An Integrated Computational and Experimental Approach to Identifying Inhibitors for SARS-CoV-2 3CL Protease

The newly evolved SARS-CoV-2 has caused the COVID-19 pandemic, and the SARS-CoV-2 main protease 3CLpro is essential for the rapid replication of the virus. Inhibiting this protease may open an alternative avenue toward therapeutic intervention. In this work, a computational docking approach was developed to identify potential small-molecule inhibitors for SARS-CoV-2 3CLpro. Totally 288 potential hits were identified from a half-million bioactive chemicals via a protein-ligand docking protocol. To further evaluate the docking results, a quantitative structure activity relationship (QSAR) model of 3CLpro inhibitors was developed based on existing small molecule inhibitors of the 3CLproSARS– CoV– 1 and their corresponding IC50 data. The QSAR model assesses the physicochemical properties of identified compounds and estimates their inhibitory effects on 3CLproSARS– CoV– 2. Seventy-one potential inhibitors of 3CLpro were selected through these computational approaches and further evaluated via an enzyme activity assay. The results show that two chemicals, i.e., 5-((1-([1,1′-biphenyl]-4-yl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-trione and N-(4-((3-(4-chlorophenylsulfonamido)quinoxalin-2-yl)amino)phenyl)acetamide, effectively inhibited 3CLpro SARS-CoV-2 with IC50’s of 19 ± 3 μM and 38 ± 3 μM, respectively. The compounds contain two basic structures, pyrimidinetrione and quinoxaline, which were newly found in 3CLpro inhibitor structures and are of high interest for lead optimization. The findings from this work, such as 3CLpro inhibitor candidates and the QSAR model, will be helpful to accelerate the discovery of inhibitors for related coronaviruses that may carry proteases with similar structures to SARS-CoV-2 3CLpro

Pairing in the iron arsenides: a functional RG treatment

We study the phase diagram of a microscopic model for the superconducting iron arsenides by means of a functional renormalization group. Our treatment establishes a connection between a strongly simplified two-patch model by Chubukov et al. and a five-band- analysis by Wang et al.. For a wide parameter range, the dominant pairing instability occurs in the extended s-wave channel. The results clearly show the relevance of pair scattering between electron and hole pockets. We also give arguments that the phase transition between the antiferromagnetic phase for the undoped system and the superconducting phase may be first order

Magnetically asymmetric interfaces in a (LaMnO3_3)/(SrMnO3_3) superlattice due to structural asymmetries

Polarized neutron reflectivity measurements of a ferromagnetic [(LaMnO$_3$)$_{11.8}$/(SrMnO$_3$)$_{4.4}$]$_6$ superlattice reveal a modulated magnetic structure with an enhanced magnetization at the interfaces where LaMnO$_3$ was deposited on SrMnO$_3$ (LMO/SMO). However, the opposite interfaces (SMO/LMO) are found to have a reduced ferromagnetic moment. The magnetic asymmetry arises from the difference in lateral structural roughness of the two interfaces observed via electron microscopy, with strong ferromagnetism present at the interfaces that are atomically smooth over tens of nanometers. This result demonstrates that atomic-scale roughness can destabilize interfacial phases in complex oxide heterostructures.Comment: 5 pages, 4 figure

An improved continuous compositional-spread technique based on pulsed-laser deposition and applicable to large substrate areas

A new method for continuous compositional-spread (CCS) thin-film fabrication based on pulsed-laser deposition (PLD) is introduced. This approach is based on a translation of the substrate heater and the synchronized firing of the excimer laser, with the deposition occurring through a slit-shaped aperture. Alloying is achieved during film growth (possible at elevated temperature) by the repeated sequential deposition of sub-monolayer amounts. Our approach overcomes serious shortcomings in previous in-situ implementations of CCS based on sputtering or PLD, in particular the variations of thickness across the compositional spread and the differing deposition energetics as function of position. While moving-shutter techniques are appropriate for PLD-approaches yielding complete spreads on small substrates (i.e. small as compared to distances over which the deposition parameters in PLD vary, typically about 1 cm), our method can be used to fabricate samples that are large enough for individual compositions to be analyzed by conventional techniques, including temperature-dependent measurements of resistivity and dielectric and magnetic and properties (i.e. SQUID magnetometry). Initial results are shown for spreads of (Sr,Ca)RuO$_3$.Comment: 6 pages, 8 figures, accepted for publication in Rev. Sci. Instru

On the error term in Weyl's law for the Heisenberg manifolds (II)

In this paper we study the mean square of the error term in the Weyl's law of an irrational $(2l+1)$-dimensional Heisenberg manifold . An asymptotic formula is established

Non-Compositional Term Dependence for Information Retrieval

Modelling term dependence in IR aims to identify co-occurring terms that are too heavily dependent on each other to be treated as a bag of words, and to adapt the indexing and ranking accordingly. Dependent terms are predominantly identified using lexical frequency statistics, assuming that (a) if terms co-occur often enough in some corpus, they are semantically dependent; (b) the more often they co-occur, the more semantically dependent they are. This assumption is not always correct: the frequency of co-occurring terms can be separate from the strength of their semantic dependence. E.g. "red tape" might be overall less frequent than "tape measure" in some corpus, but this does not mean that "red"+"tape" are less dependent than "tape"+"measure". This is especially the case for non-compositional phrases, i.e. phrases whose meaning cannot be composed from the individual meanings of their terms (such as the phrase "red tape" meaning bureaucracy). Motivated by this lack of distinction between the frequency and strength of term dependence in IR, we present a principled approach for handling term dependence in queries, using both lexical frequency and semantic evidence. We focus on non-compositional phrases, extending a recent unsupervised model for their detection [21] to IR. Our approach, integrated into ranking using Markov Random Fields [31], yields effectiveness gains over competitive TREC baselines, showing that there is still room for improvement in the very well-studied area of term dependence in IR

A Wave Function Describing Superfluidity in a Perfect Crystal

We propose a many-body wave function that exhibits both diagonal and off-diagonal long-range order. Incorporating short-range correlations due to interatomic repulsion, this wave function is shown to allow condensation of zero-point lattice vibrations and phase rigidity. In the presence of an external velocity field, such a perfect crystal will develop non-classical rotational inertia, exhibiting the supersolid behavior. In a sample calculation we show that the superfluid fraction in this state can be as large as of order 0.01 in a reasonable range of microscopic parameters. The relevance to the recent experimental evidence of a supersolid state by Chan and Kim is discussed.Comment: final version to be published in Journal of Statistical Mechanics: Theory and Experimen

Identification of the relationship between Chinese Adiantum reniforme var. sinense and Canary Adiantum reniforme

© 2014 Wang et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated