Free Energy-Based Virtual Screening and Optimization of RNase H Inhibitors of HIV‑1 Reverse Transcriptase

We report the results of a binding free energy-based virtual screening campaign of a library of 77 α-hydroxytropolone derivatives against the challenging RNase H active site of the reverse transcriptase (RT) enzyme of human immunodeficiency virus-1. Multiple protonation states, rotamer states, and binding modalities of each compound were individually evaluated. The work involved more than 300 individual absolute alchemical binding free energy parallel molecular dynamics calculations and over 1 million CPU hours on national computing clusters and a local campus computational grid. The thermodynamic and structural measures obtained in this work rationalize a series of characteristics of this system useful for guiding future synthetic and biochemical efforts. The free energy model identified key ligand-dependent entropic and conformational reorganization processes difficult to capture using standard docking and scoring approaches. Binding free energy-based optimization of the lead compounds emerging from the virtual screen has yielded four compounds with very favorable binding properties, which will be the subject of further experimental investigations. This work is one of the few reported applications of advanced-binding free energy models to large-scale virtual screening and optimization projects. It further demonstrates that, with suitable algorithms and automation, advanced-binding free energy models can have a useful role in early-stage drug-discovery programs

Photoelectrocatalytic Oxidation of Cu^II–EDTA at the TiO₂ Electrode and Simultaneous Recovery of Cu^II by Electrodeposition

The simultaneous decomplexation of Cu–EDTA and electrodeposition recovery of Cu²⁺ ions was attempted in a photoelectrocatalytic (PEC) system using TiO₂/Ti as the anode and stainless steel as the cathode. At a current density of 0.5 mA/cm², removal efficiencies of 0.05 mM Cu–EDTA by photocatalysis, electrooxidation, and PEC processes were determined to be 15, 43, and 72% at 3 h, respectively. Recovery percentages of Cu²⁺ ions were determined to be 10, 33, and 67%, respectively. These results indicated that a synergetic effect in the decomplexation of Cu–EDTA and recovery of Cu²⁺ ions occurred in the PEC process, which favored acid conditions and increased with the current densities. The removal of Cu–EDTA and Cu²⁺ ions can be described by a pseudo-first-order kinetics model. Ca²⁺ ions significantly increase the removal of Cu–EDTA and recovery of Cu²⁺ ions. Intermediates, including Cu–NTA, Cu–EDDA, acetic acid, formic acid, and oxalic acid, were identified, and a decomplexation pathway of Cu–EDTA was proposed. The Cu–EDTA decomplexation at the anode via oxidation of hydroxyl radicals was revealed. On the basis of X-ray photoelectron spectra analysis, a reduction pathway of Cu²⁺ ions at the cathode was discussed. The present study may provide a promising alternative for destruction of the metal complex and recovery of metal ions

Highly-Efficient Dendritic Cable Electrodes for Flexible Supercapacitive Fabric

In the search for clothlike wearable energy-storage devices with both high energy density and high power density, metal fibers surrounded by micro metal dendrites, as current collectors, are either rooted inside a thick layer of carbon particles or wrapped with flowerlike nano NiO in a similar manner to the root or stem system of natural plants, to form dendritic cablelike negative or positive electrodes. These dendritic cable electrodes could be further combined or woven into flexible solid-type supercapacitive garland or fabric, together with cotton wires. Benefiting from the ultra large interface of the metal dendrites current collector, it can be charged up to 1.8 V, and give an energy density of 0.1408 mWh cm^–2 and a power density of 3.01 mW cm^–2, which is capable of directly starting a small electric car with a short and flexible piece of supercapacitor

Additional file 1: of Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse

Effects of neuronal seipin knockout on Aβ1-42-induced neurotoxicity and neuroinflammation. (116 KB