Docking Study and Three‐Dimensional Quantitative Structure‐Activity Relationship (3D‐QSAR) Analyses and Novel Molecular Design of a Series of 4‐Aminoquinazolines as Inhibitors of Aurora B Kinase

The Aurora proteins are critical regulators of major mitotic events and attractive targets for anticancer therapy. 3D‐QSAR studies based on molecular docking were performed on a dataset of 40 4‐aminoquinazolines compounds. The CoMSIA model produced significantly better results than CoMFA model, with q²=0.652 and r²=0.991. The contours analysis provides useful information about the structural requirements for 4‐aminoquinazolines for inhibiting Aurora B. Scaffold hopping method was used to generate new structures based on the maximum common substructure of the training and test set compounds. The ADMET property, binding affinity and inhibitory activity of the new designed compounds were predicted, respectively. Finally 16 compounds were identified as the novel inhibitors for Aurora B kinase.     

褪黑激素受体拮抗剂的三维定量构效关系研究

采用两种分子场分析方法即比较分子场分析法（CoMFA）和比较分子相似因子分析法（CoMSIA）进行了37个褪黑激素受体拮抗剂的构效关系研究.计算结果表明，两种方法得到的构效关系模型都具有较好的预测能力.在计算中，还考察了不同格点距离和电荷计算方法对构效关系模型的影响.通过分析分子场等值面图在空间的分布，可以观察到叠合分子周围分子场特征对化合物活性的影响，为设计新的褪黑激素拮抗剂提供了一些理论依据.     

二氢吡啶类化合物的三维定量构效关系

通过分子力学和量子化学计算,得出两种二氢吡啶衍生物的低能构象,再应用比较分子力场分析方法(CoMFA)和比较分子相似性指数分析方法(CoMSIA)分别对两种构象的43个二氢吡啶衍生物进行3D-QSAR研究. 计算结果表明,用两种方法建立的两种构象的构效关系模型均有较好的预测能力.通过分析CoMFA和CoMSIA的系数等势图,直观地了解二氢吡啶衍生物的结构对生物活性的影响,为进一步设计高活性的二氢吡啶衍生物提供一定的理论依据.     

Comparative molecular field analysis and comparative molecular similarity index analysis studies on 1H NMR chemical shift of NH group of diaryl triazene derivatives

Comparative molecular field analysis (CoMFA), comparative molecular field analysis region focusing (CoMFA‐RF) for optimizing the region for the final partial least square analysis, and comparative molecular similarity indices analysis (CoMSIA) methods were employed to develop three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models of ¹H NMR chemical shift of NH proton of diaryl triazene derivatives. The best orientation was searched by all‐orientation search (AOS) strategy to minimize the effect of the initial orientation of the structures. The predictive abilities of CoMFA‐RF and CoMSIA models were determined using a test set of ten compounds affording predictive correlation coefficients of 0.721 and 0.754, respectively, indicating good predictive power. For further model validation, cross validation (leave one out), progressive scrambling, and bootstrapping were also applied. The accuracy and speed of obtained 3D‐QSAR models for the prediction of ¹H NMR chemical shifts of NH group of diaryl triazene derivatives were greater compared to some computational well‐known procedures. Copyright © 2013 John Wiley & Sons, Ltd.     

类吗啡类拮抗物的结构与抑食活性的3D-QSAR研究

用比较力场分析研究了3,4-二甲基-4-(3-羟基苯基)哌啶及其衍生物类吗啡拮抗物的结构与抑食活性的关系,考察了网格结构和探针原子的影响.结果表明,立体效应和静电作用场是描述其抑食活性和进行结构性能关系研究的最重要的结构参数.     

