Novel coumarin-based sensitive and selective fluorescent probes for biothiols in aqueous solution and in living cells
作者：
Li, Jun;Zhang, Chun-Fang;Ming, Ze-Zhong;Yang, Wen-Chao
* ;Yang, Guang-Fu
（ 期刊：
RSC Advances ,2013年3(48):26059-26065 ISSN：2046-2069
通讯作者：
Yang, Wen-Chao
作者机构：
[Yang, Guang-Fu; Li, Jun; Yang, Wen-Chao; Zhang, Chun-Fang; Ming, Ze-Zhong] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.;[Yang, Guang-Fu] Collaborat Innovat Ctr Chem Sci & Engn, Tianjin 30071, Peoples R China.
通讯机构：
[Yang, Wen-Chao] C;Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.
摘要：
Two novel coumarin-derived fluorescent probes were designed and synthesized for the quantitative determination of biothiols, such as cysteine (Cys), glutathione (GSH) and homocysteine (Hcy). Both probes selectively and sensitively detected biothiols in vitro, and successfully sensed biothiols in vivo with low cytotoxicity, suggesting their potential application for biothiol detection.
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英文
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Structural basis of femtomolar inhibitors for acetylcholinesterase subtype selectivity: Insights from computational simulations
作者：
Zhu, Xiao-Lei;Yu, Ning-Xi;Hao, Ge-Fei;Yang, Wen-Chao;Yang, Guang-Fu
* （ 期刊：
Journal of Molecular Graphics and Modelling ,2013年41:55-60 ISSN：1093-3263
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Zhu, Xiao-Lei; Yang, Wen-Chao; Yu, Ning-Xi; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.;[Yang, Guang-Fu] Cent China Normal Univ, Coll Chem, Luoyu Rd 152, Wuhan 430079, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Luoyu Rd 152, Wuhan 430079, Peoples R China.
关键词：
Acetylcholinesterase;Selectivity;Molecular dynamics;MM/PBSA pi-pi interaction
摘要：
Acetylcholinesterase (AChE) is a key enzyme of the cholinergic nervous system. More than one gene encodes the synaptic AChE target. As the most potent known AChE inhibitor, the syn1-TZ2PA6 isomer was recently shown to have higher affinity as a reversible organic inhibitor of acetylcholinesterase1 (AChE1) than the anti1-TZ2PA6 isomer. Opposite selectivity has been shown for acetylcholinesterase2 (AChE2). In an attempt to understand the selectivity of the syn1-TZ2PA6 and anti1-TZ2PA6 isomers for AChE1 and AChE2, six molecular dynamics (MD) simulations were carried out with mouse AChE (mAChE, type of AChE1), Torpedo californica AChE (TcAChE, type of AChE1), and Drosophila melanogaster AChE (DmAChE, type of AChE2) bound with syn1-TZ2PA6 and anti1-TZ2PA6 isomers. Within the structure of the inhibitor, the 3,8-diamino-6-phenylphenanthridinium subunit and 9-amino-1,2,3,4- tetrahydroacridine subunit, via π-πinteractions, made more favorable contributions to syn1-TZ2PA6 or anti1-TZ2PA6 isomer binding in the mAChE/TcAChE enzyme than the 1,2,3-triazole subunit. Compared to AChE1, the triazole subunit had increased binding energy with AChE2 due to a greater negative charge in the active site. The binding free energy calculated using the MM/PBSA method suggests that selectivity between AChE1 and AChE2 is mainly attributed to decreased binding affinity for the inhibitor. ©2013 Elsevier Inc. All rights reserved.
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Computational discovery of picomolar Q o site inhibitors of cytochrome bc 1 complex
作者：
Hao, Ge-Fei;Wang, Fu;Li, Hui;Zhu, Xiao-Lei;Yang, Wen-Chao;...
