Structure-based virtual screening of natural products as potential stearoyl-coenzyme a desaturase 1 (SCD1) inhibitors

Stearyl coenzyme A desaturase enzyme 1 (SCD1) is a key enzyme that catalyzes the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA) and plays a vital role in lipid metabolism of tumor cells. SCD1 is overexpressed in a variety of malignant tumors, and its related inhibitors showed significant anti-tumor activity in vitro and in vivo experiments, which is a new target for tumor therapy. The focus of this study is to identify novel SCD1 inhibitors from natural products through computer simulations. First, 176,602 compounds from natural product databases were virtually screened. By molecular dynamics (MD) simulations, the ligand-protein interactions of 5 compounds with high docking manifestation were analyzed accurately. Then, MM-GBSA and MM-PBMA methods were used to verify the results. Finally, ADMET prediction was performed for the 5 compounds. As a result, two natural products with potential inhibition towards SCD1 were identified, which had the excellent docking manifestation, binding mode within SCD1 pocket and stability during molecular dynamics simulation. This study provides a meaningful model for the development and optimization of new inhibitors and anti-tumor drugs targeting SCD1.     

Linked drug-drug conjugates based on triterpene and phenol structures. Rational synthesis,molecular properties,toxicity and bioactivity prediction

One of the tasks of modern medicinal chemistry is to produce new molecules that have interesting and desired biological effects. In addition, the synthetic procedure for obtaining these compounds should be at least partially smart and rational e.g. “Lego” and green approaches. The study focuses on the synthesis of several hybrid type compounds that are expected to be characterized by beneficial bioactivities. In order to hybridize natural triterpene oleanolic acid and phenol structures, the linker-mode concept was selected. The synthetic goal was achieved in two stages. The first concerns the rapid introduction of the halogenoacidic linker to active phenols selected as a result of microwave-ultrasonic (MW-US) assisted O-alkylation with the use of 2-halogenoacetic acid. The next stage of the synthetic studies involves the reaction of phenoxyacetic acid derivatives obtained containing an active carboxylic group with oleanolic acid/oxime units by the methods typical of triterpene chemistry. Novel linked ester- and iminoester-type triterpene derivatives with phenols (thymol, eugenol, paracetamol, nipagins, naphthols, curcumin and genistein) were obtained and characterized. Additionally, based on the analysis of numerous references and selected methods of computational chemistry (Molinspiration Cheminformatics, Osiris Property Explorer and PASS method) the molecular parameters and the preliminary anti-inflammatory and antinociceptive activity characterising these molecules as potential drugs were calculated and predicted.     

Cheminformatics in MS-based environmental exposomics: Current achievements and future directions

Compound annotation using MS/MS data is the major bottleneck in interpretation of mass spectrometry data during non-targeted screening and suspect screening exposomics studies. Apart from compound identification using available databases or mass spectral libraries, the true challenge comes when completely new compounds have to be identified. Along with recent advances in MS instrumentation that set grounds to a new revolutionary age in environmental exposomics, a multitude of cheminformatics annotation approaches has been developed. Herein, we review the basic principles of the cutting-edge cheminformatics MS-based approaches employed in eco-exposome annotation.We give a solid background discussing the eco-exposome concept in relation to the advances in MS instrumentation, and define the three crucial cheminformatics tasks used in the eco-exposome annotation: molecular formula assignment, compound prioritization and compound annotation. The basic principles of compound annotation are discussed, which are based on three approaches of utilizing structural information inherent to MS data. These involve direct, indirect and joint annotation approaches. We assess their performance through the ability to annotate eco-exposome constituents. We discuss future perspectives and give directions to new annotation strategies and performance evaluation protocols aiming to solve current issues hampering the incorporation of cheminformatics annotation approaches in regular eco-exposome annotation workflows.     

固体异质结界面结构预测方法及AutoInterface程序实现

预测材料异质结的界面原子结构对于理解界面对性能的影响至关重要. 目前, 从理论上预测材料界面结构仍具有极大挑战, 主要是缺乏普适有效的理论计算方法. 本文介绍了本课题组在异质结界面结构预测方面取得的最新进展. 结合马氏体相变唯象理论、 图论和随机表面行走算法, 提出了界面结构的一种有效预测方法, 可以实现自动化的计算预测. 通过GaP/TiO₂半导体异质结等展示了该方法的有效性和在催化等领域的应用前景.     

