An improved adaptive genetic algorithm for protein–ligand docking

A new optimization model of molecular docking is proposed, and a fast flexible docking method based on an improved adaptive genetic algorithm is developed in this paper. The algorithm takes some advanced techniques, such as multi-population genetic strategy, entropy-based searching technique with self-adaptation and the quasi-exact penalty. A new iteration scheme in conjunction with above techniques is employed to speed up the optimization process and to ensure very rapid and steady convergence. The docking accuracy and efficiency of the method are evaluated by docking results from GOLD test data set, which contains 134 protein-ligand complexes. In over 66.2% of the complexes, the docked pose was within 2.0 A root-mean-square deviation (RMSD) of the X-ray structure. Docking time is approximately in proportion to the number of the rotatable bonds of ligands.     

多光谱技术结合分子模拟研究头孢唑林和头孢曲松与人血清白蛋白的相互作用

头孢唑林(CFZ)属第一代β-内酰胺类半合成头孢菌素,对革兰氏阳性菌和革兰氏阴性菌均有较强的抗菌作用。头孢曲松(CRO)属第三代β-内酰胺类广谱抗生素,对敏感致病菌导致的疾病及手术后期感染预防有一定作用。人血清白蛋白(HSA)作为生物体内循环系统中含量最丰富的蛋白质,可以与多种内源性和外源性化合物可逆性结合,起到储存和转运的作用。因此,研究CFZ和CRO与HSA的相互作用对了解CFZ和CRO的药代动力学行为具有重要意义。在模拟生理条件下,采用多种光谱法和分子对接技术研究CFZ和CRO与HSA的相互作用。结果表明,在298和310 K条件下,CFZ和CRO与HSA分别形成复合物导致内源荧光猝灭,猝灭机制均为静态猝灭。在消除内滤光影响下,HSA-CFZ和HSA-CRO体系的猝灭常数(K_SV)和结合常数(K_a)均随着温度的升高而降低,结合位点数约为1。根据Fster能量转移定律,CFZ和CRO与HSA结合距离分别为2.41和1.40 nm。希尔系数(n_H)值小于1,表明CFZ和CRO分别与HSA结合后存在药物间负协同作用。热力学参数(ΔH_HSA-CFZ=-22.67 kJ·mol-1, ΔH_HSA-CRO=-39.56 kJ·mol-1, ΔS_HSA-CFZ=-4.90 J·mol-1·K-1, ΔS_HSA-CRO=-37.28 J·mol-1·K-1) 揭示,CFZ和CRO能自发地通过氢键和范德华力与HSA相结合。三维荧光光谱和圆二色谱法(CD)显示CFZ和CRO使HSA的微环境和构象发生改变。分子对接技术显示CFZ和CRO均结合在HSA的site Ⅰ结合位点上,与取代实验结果一致。本研究有助于了解CFZ和CRO在机体内的作用机制及对HSA结构和功能的影响。     

新型苯并二氢呋喃合二酮酸类化合物的合成及其与整合酶分子对接研究

以阿魏酸甲酯为原料,通过氧化偶联构建2-芳基苯并二氢呋喃骨架,再经傅克酰基化和酯缩合反应依次制得(E)-3-［2-(4-羟基-3-甲氧基-5-乙酰基)苯基-3-甲氧羰基-7-甲氧基-2,3-二氢苯［b］并呋喃-5-基］丙烯酸甲酯（3）和(E)-3-［2-(4-羟基-3-甲氧基-5-甲氧羰基乙酰基)苯基-3-甲氧羰基-7-甲氧基-2,3二氢苯并［b］呋喃-5-基］丙烯酸甲酯（4）; 4经水解反应合成3-【2-羟基-3-甲氧基-5-｛5-［2-（甲氧基羰基）乙烯基］-7-甲氧基-3-甲氧羰基-2,3-二氢苯并［b］呋喃-2-｝基】苯基-3-氧丙酸（5）,化合物3~5未见文献报道,其结构经¹H NMR, ¹³C NMR和MS(ESI)表征。采用分子对接软件Autodock vina对化合物2~5与HIV-1整合酶核心部位高度同源的PFV IN（PDB: 3L2V）进行对接,计算结果显示该类化合物能与整合酶形成稳定的复合物,具有1,3-二酮基团的化合物3, 4和5能与整合酶中金属离子产生螯合作用,其中化合物5的结合作用最强。     