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY ,2012年134(27):11168-11176 ISSN：0002-7863
通讯作者：
Wu, Jia-Wei
作者机构：
[Yang, Guang-Fu; Wang, Fu; Zhu, Xiao-Lei; Yang, Wen-Chao; Li, Hui; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Wu, Jia-Wei; Li, Hui] Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China.;[Huang, Li-Shar; Berry, Edward A] SUNY Upstate Med Univ, Dept Biochem & Mol Biol, Syracuse, NY 13210 USA.
通讯机构：
[Wu, Jia-Wei] T;Tsinghua Univ, Sch Life Sci, Tsinghua Peking Ctr Life Sci, MOE Key Lab Prot Sci, Beijing 100084, Peoples R China.
摘要：
A critical challenge to the fragment-based drug discovery (FBDD) is its low-throughput nature due to the necessity of biophysical method-based fragment screening. Herein, a method of pharmacophore-linked fragment virtual screening (PFVS) was successfully developed. Its application yielded the first picomolar-range Q o site inhibitors of the cytochrome bc 1 complex, an important membrane protein for drug and fungicide discovery. Compared with the original hit compound 4 (K i = 881.80 nM, porcine bc 1), the most potent compound 4f displayed 20 507-fold improved binding affinity (K i = 43.00 pM). Compound 4f was proved to be a noncompetitive inhibitor with respect to the substrate cytochrome c, but a competitive inhibitor with respect to the substrate ubiquinol. Additionally, we determined the crystal structure of compound 4e (K i = 83.00 pM) bound to the chicken bc 1 at 2.70 Å resolution, providing a molecular basis for understanding its ultrapotency. To our knowledge, this study is the first application of the FBDD method in the discovery of picomolar inhibitors of a membrane protein. This work demonstrates that the novel PFVS approach is a high-throughput drug discovery method, independent of biophysical screening techniques. © 2012 American Chemical Society.
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英文
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Synthesis and Antifungal Activity of Novel Sclerotiorin Analogues
作者：
Lin, Long;Mulholland, Nick;Wu, Qiong-You;Beattie, David;Huang, Shao-Wei;...
期刊：
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY ,2012年60(18):4480-4491 ISSN：0021-8561
通讯作者：
Gu, Yu-Cheng
作者机构：
[Yang, Guang-Fu; Wu, Qiong-You; Huang, Shao-Wei; Lin, Long] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Irwin, Dianne; Clough, John; Gu, Yu-Cheng; Mulholland, Nick; Beattie, David] Syngenta Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks, England.
通讯机构：
[Gu, Yu-Cheng] S;Syngenta Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks, England.
关键词：
sclerotiorin;azaphilone;fungicides;natural product
摘要：
Sclerotiorin 1, first isolated from Penicillium sclerotiorum, has weak antifungal activity and belongs to the azaphilone-type family of natural products. Several series of sclerotiorin analogues were designed and synthesized with the aim of discovering novel fungicides with improved activity. The syntheses involved two key steps, cycloisomerization and then oxidation, and used a simple and efficient Sonogashira cross-coupling reaction to construct the required functionalized precursor. With sclerotiorin as a control, the activities of the newly synthesized analogues were evaluated against seven fungal pathogens, and several promising candidates (compounds 3a<inf>1</inf>, 3d<inf>2</inf>, 3e<inf>2</inf>, 3f<inf>2</inf> and 3k<inf>2</inf>) with greater activity and simpler structures than sclerotiorin were discovered. In addition, preliminary structure-activity relationships were studied, which revealed that not only the chlorine or bromine substituent at the 5-position of the nucleus but also the phenyl group at the 3-position and the substituent pattern on it contributed crucially to the observed antifungal activity. Analogues with a methyl substituent at the 1-position have reduced levels of activity, while those with a free hydroxyl group in place of acetoxy at the quaternary center of the bicyclic ring system retain activity. ©2012 American Chemical Society.
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英文
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PH-responsive surface activity and solubilization with novel pyrrolidone-based gemini surfactants
作者：
Zan Jiang;Xuefeng Li;Guangfu Yang
（ ;Li Cheng;Bo Cai;...
