Pharmacophore-Based Virtual Screening,Quantum Mechanics Calculations,and Molecular Dynamics Simulation Approaches Identified Potential Natural Antiviral Drug Candidates against MERS-CoV S1-NTD

Middle East respiratory syndrome coronavirus (MERS-CoV) is a highly infectious zoonotic virus first reported into the human population in September 2012 on the Arabian Peninsula. The virus causes severe and often lethal respiratory illness in humans with an unusually high fatality rate. The N-terminal domain (NTD) of receptor-binding S1 subunit of coronavirus spike (S) proteins can recognize a variety of host protein and mediates entry into human host cells. Blocking the entry by targeting the S1-NTD of the virus can facilitate the development of effective antiviral drug candidates against the pathogen. Therefore, the study has been designed to identify effective antiviral drug candidates against the MERS-CoV by targeting S1-NTD. Initially, a structure-based pharmacophore model (SBPM) to the active site (AS) cavity of the S1-NTD has been generated, followed by pharmacophore-based virtual screening of 11,295 natural compounds. Hits generated through the pharmacophore-based virtual screening have re-ranked by molecular docking and further evaluated through the ADMET properties. The compounds with the best ADME and toxicity properties have been retrieved, and a quantum mechanical (QM) based density-functional theory (DFT) has been performed to optimize the geometry of the selected compounds. Three optimized natural compounds, namely Taiwanhomoflavone B (Amb23604132), 2,3-Dihydrohinokiflavone (Amb23604659), and Sophoricoside (Amb1153724), have exhibited substantial docking energy >−9.00 kcal/mol, where analysis of frontier molecular orbital (FMO) theory found the low chemical reactivity correspondence to the bioactivity of the compounds. Molecular dynamics (MD) simulation confirmed the stability of the selected natural compound to the binding site of the protein. Additionally, molecular mechanics generalized born surface area (MM/GBSA) predicted the good value of binding free energies (ΔG bind) of the compounds to the desired protein. Convincingly, all the results support the potentiality of the selected compounds as natural antiviral candidates against the MERS-CoV S1-NTD.     

Interaction between Curcumin and β-Casein: Multi-Spectroscopic and Molecular Dynamics Simulation Methods

Effect of temperature and pH on the interaction of curcumin with β-casein was explored by fluorescence spectroscopy, ultraviolet-visible spectroscopy and molecular dynamics simulation. The spectroscopic results showed that curcumin could bind to β-casein to form a complex which was driven mainly by electrostatic interaction. The intrinsic fluorescence of β-casein was quenched by curcumin through static quenching mechanism. The binding constants of curcumin to β-casein were 6.48 × 10⁴ L/mol (298 K), 6.17 × 10⁴ L/mol (305 K) and 5.73 × 10⁴ L/mol (312 K) at pH 2.0, which was greater than that (3.98 × 10⁴ L/mol at 298 K, 3.90 × 10⁴ L/mol at 305 K and 3.41 × 10⁴ L/mol at 312 K) at pH 7.4. Molecular docking study showed that binding energy of β-casein-curcumin complex at pH 2.0 (−7.53 kcal/mol) was lower than that at pH 7.4 (−7.01 kcal/mol). The molecular dynamics simulation study showed that the binding energy (−131.07 kJ/mol) of β-casein-curcumin complex was relatively low at pH 2.0 and 298 K. α-Helix content in β-casein was decreased and random coil content was increased in the presence of curcumin. These results can promote a deep understanding of interaction between curcumin and β-casein and provide a reference for improving the bioavailability of curcumin.     

