An ancestral molecular response to nanomaterial particulates.

The varied transcriptomic response to nanoparticles has hampered the understanding of the mechanism of action. Here, by performing a meta-analysis of a large collection of transcriptomics data from various engineered nanoparticle exposure studies, we identify common patterns of gene regulation that impact the transcriptomic response. Analysis identifies deregulation of immune functions as a prominent response across different exposure studies. Looking at the promoter regions of these genes, a set of binding sites for zinc finger transcription factors C2H2, involved in cell stress responses, protein misfolding and chromatin remodelling and immunomodulation, is identified. The model can be used to explain the outcomes of mechanism of action and is observed across a range of species indicating this is a conserved part of the innate immune system.

Comparative binding effects of aspirin and anti-inflammatory Cu complex in the active site of LOX-1.

(1)H NMR Saturation Transfer Difference (STD) experiments were applied to study the binding of aspirin and of an anti-inflammatory complex of Cu(I), namely [Cu(tpp)(pmt)](2) [pmt = 2-mercaptopyrimidine), synthesized in an attempt to develop novel metallotherapeutic molecules. While aspirin showed only very weak binding, the complex [Cu(tpp)(pmt)](2) clearly favored binding to LOX-1. In silico docking experiments in LOX-1 showed that aspirin does only weakly bind to LOX-1, while the complex binds with high affinity. In addition, docking experiments and molecular dynamics (MD) simulations showed that the complex binds via hydrogen bonding (HB), to an allosteric site of LOX-1, revealing that this enzyme has more than one accessible site for complex metallotherapeutic molecules. When aspirin was added in the solution containing LOX and the complex [Cu(tpp)(pmt)](2), the former was shown to hinder the binding of the Cu complex significantly. This may be interpreted as the copper complex aiding the transfer of aspirin through an acid-base reaction at the LOX enzyme which subsequently blocks its binding.

Ligand and structure based virtual screening strategies for hit-finding and optimization of hepatitis C virus (HCV) inhibitors.

Virtual Screening (VS) has experienced increased attention into the recent years due to the large datasets made available, the development of advanced VS techniques and the encouraging fact that VS has contributed to the discovery of several compounds that have either reached the market or entered clinical trials. Hepatitis C Virus (HCV) nonstructural protein 5B (NS5B) has become an attractive target for the development of antiviral drugs and many small molecules have been explored as possible HCV NS5B inhibitors. In parallel with experimental practices, VS can serve as a valuable tool in the identification of novel effective inhibitors. Different techniques and workflows have been reported in literature with the goal to prioritize possible potent hits. In this context, different virtual screening strategies have been deployed for the identification of novel Hepatitis C Virus (HCV) inhibitors. This work reviews recent applications of virtual screening in an effort to identify novel potent HCV inhibitors.