期刊：
LANGMUIR ,2012年28(18):7174-7181 ISSN：0743-7463
通讯作者：
Dong, Jinfeng
作者机构：
[Zan Jiang; Li Cheng; Xuefeng Li; Jinfeng Dong; Bo Cai; Yi Yang] Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.;[Guangfu Yang] Huazhong Normal Univ, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
通讯机构：
[Dong, Jinfeng] W;Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.
摘要：
A new series of pH-responsive Gemini surfactants with 2-pyrrolidone head groups, N,N′-dialkyl-N,N′-di(ethyl-2-pyrrolidone)ethylenediamine (Di-C<inf>n</inf>P, where n = 6, 8 10, 12), were synthesized and characterized by <sup>1</sup>H NMR, <sup>13</sup>C NMR, ESI-MS, and elemental analysis. The surface activity and micellization behavior at acidic, neutral, and basic conditions were characterized by equilibrium surface tension and fluorescence techniques. It was found that the surface activity of Di-C<inf>n</inf>P depends on the pH of aqueous solutions due to the protonation state of surfactant molecules when pH was varied. The new compounds have lower cmc and γ<inf>cmc</inf> in comparison with that of m-2-m type conventional cationic Gemini surfactants and gluconamide-type nonionic Gemini surfactants. Fluorescence data confirm that micelles are formed when the concentration is above the cmc. Since micellization is of fundamental importance in surfactant applications such as solubilization, microemulsion, and related technologies, the significant difference in cmc at different pH of this new Gemini surfactant is employed to solubilize cyclohexane. The preliminary result indeed shows that the solubilization capacity of Di-C<inf>n</inf>P can be tuned by pH. ©2012 American Chemical Society.
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英文
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Design and syntheses of novel N -(benzothiazol-5-yl)-4,5,6,7-tetrahydro-1 H -isoindole-1,3(2 H)-dione and N -(benzothiazol-5-yl)isoindoline-1,3-dione as potent protoporphyrinogen oxidase inhibitors
作者：
Jiang, Li-Li;Zuo, Yang;Wang, Zhi-Fang;Tan, Yin;Wu, Qiong-You;...
期刊：
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY ,2011年59(11):6172-6179 ISSN：0021-8561
通讯作者：
Xi, Zhen
作者机构：
[Yang, Guang-Fu; Wu, Qiong-You; Jiang, Li-Li; Zuo, Yang; Wang, Zhi-Fang; Tan, Yin] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xi, Zhen] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
通讯机构：
[Xi, Zhen] N;Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
关键词：
protoporphyrinogen oxidase;4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione;isoindoline-1,3-dione;benzothiazole;herbicide
摘要：
Discovery of protoporphyrinogen oxidase (PPO, EC 1.3.3.4) inhibitors has been one of the hottest research areas in the field of herbicide development for many years. As a continuation of our research work on the development of new PPO-inhibiting herbicides, a series of novel N-(benzothiazol-5-yl)-4,5,6,7- tetrahydro-1H-isoindole-1,3(2H)-diones (1a-p) and N-(benzothiazol-5-yl) isoindoline-1,3-diones (2a-h) were designed and synthesized according to the ring-closing strategy of two ortho-substituents. The bioassay results indicated that some newly synthesized compounds exhibited higher PPO inhibition activity than the control of sulfentrazone. Compound 1a, S-(5-(1,3-dioxo-4,5,6,7- tetrahydro-1H-isoindol-2(3H)-yl)-6-fluorobenzothiazol-2-yl) O-methyl carbonothioate, was identified as the most potent inhibitor with k<inf>i</inf> value of 0.08 μM, about 9 times higher than that of sulfentrazone (k <inf>i</inf> = 0.72 μM). Further green house assay showed that compound 1b, methyl 2-((5-(1,3-dioxo-4,5,6,7-tetrahydro-1H-isoindol-2(3H)-yl)-6- fluorobenzothiazol-2-yl)thio)acetate, exhibited herbicidal activity comparable to that of sulfentrazone even at a concentration of 37.5 g ai/ha. In addition, among six tested crops, wheat exhibited high tolerance to compound 1b even at a dosage of 300 g ai/ha. These results indicated that compound 1b might have the potential to be developed as a new herbicide for weed control of wheat field. ©2011 American Chemical Society.
