results were corroborated with infrared spectroscopy and scanning electron microscopy data