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A similarity search was conducted on the U.S. Enhanced National Cancer Institute Database Browser 2.2 to find structures related to 1,5-dihydroxy-9H-xanthen-9-one, a previously established EGFR-TK inhibitor. Compounds were virtually screened and selected for bioactivity testing revealed 5 candidates, mostly displayed stronger antiproliferative activities than erlotinib with IC

The 20S core particle of the eukaryotic proteasome is composed of two α- and two β-rings, each of which is a hetero-heptamer composed of seven homologous but distinct subunits. Although formation of the eukaryotic proteasome is a highly ordered process assisted by assembly chaperones, α7, an α-ring component, has the unique property of self-assembling into a homo-tetradecamer. We used biophysical methods to characterize the oligomeric states of this proteasome subunit and its interaction with α6, which makes direct contacts with α7 in the proteasome α-ring. We determined a crystal structure of the α7 tetradecamer, which has a double-ring structure. Sedimentation velocity analytical ultracentrifugation and mass spectrometric analysis under non-denaturing conditions revealed that α7 exclusively exists as homo-tetradecamer in solution and that its double-ring structure is disassembled upon the addition of α6, resulting in a 1:7 hetero-octameric α6–α7 complex. Our findings suggest that proteasome formation involves the disassembly of non-native oligomers, which are assembly intermediates.

Paramagnetism-assisted nuclear magnetic resonance (NMR) techniques can provide long-range structural information complemented with local information derived from chemical-shift perturbation and nuclear Overhauser effect data. Here, we address the application of paramagnetic relaxation enhancement (PRE) to detect inhibitor-induced conformational change of a drug target protein using human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) as a model protein. Using a site-specific spin-labeled HIV-1 RT mutant with selective (13) C labeling, conformation-dependent PREs were successfully observed reflecting the stabilization of an open conformation of this enzyme caused by inhibitor binding. This study demonstrates that the paramagnetism-assisted NMR approach offers an alternative strategy in protein-based drug screening to identify allosteric inhibitors of a target protein.

The work demonstrates, for the first time, natural biological changes in fish during maturing processes using a unique combination of different biochemical techniques. Northeast Arctic cod caught by demersal trawls were studied in three Barents Sea areas during February–March 2008. Older larger cod from area A (between North Kanin Bank and Eastern Basin) had higher food utilization efficiency (with females showing highest white muscle protein synthesis capacity) than those from areas B (Kanin Bank) and C (Central Bank). Populations in areas A and C living in separate environments showed parallel regressions of pyloric caecal slope T/C ratio, with different elevations of trypsin specific activities and trypsin isozymes expressions. Approximately 30 trypsin isozymes were observed, with 13 isozymes of possibly exogenous trypsin isozyme fragments from prey items found at higher percentage of cod in areas A and B with higher food varieties. Larger maturing cod required higher energy from carbohydrate (probably phytoplankton), as amylase specific activity correlated with body weight. White muscle RNA levels were varied among females from different areas, but not among males. RNA and RNA/protein ratio levels were higher in oocytes than white muscle, and these levels decreased in higher developed oocytes. Oocyte trypsin-like specific activity in areas B < A < C (with oocyte T/C ratio in areas B > A > C) illustrated that females from area B (youngest with lowest oocyte protein turnover) had highest maturation rate, and would reach their spawning area(s) before those from areas A and C. Younger females (probably also males) living closer to coastal area with higher temperature and food varieties would reach sexual maturity faster than older cod and those living far from coastal area. Ecological effects on food utilization, trypsin isozymes, and performance qualities of growth and maturation in Northeast Arctic cod (Gadus morhua L.)

Background Structural modifications of thiazolidinediones at 3rd and 5th position have exhibited significant biological activities. In view of the facts, and based on in silico studies carried out on thiazolidine-2,4-diones as HIV-1- RT inhibitors, a novel series of 2,4-thiazolidinedione analogs have been designed and synthesized. Methods Title compounds were prepared by the reported method. Conformations of the structures were assigned on the basis of results of different spectral data. The assay of HIV-1 RT was done as reported by Silprasit et al. Antimicrobial activity was determined by two fold serial dilution method. Docking study was performed for the highest active compounds by using Glide 5.0. Results The newly synthesized compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, compound 24 showed significant HIV-1 RT inhibitory activity with 73% of inhibition with an IC50 value of 1.31 μM. Compound 10 showed highest activity against all the bacterial strains. A molecular modeling study was carried out in order to investigate the possible interactions of the highest active compounds 24, 10 and 4 with the non nucleoside inhibitory binding pocket(NNIBP) of RT, active site of GlcN-6-P synthase and cytochrome P450 14-α-sterol demethylase from Candida albicans (Candida P450DM) as the target receptors respectively using the Extra Precision (XP) mode of Glide software. Conclusion A series of novel substituted 2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(phenyl)propanamides (4–31) have been synthesized and evaluated for their HIV-1 RT inhibitory activity, antibacterial and antifungal activities. Some of the compounds have shown significant activity. Molecular docking studies showed very good interaction.