一类吡唑衍生物的3D-QSAR研究

通过比较分子力场分析方法（CoMFA）和比较分子相似性指数分析方法 (CoMSIA),系统研究了30个2-烷基（烷硫基）-5-吡唑基-1,3,4-噁二唑（噻二? 颉⑷颍├嗷衔镆种扑疚瓶莶【锘钚缘娜酆隙抗剐Ч叵怠６杂? CoMFA,研究了不同移动步长对考虑静电场和立体场作用时构效关系的影响;对于 CoMSIA,研究了移动步长、场的组合、衰减因子α等参数变化对构效关系的影响, 发现当考虑立体场、疏水场、氢键受体场的贡献时能得到较好的结果。分别得到了 两种方法最为理想的3D-QSAR模型,所得三维等值线图为发现更高活性化合物提供 了有力的指导作用。     

Molecular modeling studies of human immunodeficiency virus type 1 protease inhibitors using three‐dimensional quantitative structure‐activity relationship,virtual screening,and docking simulations

In this paper, two 3‐dimensional quantitative structure‐activity relationship models for 60 human immunodeficiency virus (HIV)‐1 protease inhibitors were established using random sampling analysis on molecular surface and translocation comparative molecular field vector analysis (Topomer CoMFA). The non–cross‐validation (r²), cross‐validation (q²), correlation coefficient of external validation (Q²_ext), and F of 2 models were 0.94, 0.80, 0.79, and 198.84 and 0.94, 0.72, 0.75, and 208.53, respectively. The results indicated that 2 models were reasonable and had good prediction ability. Topomer Search was used to search R groups in the ZINC database, 20 new compounds were designed, and the Topomer CoMFA model was used to predicate the biological activity. The results showed that 18 new compounds were more active than the template molecule. So the Topomer Search is effective in screening and can guide the design of new HIV/AIDS drugs. The mechanism of action was studied by molecular docking, and it showed that the protease inhibitors and Ile50, Asp25, and Arg8 sites of HIV‐1 protease have interactions. These results have provided an insight for the design of new potent inhibitors of HIV‐1 protease.     

A 3D‐QSAR Study of Celebrex‐Based Pdk1 Inhibitors Using Comfa Method

A 3D‐QSAR study of celebrex‐based compounds of PDK1 inhibitors using comparative molecular field analysis (CoMFA) was carried out. The structures of the compounds were obtained using quantum chemistry calculation. CoMFA calculations for a number of grouped subsets of compounds gave q² values of correlation in the range from 0 to 0.8. The low q² values should be mainly due to the narrow span of biological activity. Calculations for several subsets of 11–13 compounds gave high q² values, with 0.5–0.8. Factors affecting the results of the calculations are discussed. Calculated results with high q² values suggest that further chemical modifications of the compounds could lead to enhanced activity and could be an aid in the design of celebrex‐based cancer drugs.     

苯甲酰胺类化合物的结构/活性的定量构效关系研究

用分子连接性指数及比较分子力场分析分别研究了苯甲酰胺类化合物的结构与抗炎活性的关系，结果表明，三维空间上立体效应是描述该类化合物的抗炎活性和进行结构与性能关系研究的最重要的结构参数。     

HEPT类逆转录酶抑制剂的三维定量构效关系

利用比较分子力场分析(CoMFA)方法对32个HEPT类HIV-1逆转录酶抑制剂(RTIs)的三维定量构效关系(3D-QSAR)进行了分析,建立了HIV-1逆转录酶抑制剂的3种3D-QSAR模型,发现影响其生物活性的主要因素为立体场因素,这与HIV-1RT的非底物结合部位(NNBS)的疏水性环境相吻合.进一步分析表明,适当长度的1-位侧链对保持化合物的抗病毒活性致关重要;增大5-位取代基的体积可增强生物活性;在1-位苄氧甲基的对位引入大体积基团有利于提高活性.同时考察立体场、静电场与生物活性的关系,表明,CoMFA模型为最佳预测模型,其交叉验证系数R_CV²=0.870,传统相关系数R²=0.986,标准偏差SE=0.146,F=294.546.用此模型预测了检验组3个HEPT类化合物的-lgEC₅₀,R_pred²=0.850,表明模型具有很好的预测能力,可为HEPT类HIV-1逆转录酶抑制剂的结构优化提供理论指导.     