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英文
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Subnanomolar inhibitor of cytochrome bc1 complex designed by optimizing interaction with conformationally flexible residues
作者：
Pei-Liang Zhao;Le Wang;Xiao-Lei Zhu;Xiaoqin Huang;Chang-Guo Zhan;...
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY ,2010年132(1):185-194 ISSN：0002-7863
通讯作者：
Zhan, Chang-Guo
作者机构：
[Guang-Fu Yang; Xiao-Lei Zhu; Pei-Liang Zhao] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Coll Chem, Minist Educ, Wuhan 430079, Peoples R China.;[Chang-Guo Zhan; Xiaoqin Huang] Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA.;[Jia-Wei Wu; Le Wang] Tsinghua Univ, Key Lab Bioinformat, Dept Biol Sci & Biotechnol, MOE, Beijing 100084, Peoples R China.;[Chang-Guo Zhan] Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, 725 Rose St, Lexington, KY 40536 USA.
通讯机构：
[Zhan, Chang-Guo] U;Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, 725 Rose St, Lexington, KY 40536 USA.
会议名称：
International conference of molecular simulations and applied informatics technologies
会议时间：
2010-01-01
会议地点：
Wuhan(CN)
会议论文集名称：
The 5th International conference of molecular simulations and applied informatics technologies : [Life science articles proceedings]
关键词：
Inhibitor;Cytochrome;Interaction
摘要：
Cytochrome bc1 complex (EC 1.10.2.2, bc1), an essential component of the cellular respiratory chain and the photosynthetic apparatus in photosynthetic bacteria, has been identified as a promising target* for new drugs and agricultural fungicides. X-ray diffraction structures of the free bc1 complex and its complexes with various inhibitors revealed that the phenyl group of Phe274 in the binding pocket exhibited significant conformational flexibility upon different inhibitors binding to optimize respective n-n interactions, whereas the side chains of other hydrophobic residues showed conformational stability. Therefore, in the present study, a strategy of optimizing the π-π interaction with conformationally flexible residues was proposed to design and discover new bc1 inhibitors with a higher potency. Eight new compounds were designed and synthesized, among which compound 5c, with a Ki value of 570 pM, was identified as the most promising drug or fungicide candidate, significantly more potent than the commercially available bc1 inhibitors, including azoxystrobin (AZ), kresoximmethyl (KM), and pyraclostrobin (PY). To our knowledge, this is the first bc1 inhibitor discovered from structure-based design with a potency of subnanomolar Ki value. For all of the compounds synthesized and assayed, the calculated binding free energies correlated reasonably well with the binding free energies derived from the experimental Ki values, with a correlation coefficient of r2=0.89. The further inhibitory kinetics studies revealed that 5c is a noncompetitive inhibitor with respect to substrate cytochrome c, but it is a competitive inhibitor with respect to substrate ubiquinol. Due to its subnanomolar Ki potency and slow dissociation rate constant (k-0=0.00358 s-1), 5c could be used as a specific probe for further elucidation of the mechanism of bc1 function and as a new lead compound for future drug discovery.
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英文
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Computational mutation scanning and drug resistance mechanisms of HIV-1 protease inhibitors
作者：
Hao, Ge-Fei;Yang, Guang-Fu
* （ ;Zhan, Chang-Guo
期刊：
JOURNAL OF PHYSICAL CHEMISTRY B ,2010年114(29):9663-9676 ISSN：1520-6106
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.;[Zhan, Chang-Guo] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.