Exploring the Limits of Transition-Metal Fluorination at High Pressures

Fluorination is a proven method for challenging the limits of chemistry, both structurally and electronically. Here we explore computationally how pressures below 300 GPa affect the fluorination of several transition metals. A plethora of new structural phases are predicted along with the possibility for synthesizing four unobserved compounds: TcF₇, CdF₃, OsF₈, and IrF₈. The Ir and Os octaflourides are both predicted to be stable as quasi-molecular phases with an unusual cubic ligand coordination, and both compounds formally correspond to a high oxidation state of +8. Electronic-structure analysis reveals that otherwise unoccupied 6p levels are brought down in energy by the combined effects of pressure and a strong ligand field. The valence expansion of Os and Ir enables ligand-to-metal F 2p→M 6p charge transfer that strengthens M−F bonds and decreases the overall bond polarity. The lower stability of IrF₈, and the instability of PtF₈ and several other compounds below 300 GPa, is explained by the occupation of M−F antibonding orbitals in octafluorides with a metal-valence-electron count exceeding 8.     

Predicting Regioselectivity in Radical C−H Functionalization of Heterocycles through Machine Learning

Radical C−H bond functionalization provides a versatile approach for elaborating heterocyclic compounds. The synthetic design of this transformation relies heavily on the knowledge of regioselectivity, while a quantified and efficient regioselectivity prediction approach is still elusive. Herein, we report the feasibility of using a machine learning model to predict the transition state barrier from the computed properties of isolated reactants. This enables rapid and reliable regioselectivity prediction for radical C−H bond functionalization of heterocycles. The Random Forest model with physical organic features achieved 94.2 % site accuracy and 89.9 % selectivity accuracy in the out-of-sample test set. The prediction performance was further validated by comparing the machine learning results with additional substituents, heteroarene scaffolds and experimental observations. This work revealed that the combination of mechanism-based computational statistics and machine learning model can serve as a useful strategy for selectivity prediction of organic transformations.     

Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach

The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion-corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol⁻¹) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher-order molecular ICCs with functional properties.     

基于层次分析法的隧道综合地质预报优化

隧道综合地质预报是解决隧道施工期地质问题、降低施工风险的一项重要技术手段。鉴于目前综合预报多为简单的数量上的综合,为更加有效地利用综合预报技术,首先归纳地质分析辨识常见不良地质体的方法,通过地质分析法初步判定隧道掌子面前方可能存在的地质异常,并结合层次分析法的基本思路,将影响预报手段的指标量化,即赋予预报方法权重,建立二级综合评价指标体系,研究不同预报方法对特定工程地质条件的适用性,以选择几种最优预报方法。主要研究结论如下:利用地质分析法定性、层次分析法定量的方法优选预报手段,减少了综合超前地质预报中物探手段选择的随意性,并据此建立综合预报体系。最后将该体系应用于紫荆山隧道F2断层的预报中,成功预报了ZK221+960处地下暗河,避免了施工事故的发生,取得了一定的经济效益,证明了通过层次分析法来优化综合预报方法的可行性。     

16Mn钢在不同条件下的疲劳行为研究

对截面为3 mm×3mm的16Mn钢试件在空气和3.5%NaCl溶液中分别进行疲劳试验,获得了S-N曲线,并对疲劳试样表面和断口形貌进行了观察.结果表明:与空气相比,3.5%NaCl腐蚀溶液使16Mn钢的疲劳强度显著降低;在空气中疲劳试样只有一个萌生于试样表面基体的裂纹源,而在3.5%NaCl溶液中一般有多个裂纹源,而...     

我国生猪年度供给量预测研究

在运用协整检验、成本分析等方法对生猪供给量的影响因素进行分析的基础上,综合运用了回归分析、专家经验分析、指数平滑、情景预测等预测和决策方法,对我国2010-2012年的生猪年度供给量进行了预测.预测结果表明,在不发生影响生猪供给的重大突发事件的情况下,2010-2012年我国生猪产量将呈逐年上升的趋势.