3C-like蛋白酶抑制剂的构效关系、分子对接和分子动力学

3C-like蛋白酶是中东呼吸综合征冠状病毒（MERS-CoV）等其它冠状病毒的繁殖过程中极为重要的蛋白酶。它已成为人类在抗冠状病毒领域中的研究热点。本文基于计算生物学方法对与MERS-CoV同属的蝙蝠冠状病毒HKU4（HKU4-CoV）的43个肽类3C-like蛋白酶抑制剂分子,建立三维定量构效关系（3D-QSAR）模型。在基于配体叠合的基础上,发现比较分子相似性指数分析法（CoMSIA）中的四个场组合（位阻场、静电场、氢键供体场与氢键受体场）为最优的模型（Q²=0.522,R_ncv²=0.996,R_pre²=0.904;Q²：交叉验证相关系数,R_ncv²：非交叉验证相关系数,R_pre²：验证集分子的预测值相关系数）,并借助该模型通过分子对接（docking）与分子动力学（MD）方法阐明了配受体结合作用。实验结果表明：（1）基于最优的CoMSIA模型基础上的三维等势图形象地说明了分子基团的位阻作用、静电作用、氢键供体与氢键受体作用对分子生物活性的影响;（2）分子对接研究结果显示了疏水性以及结晶水、氨基酸His166和Glu169在配体和受体结合过程中产生重要作用;（3）分子动力学模拟进一步验证了分子对接模型的可靠性,并发现了两个新的关键氨基酸Ser24与Gln192,它们与配体产生了两个较强的氢键。此外,根据这些结果,一些新的具有潜在抑制活性的肽类化合物作为3C-like蛋白酶抑制剂被获得。以上结果能够帮助深入了解3C-like蛋白酶与肽类抑制剂的作用机理,并且能够为今后的抗MERS-CoV药物设计提供有价值的参考。     

Recent Advances in In Silico Target Fishing

In silico target fishing, whose aim is to identify possible protein targets for a query molecule, is an emerging approach used in drug discovery due its wide variety of applications. This strategy allows the clarification of mechanism of action and biological activities of compounds whose target is still unknown. Moreover, target fishing can be employed for the identification of off targets of drug candidates, thus recognizing and preventing their possible adverse effects. For these reasons, target fishing has increasingly become a key approach for polypharmacology, drug repurposing, and the identification of new drug targets. While experimental target fishing can be lengthy and difficult to implement, due to the plethora of interactions that may occur for a single small-molecule with different protein targets, an in silico approach can be quicker, less expensive, more efficient for specific protein structures, and thus easier to employ. Moreover, the possibility to use it in combination with docking and virtual screening studies, as well as the increasing number of web-based tools that have been recently developed, make target fishing a more appealing method for drug discovery. It is especially worth underlining the increasing implementation of machine learning in this field, both as a main target fishing approach and as a further development of already applied strategies. This review reports on the main in silico target fishing strategies, belonging to both ligand-based and receptor-based approaches, developed and applied in the last years, with a particular attention to the different web tools freely accessible by the scientific community for performing target fishing studies.     

Three-dimensional profile measurement of small lens using subpixel localization with color grating

In this paper a measurement method of three-dimensional profiles and a reconstruction system using subpixel localization with color gratings projection is described. The system has the effects of identical contrast on gratings for easier identification, switchable picture-in-picture on the display, and adjustable gratings with an adjustment module.The measurement method includes the following: the projection step; image extraction step; image fine-tuning step; subpixel localization processing step; and reconstruction step. A projection apparatus emits a grating towards a small lens under measurement, and forms a grating image on the small lens under measurement. The contrast values of the plurality of grating stripes of the grating image are identical. The grating image and picture-in-picture of a display can be fine-tuned and reconstruct the three-dimensional profiles of the small lens. This method can help improve measurement competence in the reverse engineering industry.     

