Drug Discovery Using Chemical Systems Biology: Weak Inhibition of Multiple Kinases May Contribute to the Anti-Cancer Effect of Nelfinavir

Nelfinavir is a potent HIV-protease inhibitor with pleiotropic effects in cancer cells. Experimental studies connect its anti-cancer effects to the suppression of the Akt signaling pathway, but the actual molecular targets remain unknown. Using a structural proteome-wide off-target pipeline, which integrates molecular dynamics simulation and MM/GBSA free energy calculations with ligand binding site comparison and biological network analysis, we identified putative human off-targets of Nelfinavir and analyzed the impact on the associated biological processes. Our results suggest that Nelfinavir is able to inhibit multiple members of the protein kinase-like superfamily, which are involved in the regulation of cellular processes vital for carcinogenesis and metastasis. The computational predictions are supported by kinase activity assays and are consistent with existing experimental and clinical evidence. This finding provides a molecular basis to explain the broad-spectrum anti-cancer effect of Nelfinavir and presents opportunities to optimize the drug as a targeted polypharmacology agent

The effect of increasing fine sediment load and drying duration on the re-emergence of Gammarus pulex (Amphipoda: Gammaridae) from the subsurface following flow resumption

1. Environmental change and growing anthropogenic pressure on water resources is increasing the duration and intensity of drying events in streams in many geographical locations. Favourable sediment characteristics (e.g. high porosity and low fine sediment load within the substrate matrix) may facilitate benthic macroinvertebrate use of subsurface sediments in response to drying. However, the influence of sedimentary characteristics on the use and subsequent recovery of macroinvertebrates from initial vertical migration into, survival during unfavourable conditions within and subsequent re-emergence from subsurface sediments has not been directly observed. 2. Transparent mesocosm tanks were used to directly observe the vertical movement and subsequent re-emergence of G. pulex from subsurface sediments in response to increasing dry period (1 day, 7 days or 21 days) and fine sediment load (0.5–1 mm particle diameter used for light and heavy sediment treatment) and following rehydration and resumption of flowing conditions. 3. Increasing volumes of fine sediment addition limited the ability of G. pulex to access subsurface sediment in response to drying and re-emerge following rehydration. The longest dry period (21 days) reduced the ability of G. pulex to re-emerge from the subsurface sediments following rehydration and flow resumption. 4. Increasing fine sediment load negatively affects taxa using subsurface sediments as a refuge. Increased fine sediment deposition has the potential to reduce both access to the sub-surface and re-emergence once surface flow resumes. 5. As many rivers are beginning to dry out, or are showing prolonged drying due to global warming, it is increasingly important that river management reduces the input of fine sediment into rivers and increase sediment porosity of riverbeds to facilitate access into the subsurface refuge by benthic fauna

A reconnaissance survey of channel bank particulate phosphorus concentrations, controls and estimated contributions to riverine loads across England

Channel banks can contribute a significant proportion of fine-grained (20% of the riverine total PP load increased from 15 to 25 (corresponding range of 17–35 using the 25th and 75th percentiles of measured TP concentrations). Collectively, these 25 waterbodies account for 0.2% of the total inland WFD waterbody area comprising England