Putative bioactive conformations of amide linked cyclic myelin basic protein peptide analogues associated with experimental autoimmune encephalomyelitis

The solution models of cyclo(87−99) MBP87-99, cyclo(87−99) [Ala91,96] MBP87-99, and cyclo(87−99) [Arg91, Ala96] MBP87-99 have been determined through 2D NMR spectroscopy in DMSO-d6. Chemical shift analysis has been performed in an attempt to elucidate structural changes occurring upon substitution of native residues. NMR-derived geometrical constraints have been used in order to calculate high-resolution conformers of the above peptides. Conformational analysis of the three synthetic analogues show that the bioactivity, or the lack of it, may possibly be due to the distinct local structure observed and the subsequent differences in the overall topology and exposed area after binding with Major Histocompatibility Complex II (MHC II). It is believed that an overall larger solvent accessible area blocks the approach and binding of the T-cell receptor (TCR) on the altered peptide ligand (APL)−MHC complex, whereas more compact structures do not occlude weak interactions with an approaching TCR and can cause Experimental Autoimmune Encephalomyelitis (EAE) antagonism. A pharmacophore model based on the structural data has been generated

Synthesis and Characterization of Novel Poly( N

Poly(N-vinylcaprolactam-co-itaconic acid), P(VC-co-IA), gels were synthesized in ethanol by using the free radical cross-linking polymerization method at 60 degrees C for 24 h in the presence of azobis(isobutyronitrile) (AIBN) and ally] methacrylate (AMA) as the initiator and the cross-linking agent, respectively. In order to determine the effect of the synthesis medium on the percentage of gelation (PG) and equilibrium swelling value (ESV), an ethanol/distilled water mixture (80:20, v/v) was also used as the synthesis medium for poly(N-vinylcaprolactam) (PVC) and P(VC-co-IA) gels. The swelling behaviors of the gels were investigated in distilled water at various temperatures and in different pH buffer solutions. Structural, morphologic, and thermal characterization studies of the gels were carried out using Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and thermal gravimetric analysis (TGA), respectively. The lowest PG and highest ESV were obtained for the gel including 5 mol % IA, which was the gel synthesized in the ethanol/distilled water mixture. PVC synthesized in ethanol/water mixture had the highest percentage of gelation. All the gels displayed pH- and temperature-sensitive swelling behavior. The swelling kinetics of the copolymer gels synthesized in ethanol was investigated at pH 10.0, and it was determined that gels containing 5 and 10 mol % of IA indicated non-Fickian and case II swelling behavior, respectively

Identification of structural requirements of estrogen receptor modulators using pharmacoinformatics techniques for application to estrogen therapy

An attempt was made in the present study to explore the structural requirements of known estrogen receptor (ER) modulators for biological activity using pharmacoinformatics approaches to elucidate critical functionalities for new, potent and less toxic chemical agents for successful application in estrogen therapy. For this purpose a group of non-steroidal ligands, 7-thiabicyclo[2.2.1]hept-2-ene-7- oxide derivatives were collected from the literature to perform quantitative structure-activity relationship (QSAR), pharmacophore and molecular docking studies. The 2D QSAR models (R2 α = 0.857, seα = 0.370, Q2 α = 0.848, R2 pred-α = 0.675, spα = 0.537; R2 β = 0.874, seβ = 0.261, Q2 β = 0.859, R2 pred-β = 0.659, spβ = 0.408) explained that hydrophobicity and molar refractivity were crucial for binding affinity in both α- and β-subtypes. The space modeling study (R2 α = 0.955, seα = 1.311, Q2 α = 0.932, R2 pred-α = 0.737, spα = 0.497; R2 β = 0.885, seβ = 1.328, Q2 β = 0.878, R2 pred-β = 0.769, spβ = 0.336) revealed the importance of HB donor and hydrophobic features for both subtypes, whereas, HB acceptor and aromatic ring were critical for α- and β-subtypes respectively. The functionalities developed in the QSAR and pharmacophore studies were substantiated by molecular docking which provided the preferred orientation of ligands for effective interaction at the active site cavity.MA Islam and TS Pillay were funded by the University of Pretoria Vice Chancellor’s post-doctoral fellowship and National Research Foundation (NRF), South Africa Innovation Post-doctoral fellowship schemes.http://link.springer.com/journal/442017-03-31hb2016Chemical Patholog