Dynamics of paramagnetic agents by off-resonance rotating frame technique

Off-resonance rotating frame technique offers a novel tool to explore the dynamics of paramagnetic agents at high magnetic fields (B0 > 3T). Based on the effect of paramagnetic relaxation enhancement in the off-resonance rotating frame, a new method is described here for determining the dynamics of paramagnetic ion chelates from the residual z-magnetizations of water protons. In this method, the dynamics of the chelates are identified by the difference magnetization profiles, which are the subtraction of the residual z-magnetization as a function of frequency offset obtained at two sets of RF amplitude omega(1) and pulse duration tau. The choices of omega(1) and tau are guided by a 2-D magnetization map that is created numerically by plotting the residual z-magnetization as a function of effective field angle theta and off-resonance pulse duration tau. From the region of magnetization map that is the most sensitive to the alteration of the paramagnetic relaxation enhancement efficiency R(1rho)/R1, the ratio of the off-resonance rotating frame relaxation rate constant R(1rho) verse the laboratory frame relaxation rate constant R(1), three types of difference magnetization profiles can be generated. The magnetization map and the difference magnetization profiles are correlated with the rotational correlation time tauR of Gd-DTPA through numerical simulations, and further validated by the experimental data for a series of macromolecule conjugated Gd-DTPA in aqueous solutions. Effects of hydration water number q, diffusion coefficient D, magnetic field strength B0 and multiple rotational correlation times are explored with the simulations of the magnetization map. This method not only provides a simple and reliable approach to determine the dynamics of paramagnetic labeling of molecular/cellular events at high magnetic fields, but also a new strategy for spectral editing in NMR/MRI based on the dynamics of paramagnetic labeling in vivo.     

Synthesis,spectral characterization,molecular docking studies,biological activity of (E)-2-((E)-3-(3,4,5-trimethoxyphenyl)allylidene) and (E)-N-phenyl 2-((E)-3-(3,4,5-trimethoxyphenyl)allylidene)hydrazinecarbothioamides and their Cu(II) complexes

Two slightly distorted octahedral complexes of copper(II) with (E)-2-((E)-3-(3,4,5-trimethoxyphenyl)allylidene)hydrazinecarbothioamide (L1) common name 3,4,5-trimethoxy-cinnamaldehydethiosemicarbazone and (E)-N-phenyl-2-((E)-3-(3,4,5-trimethoxyphenyl)-allylidene)hydrazinecarbothioamide (L2) common name 3,4,5-trimethoxycinnamaldehyde-4-phenylthiosemicarbazone have been synthesized. The two free ligands and their copper(II) complexes were characterized by spectroscopic techniques like FT-IR, FT-Raman, UV, EPR, Powder X-ray diffraction and cyclic voltammetry. The EPR spectra evidenced a rhombically distorted octahedron geometry for both the copper(II) complexes. The band gap calculations for the ligands L1, L2 and their complexes Cu(L1)₂Cl₂ and Cu(L2)₂Cl₂ were found to be 2.98, 2.61, 2.66 and 2.50 eV respectively. Cu(L1)₂Cl₂ and Cu(L2)₂Cl₂ have shown 50% of viability at 80 μg/ml and 60 μg/ml. The anti-oxidant activity study revealed that the compounds are good reductants of DPPH radical. Moderate to good anti-bacterial activity is shown by the compounds against the Gram-positive and Gram-negative bacteria. Molecular docking studies have been carried out to predict the orientation and binding mode of analysis in the active site. The synthesized ligand and complex well occupy (catalytic triad and adenine-binding site) in the active site of β-ketoacyl-acyl carrier protein synthase III enzyme, and also well occupy in helix 11 (in the DCS complex) of human estrogen receptor. Moreover they form water mediated hydrogen bond and hydrogen bond with Cys530 residue.