会议名称：
International conference of molecular simulations and applied informatics technologies
会议时间：
2010-01-01
会议地点：
Wuhan(CN)
会议论文集名称：
The 5th International conference of molecular simulations and applied informatics technologies : [Life science articles proceedings]
摘要：
The drug resistance of various clinically available HIV-1 protease inhibitors has been studied using a new computational protocol, that is, computational mutation scanning (CMS), leading to valuable insights into the resistance mechanisms and structureresistance correction of the HIV-1 protease inhibitors associated with a variety of active site and nonactive site mutations. By using the CMS method, the calculated mutation-caused shifts of the binding free energies linearly correlate very well with those derived from the corresponding experimental data, suggesting that the CMS protocol may be used as a generalized approach to predict drug resistance associated with amino acid mutations. Because it is essentially important for understanding the structure-resistance correlation and for structure-based drug design to develop an effective computational protocol for drug resistance prediction, the reasonable and computationally efficient CMS protocol for drug resistance prediction should be valuable for future structure-based design and discovery of antiresistance drugs in various therapeutic areas.
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英文
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Computational determination of fundamental pathway and activation barriers for acetohydroxyacid synthasecatalyzed condensation reactions of α-keto acids
作者：
Xiong, Ying;Liu, Junjun;Yang, Guang-Fu
（ ;Zhan, Chang-Guo
* 期刊：
Journal of Computational Chemistry ,2010年31(8):1592-1602 ISSN：0192-8651
通讯作者：
Zhan, Chang-Guo
作者机构：
[Zhan, Chang-Guo; Xiong, Ying; Liu, Junjun] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.;[Yang, Guang-Fu; Xiong, Ying; Liu, Junjun] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.;[Zhan, Chang-Guo] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, 725 Rose St, Lexington, KY 40536 USA.
通讯机构：
[Zhan, Chang-Guo] U;Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, 725 Rose St, Lexington, KY 40536 USA.
关键词：
enzyme;catalytic mechanism;reaction pathway;QM/MM calculation
摘要：
Acetohydroxyacid synthase (AHAS) is the first common enzyme in the biosynthetic pathway leading to the production of various branched-chain amino acids. AHAS is recognized as a promising target for new antituberculosis drugs, antibacterial drugs, and herbicides. Extensive first-principles quantum mechanical (QM) and hybrid quantum mechanical/molecular mechanical (QM/MM) calculations have enabled us, in this study, to uncover the fundamental reaction pathway, determine the activation barriers, and obtain valuable insights concerning the specific roles of key amino acid residues for the common steps of AHAS-catalyzed condensation reactions of a-keto acids. The computational results reveal that the rate-determining step of the AHAS-catalyzed reactions is the second reaction step and that the most important amino acid residues involved in the catalysis include Glu144', Gln207', Gly121', and Gly511 that form favorable hydrogen bonds with the reaction center (consisting of atoms from the substrate and cofactor) during the reaction process. In addition, Glu144' also accepts a proton from cofactor thiamin diphosphate (ThDP) through hydrogen bonding during the catalytic reaction. The favorable interactions between the reaction center and protein environment remarkably stabilize the transition state and, thus, lower the activation barrier for the rate-determining reaction step by similar to 20 kcal/mol. The activation barrier calculated for the rate-determining step is in good agreement with the experimental activation barrier. The detailed structural and mechanistic insights should be valuable for rational design of novel, potent AHAS inhibitors that may be used as promising new antituberculosis drugs, antibacterial drugs. and/or herbicides to overcome drug resistance problem. (C) 2009 Wiley Periodicals, Inc. J Comput Chem 31: 1592-1602, 2010
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英文
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QSAR and 3D-QSAR studies of the diacyl-hydrazine derivatives containing furan rings based on the density functional theory
作者：
Li Zhang;ZiNing Cui;Bin Yin;GuangFu Yang
（ ;Yun Ling;...