Molecular interaction of silybin with hyaluronidase: A spectroscopic and molecular docking study

In this study, the molecular interaction of silybin with hyaluronidase was investigated by spectroscopic methods and molecular docking. It was found that silybin had strong ability to quench the intrinsic fluorescence of hyaluronidase by a static quenching procedure. The binding constants were obtained at three temperatures (293, 298, and 310 K). The results of synchronous fluorescence and three-dimensional fluorescence and molecular docking showed that silybin bound into the hyaluronidase cavity site and the binding of silybin to hyaluronidase could induce micro-environmental and conformational changes in hyaluronidase, which resulted in the reduced hyaluronidase activity. The thermodynamic parameter analysis and molecular docking experiments revealed that all types of non-covalent interaction, including hydrogen bonding interaction, van der Waals forces, hydrophobic interaction, and electrostatic interaction were present in the binding process of silybin with hyaluronidase. The results obtained here will provide direct evidence at a molecular level to understand the mechanism of the inhibitory effect of silybin against hyaluronidase.     

Investigation on the interaction of glipizide with bovine hemoglobin by spectroscopy and molecular docking

This study aims to investigate the interaction between glipizide and bovine hemoglobin using fluorescence quenching, circular dichroism spectroscopy in various temperatures (293, 303, and 310?K) and molecular docking methods. The results demonstrated that glipizide could cause strong fluorescence quenching of bovine hemoglobin by a dynamic quenching mechanism, during which the hydrophobic interaction played a dominant role in this system. The order of magnitude of binding constant is 10⁴, and the number of binding site in the system was close to 1. It also showed that tyrosine residues and tryptophan residues were both involved in the binding of glipizide with bovine hemoglobin, and was closer to the later. Circular dichroism spectra revealed that the conformation of bovine hemoglobin was changed during the binding reaction. The interaction of the system was studied by both spectroscopic method and molecular docking simulation, and the conclusions are consistent.     

同步荧光光谱法结合分子对接研究金雀花碱与牛血清白蛋白间相互作用

金雀花碱(Cy)是一种生物碱,主要存在于豆科毒豆属植物种子中。Cy具有较强的生物活性,特别是作为戒烟药物已得到广泛应用。在模拟生理条件下,应用荧光光谱法研究了Cy同牛血清白蛋白(BSA)之间的相互作用以及Cy猝灭BSA荧光发射的机理。详细考查了水浴温度、水浴时间以及溶液pH等因素对荧光猝灭的影响,并且通过Stem-Volmer方程计算了Cy与BSA间的结合类型、结合位点数目以及结合常数。结果表明,Cy与BSA可形成摩尔比为1∶1的非共价复合物,其结合常数为5.6×103,其猝灭类型为静态猝灭。同步荧光光谱研究结果表明,Cy的结合主要影响BSA 的Trp残基的荧光发射。进一步应用分子对接研究表明,氢键与疏水作用是Cy与BSA形成复合物的主要推动力。Cy与BSA中Trp213及其周围的氨基酸残基间存在氢键与疏水作用,这种作用将改变Trp213所处微环境的疏水情况,从而导致BSA的荧光发生猝灭。     

光谱法和分子对接模拟技术研究托拉塞米与胃蛋白酶和胰蛋白酶的相互作用

托拉塞米(TOR)属于吡啶磺酰脲类袢利尿剂,被广泛有效地用于高血压,心脏衰竭,慢性肾功能衰竭和肝脏疾病的治疗。TOR在治疗过程中易引起的不良反应之一为轻微肠胃不适。然而,TOR与消化蛋白酶(胰蛋白酶和胃蛋白酶)分子间的相互作用鲜有报道。在模拟生理条件下,采用荧光光谱、紫外-可见吸收光谱、圆二色谱和分子对接技术研究了不同温度下托拉塞米(Torasemide, TOR)与胃蛋白酶(Pepsin)和胰蛋白酶(Trypsin)间的相互作用。所有荧光数据均进行了内滤光校正以获得更准确的结合参数。结果表明,TOR-Pepsin和TOR-Trypsin体系的猝灭常数(K_SV)均与温度呈负相关,说明TOR与Pepsin及Trypsin之间的作用机制均为静态荧光猝灭。利用紫外-可见吸收光谱、同步荧光光谱、3D荧光光谱和圆二色光谱法考查了TOR对Trypsin和Pepsin构象的影响。结果发现胃蛋白酶或胰蛋白酶中酪氨酸残基的极性改变较色氨基更明显,TOR可改变色氨酸残基的微环境并降低Trypsin和Pepsin中β-折叠结构,进而可能影响其生理功能。分子对接结果表明,TOR与Pepsin的结合位点位于由Asp-32和Asp-215组成的活性中心周围,从而抑制Pepsin活性。而TOR通过疏水作用力结合在Trypsin的口袋型底物结合位点(S1口袋),促进底物进入酶活性中心,最终表现为Trypsin活性升高。该研究探讨了TOR与胃蛋白酶和胰蛋白酶的结合作用和毒性机制,为TOR的安全使用提供重要依据。     

