<i>In Situ</i> Chemical Modification of Schottky Barrier in Solution-Processed Zinc Tin Oxide Diode

Here we present a novel <i>in situ</i> chemical modification process to form vertical Schottky diodes using palladium (Pd) rectifying bottom contacts, amorphous zinc tin oxide (Zn–Sn–O) semiconductor made via acetate-based solution process, and molybdenum top ohmic contacts. Using X-ray photoelectron spectroscopy depth profiling, we show that oxygen plasma treatment of Pd creates a PdO_<i>x</i> interface layer, which is then reduced back to metallic Pd by <i>in situ</i> reactions during Zn–Sn–O film annealing. The plasma treatment ensures an oxygen-rich environment in the semiconductor near the Schottky barrier, reducing the level of oxygen-deficiency-related defects and improving the rectifying contact. Using this process, we achieve diodes with high forward current density exceeding 10³A cm^–2 at 1 V, rectification ratios of >10², and ideality factors of around 1.9. The measured diode current–voltage characteristics are compared to numerical simulations of thermionic field emission with sub-bandgap states in the semiconductor, which we attribute to spatial variations in metal stoichiometry of amorphous Zn–Sn–O. To the best of our knowledge, this is the first demonstration of vertical Schottky diodes using solution-processed amorphous metal oxide semiconductor. Furthermore, the <i>in situ</i> chemical modification method developed here can be adapted to tune interface properties in many other oxide devices

Concerted Cyclization of Lanosterol C‑Ring and D‑Ring Under Human Oxidosqualene Cyclase Catalysis: An ab Initio QM/MM MD Study

Human oxidosqualene cyclase (OSC) is one key enzyme in the biosynthesis of cholesterol. It can catalyze the linear-chain 2,3-oxidosqualene to form lanosterol, the tetracyclic (6–6–6–5 members for A–B–C–D rings) cholesterol precursor. It also has been treated as a novel antihyperlipidemia target. In addition, the structural diversity of cyclic terpenes in plants originates from the cyclization of 2,3-oxidosqualene. The enzyme catalytic mechanism is considered to be one of the most complicated ones in nature, and there are a lot of controversies about the mechanism in the past half a century. Herein, state-of-the-art ab initio QM/MM MD simulations are employed to investigate the detailed cyclization mechanism of C-ring and D-ring formation. Our study reveals that the C and D rings are formed near-synchronously from a stable “6–6–5” ring intermediate. Interestingly, the transition state of this concerted reaction presents a “6–6-6” structure motif, while this unstable “6–6-6” structure in our simulations is thought to be a stable intermediate state in most previous hypothetical mechanisms. Furthermore, as the tailed side chain of 2,3-oxidosqualene shows a β conformation while it is α conformation in lanosterol, finally, it is observed that the rotatable “tail” chain prefers to transfer β conformation to α conformation at the “6–6–5” intermediate state

Enhancing Molecular Shape Comparison by Weighted Gaussian Functions

Shape comparing technologies based on Gaussian functions have been widely used in virtual screening of drug discovery. For efficiency, most of them adopt the First Order Gaussian Approximation (FOGA), in which the shape density of a molecule is represented as a simple sum of all individual atomic shape densities. In the current work, the effectiveness and error in shape similarity calculated by such an approximation are carefully analyzed. A new approach, which is called the Weighted Gaussian Algorithm (WEGA), is proposed to improve the accuracy of the first order approximation. The new approach significantly improves the accuracy of molecular volumes and reduces the error of shape similarity calculations by 37% using the hard-sphere model as the reference. The new algorithm also keeps the simplicity and efficiency of the FOGA. A program based on the new method has been implemented for molecular overlay and shape-based virtual screening. With improved accuracy for shape similarity scores, the new algorithm also improves virtual screening results, particularly when a shape-feature combo scoring function is used

Protein–Ligand-Based Pharmacophores: Generation and Utility Assessment in Computational Ligand Profiling

Ligand profiling is an emerging computational method for predicting the most likely targets of a bioactive compound and therefore anticipating adverse reactions, side effects and drug repurposing. A few encouraging successes have already been reported using ligand 2-D similarity searches and protein–ligand docking. The current study describes the use of receptor–ligand-derived pharmacophore searches as a tool to link ligands to putative targets. A database of 68,056 pharmacophores was first derived from 8,166 high-resolution protein–ligand complexes. In order to limit the number of queries, a maximum of 10 pharmacophores was generated for each complex according to their predicted selectivity. Pharmacophore search was compared to ligand-centric (2-D and 3-D similarity searches) and docking methods in profiling a set of 157 diverse ligands against a panel of 2,556 unique targets of known X-ray structure. As expected, ligand-based methods outperformed, in most of the cases, structure-based approaches in ranking the true targets among the top 1% scoring entries. However, we could identify ligands for which only a single method was successful. Receptor–ligand-based pharmacophore search is notably a fast and reliable alternative to docking when few ligand information is available for some targets. Overall, the present study suggests that a workflow using the best profiling method according to the protein–ligand context is the best strategy to follow. We notably present concrete guidelines for selecting the optimal computational method according to simple ligand and binding site properties

Discovery of New Selective Human Aldose Reductase Inhibitors through Virtual Screening Multiple Binding Pocket Conformations

Aldose reductase reduces glucose to sorbitol. It plays a key role in many of the complications arising from diabetes. Thus, aldose reductase inhibitors (ARI) have been identified as promising therapeutic agents for treating such complications of diabetes, as neuropathy, nephropathy, retinopathy, and cataracts. In this paper, a virtual screening protocol applied to a library of compounds in house has been utilized to discover novel ARIs. IC₅₀’s were determined for 15 hits that inhibited ALR2 to greater than 50% at 50 μM, and ten of these have an IC₅₀ of 10 μM or less, corresponding to a rather substantial hit rate of 14% at this level. The specificity of these compounds relative to their cross-reactivity with human ALR1 was also assessed by inhibition assays. This resulted in identification of novel inhibitors with IC₅₀’s comparable to the commercially available drug, epalrestat, and greater than an order of magnitude better selectivity