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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

Targeted cancer therapy has become one of the high potential cancer treatments. Human topoisomerase II (hTopoII), which catalyzes the cleavage and rejoining of double-stranded DNA, is an important molecular target for the development of novel cancer therapeutics. In order to diversify the pharmacological activity of chalcones and to extend the scaffold of topoisomerase inhibitors, a series of chalcones was screened against hTopoIIα by computational techniques, and subsequently tested for their in vitro cytotoxicity. From the experimental IC50 values, chalcone 3d showed a high cytotoxicity with IC50 values of 10.8, 3.2 and 21.1 µM against the HT-1376, HeLa and MCF-7 cancer-derived cell lines, respectively, and also exhibited an inhibitory activity against hTopoIIα-ATPase that was better than the known inhibitor, salvicine. The observed ligand–protein interactions from a molecular dynamics study affirmed that 3d strongly interacts with the ATP-binding pocket residues. Altogether, the newly synthesised chalcone 3d has a high potential to serve as a lead compound for topoisomerase inhibitors.

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.