洋刀豆脲酶与抑制剂相互作用的分子对接和分子动力学研究

通过洋刀豆脲酶抑制剂的筛选实验得到具有较好抑制活性的化合物2-乙酰基-γ-丁内酯(COM), 其半数抑制浓度在微摩尔浓度级别(IC₅₀＝375 μmol•L^－l). 在此基础上, 使用分子对接和分子动力学(MD)模拟的方法研究洋刀豆脲酶与抑制剂乙酰氧肟酸(AHA)及活性化合物COM之间的相互作用. 用Gold3.0程序将两个小分子与洋刀豆脲酶的晶体结构进行对接, 对接得到的复合物模型使用Amber程序进行MD模拟研究. 模拟过程中, 脲酶结构中的双核镍离子活性中心选用non-bonded模型. 研究结果显示: AHA与洋刀豆脲酶结合时, Ni(1)和Ni(2)均为五配位|COM与洋刀豆脲酶结合时Ni(1)为五配位, Ni(2)为六配位的结合模型更加合理. 这些研究为了解洋刀豆脲酶与抑制剂之间的相互作用提供了重要的参考信息.     

大麻素受体CB1三维结构的同源模建及其对接研究

大麻素CB1受体属于G蛋白偶联受体. 以牛视紫红质的晶体结构为模板, 利用同源模建法对CB1受体的三维结构进行了模拟, 并采用分子动力学方法对模型进行了修正和优化. 在此基础上, 分析了活性位点的组成和结构, 研究了拮抗剂利莫那班与CB1受体的对接, 明确了CB1受体与利莫那班结合时起重要作用的氨基酸残基. 发现利莫那班与CB1受体残基Lys192形成氢键相互作用是CB1受体拮抗剂的重要分子作用基础.     

球形透镜表面特性数值分析

球形透镜表面在一些高精度的光学系统变得越来越重要,它们和其他透镜表面一样必须满足一样的质量标准。本文采用数值计算方法分析了球形透镜的表面特性,并以Snell定律为基础,建立了用于计算球形表面特性的公式。通过与已有的球面特性公式进行比较,采用该方法计算球形透镜表面特性的拟合误差小于1μm。     

Vacuum heating evaluation for plasmas of exponentially decreasing density profile

Ultra-short pulse lasers have opened a regime of laser-plasma interaction where plasmas have scale lengths shorter than the laser wavelength and allow the possibility of generating near-solid density plasmas. The interaction of high-intensity laser beams with sharply bounded high-density and small scale length plasmas is considered. Absorption of the laser energy associated with the mechanism of dragging electrons out of the plasma into the vacuum and sending them back into the plasma with the electric field component along the density gradient, so called vacuum heating, is studied. An exponentially decreasing electron density profile is assumed. The vector potential of the electromagnetic field propagating through the plasma is calculated and the behaviour of the electric and magnetic components of the electromagnetic field is studied. The fraction of laser power absorbed in this process is calculated and plotted versus the laser beam incidence angle, illumination energy, and the plasma scale length.