Synthesis,Bioactivities and Structure Activity Relationship of N‐4‐Methyl‐1,2,3‐thiadiazole‐5‐carbonyl‐N′‐phenyl Ureas

Twenty nine novel N‐4‐methyl‐1,2,3‐thiadiazole‐5‐carbonyl‐N′‐phenyl ureas were designed and synthesized, and their structures were confirmed by proton nuclear magnetic resonance (¹H NMR), infra red spectroscopy (IR) and high‐resolution mass spectroscopy (HRMS). Compounds V‐9 , V‐11 , V‐12 , V‐15 , V‐19 , V‐21 , V‐22 and V‐24 exhibit excellent activity against Culex pipiens pallens. Compounds V‐12 and V‐22 present good insecticidal activity against Plutella xylostella L. Their median lethal concentrations (LC₅₀) are 164.15 and 89.69 mg·L^?1, respectively. Compound V‐11 also has potential wide spectrum of fungicide activity. Its median effective concentrations (EC₅₀) detected from 3.82 µg·mL^?1 against Physalospora piricola to 31.60 µg·mL^?1 against Cercospora arachidicola. Compounds V‐15 and V‐24 show outstanding induction activities as same as positive controls TDL and ningnanmycin, furthermore V‐24 has the highest induction activity of 41.85%±4.43%. To elucidate the structure activity relationship in these compounds, a 3D‐QSAR model has been built. The established model showed a reliable predicting ability with q² values of 0.643 and r² values of 0.982.     

3D－QSAR Study on Diindolylmethane and Its Analogues with Comparative Molecular Field Analysis(CoMFA)

Comparative molecular field analysis (CoMFA),a three dimensional quantitative structure-activity relationship (3D-QSAR) method was applied to a series of diindolylmethane(DIM) analogs to study the relationship between their structure and their induction of CYP 1A1-associated ethoxyresorufin-O-deethylase(EROD) activity.A DISCO model of pharmacophore was derved to guide the superposition of the compounds.The coefficient of cross-validation (q^2) and non cross-validation(r^2) for the model established by the study are 0.827 and 0.988 respectively,the value of variance ratio (F) is 103.53 and standard error estimate (SEE)is 0.044.These values indicate that the CoMFA model derived is significant and might have a good prediction for the catalytic activity of DIM compounds.As a consequence,the predicted activity values of new designed compounds were all higher than that of the reported value.     

Ligand and structure‐based models for the prediction of ligand‐receptor affinities and virtual screenings: Development and application to the β2‐adrenergic receptor

In this study, we evaluated the applicability of ligand‐based and structure‐based models to quantitative affinity predictions and virtual screenings for ligands of the β₂‐adrenergic receptor, a G protein‐coupled receptor (GPCR). We also devised and evaluated a number of consensus models obtained through partial least square regressions, to combine the strengths of the individual components. In all cases, the bioactive conformation of each ligand was derived from molecular docking at the crystal structure of the receptor. We identified the most effective models applicable to the different scenarios, in the presence or in the absence of a training set. For ranking the affinity of closely related analogs when a training set is available, a ligand‐based consensus model (LI‐CM) seems to be the best choice, while the structure‐based MM‐GBSA score seems the best alternative in the absence of a training set. For virtual screening purposes, the structure‐based MM‐GBSA score was found to be the method of choice. Consensus models consistently had performances superior or close to those of the best individual components, and were endowed with a significantly increased robustness. Given multiple models with no a priori knowledge of their predictive capabilities, constructing a consensus model ensures results very close to those that the best model alone would have yielded. © 2009 Wiley Periodicals, Inc. J Comput Chem 2010     

本征值方法在抗氧化剂定量构效关系研究中的应用

Antioxidants are of great interest because of their involvement in many important biological and industrial processes. It is meaningful to study their structure-antioxidant activity relationship (SAAR) and design novel, efficient and low-toxicity antioxidant. In this paper, Eigen Value Analysis (EVA), a 3-dimensional quantitative structure activity relationship (3-D QSAR) method, was employed to study antioxidant SAAR. Significant relational models were obtained with all the PLS cross-validate qcv^2 values being larger than 0.5, meaning that the models have sound predictive power. Compared with other QSAR methods, EVA possesses several advantages, especially that it does not need alignment. It should be believed that EVA will be an efficient approach to SAAR.     

Structure–Activity Relationship in the Domain of Odorants Having Marine Notes

We synthesized or re‐synthesized a large series of 2H‐1,5‐benzodioxepin‐3(4H)‐ones 9 (Scheme 1), 4,5‐dihydro‐1‐benzoxepin‐3(2H)‐ones 10 (Schemes 3 and 4) and 5,6,8,9‐tetrahydro‐7H‐benzocyclohepten‐7‐ones 11 (Schemes 5 and 6), since the lead compound for the olfactory note of perfumes based on marine accords is a well‐known benzodioxepinone named Calone 1951^® ( 9b ). We meticulously described the odor profile of each synthesized compound and discussed relevant structure–odor relationships (Tables 1–3). In particular, we revealed a correlation between the conformation of the seven‐membered ring and the activities of these compounds (Table 4 and Fig. 3). We also clarified the effect of the position and the size of the alkyl substituent at the aromatic ring.     

Three‐dimensional reference interaction site model self‐consistent field analysis of solvent and substituent effects on the absorption spectra of Brooker's merocyanine

Solvent and substituent effects on the absorption spectra of Brooker's merocyanine (BM) are investigated using the three‐dimensional reference interaction site model self‐consistent field method and time‐dependent density functional theory. The π–π* excitation energies are computed for BM and its derivative 2,6‐di‐tert‐butyl (di‐t‐Bu) BM. The behaviors of the computed excitation energies with increasing solvent polarity are in good agreement with those of the corresponding experimental measurements. In addition, analysis of the solute–solvent interaction energies and spatial distribution functions reveals that the effects of the solvent on the absorption spectra are reduced by the steric hindrance of the t‐Bu groups. Furthermore, from the difference in the solute–solvent interaction energies of BM and di‐t‐Bu BM, it is shown that the effect of the t‐Bu substituents on the absorption spectrum is greater in high‐polarity solvents. © 2015 Wiley Periodicals, Inc.     

Three‐dimensional structural analysis of a block copolymer by scanning electron microscopy combined with a focused ion beam

A three‐dimensional (3D) lamellar structure of a poly(styrene‐block‐isoprene) block copolymer was observed at submicrometer and micrometer levels by scanning electron microscopy combined with a focused ion beam (FIB–SEM). The 3D lamellar structure with an exceptionally large periodicity, about 0.1 μm, was successfully reconstructed, and the size of the reconstructed image by FIB–SEM was 6.0 × 6.0 × 4.0 μm³, which was greater than the transmission electron microtomography data, 3.8 × 3.9 × 0.24 μm³, by a factor of about 40. This result indicates that 3D reconstruction using FIB–SEM is quite useful for direct 3D observations, especially analyses of polymeric materials at the submicrometer and micrometer levels. © 2007 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 45: 677–683, 2007     

Potential Therapeutic Target Protein Tyrosine Phosphatase-1B for Modulation of Insulin Resistance with Polyphenols and Its Quantitative Structure–Activity Relationship

The increase in the number of cases of type 2 diabetes mellitus (T2DM) and the complications associated with the side effects of chemical/synthetic drugs have raised concerns about the safety of the drugs. Hence, there is an urgent need to explore and identify natural bioactive compounds as alternative drugs. Protein tyrosine phosphatase 1B (PTP1B) functions as a negative regulator and is therefore considered as one of the key protein targets modulating insulin signaling and insulin resistance. This article deals with the screening of a database of polyphenols against PTP1B activity for the identification of a potential inhibitor. The research plan had two clear objectives. Under first objective, we conducted a quantitative structure–activity relationship analysis of flavonoids with PTP1B that revealed the strongest correlation (R² = 93.25%) between the number of aromatic bonds (naro) and inhibitory concentrations (IC₅₀) of PTP1B. The second objective emphasized the binding potential of the selected polyphenols against the activity of PTP1B using molecular docking, molecular dynamic (MD) simulation and free energy estimation. Among all the polyphenols, silydianin, a flavonolignan, was identified as a lead compound that possesses drug-likeness properties, has a higher negative binding energy of −7.235 kcal/mol and a pKd value of 5.2. The free energy-based binding affinity (ΔG) was estimated to be −7.02 kcal/mol. MD simulation revealed the stability of interacting residues (Gly183, Arg221, Thr263 and Asp265). The results demonstrated that the identified polyphenol, silydianin, could act as a promising natural PTP1B inhibitor that can modulate the insulin resistance.