期刊：
SCIENCE IN CHINA SERIES B-CHEMISTRY ,2010年53(6):1322-1331 ISSN：1006-9291
通讯作者：
Yang XinLing
作者机构：
[Yin Bin; Ling Yun; Zhang Li; Cui ZiNing; Yang XinLing] China Agr Univ, Coll Sci, Dept Appl Chem, Minist Agr,Key Lab Pesticide Chem & Applicat Tech, Beijing 100193, Peoples R China.;[Zhang Li; Yang GuangFu] Huazhong Normal Univ, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
通讯机构：
[Yang XinLing] C;China Agr Univ, Coll Sci, Dept Appl Chem, Minist Agr,Key Lab Pesticide Chem & Applicat Tech, Beijing 100193, Peoples R China.
关键词：
diacyl-hydrazine;QSAR;3D-QSAR;DFT;insect growth regulator
摘要：
QSAR studies of 27 diacyl-hydrazine derivatives containing furan rings were conducted and compared with the DFT method and AM1-MOPAC method. q <sup>2</sup> values of 0.61 and 0.40 validated the predictability and reliability of eq. (5) from the DFT method were higher than those of eq. (6) from the AM1-MOPAC method. The DFT-optimized conformations and ESP-fitting charges of the target compounds were also used for 3D-QSAR analysis, including CoMFA and CoMSIA. The leave-one-out cross-validation correlation coefficient and the good correlation between the predicted and experimental activities of excluded test compounds revealed that CoMFA and CoMSIA models were robust. The QSAR results were consistent with the 3D-QSAR results, indicating that the electrostatic and hydrophobic properties of the target compounds were significant to the biological activity. These models are useful tools for predicting the larvicidal activities of new compounds and designing new specific insect growth regulators. ©2010 Science China Press and Springer-Verlag Berlin Heidelberg.
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英文
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Structural assignment of 6-oxy purine derivatives through computational modeling, synthesis, x-ray diffraction, and spectroscopic analysis
作者：
Zhao, Xinyun;Chen, Xi;Yang, Guang-Fu
（ ;Zhan, Chang-Guo
* 期刊：
JOURNAL OF PHYSICAL CHEMISTRY B ,2010年114(20):6968-6972 ISSN：1520-6106
通讯作者：
Zhan, Chang-Guo
作者机构：
[Zhan, Chang-Guo; Chen, Xi; Zhao, Xinyun] Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA.;[Yang, Guang-Fu; Chen, Xi; Zhao, Xinyun] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ China, Coll Chem, Wuhan 430079, Peoples R China.;[Zhan, Chang-Guo] Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, 725 Rose St, Lexington, KY 40536 USA.
通讯机构：
[Zhan, Chang-Guo] U;Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, 725 Rose St, Lexington, KY 40536 USA.
摘要：
6-Oxy purine derivatives have been considered as potential therapeutic agents in various drug discovery efforts reported in the literature. However, the structural assignment of this important class of compounds has been controversial concerning the specific position of a hydrogen atom in the structure. To theoretically determine the most favorable type of tautomeric form of 6-oxy purine derivatives, we have carried out first-principles electronic structure calculations on the possible tautomeric forms (A, B, and C) and their relative stability of four representative 6-oxy purine derivatives (compounds 1-4). The computational results in both the gas phase and aqueous solution clearly reveal that the most favorable type of tautomeric form of these compounds is A, in which a hydrogen atom bonds with the N1 atom on the purine ring. To examine the computational results, one of the 6-oxy purine derivatives (i.e., compound 4) has been synthesized and its structure has been characterized by X-ray diffraction and spectroscopic analysis. All of the obtained computational and experimental data are consistent with the conclusion that the 6-oxy purine derivative exists in tautomer A. The conclusive structural assignment reported here is expected to be valuable for future computational studies on 6-oxy purine derivative binding with proteins and for computational drug design involving this type of compounds. ©2010 American Chemical Society.
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英文
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Computational Simulations of the Interactions between Acetyl-Coenzyme-A Carboxylase and Clodinafop: Resistance Mechanism Due to Active and Nonactive Site Mutations
作者：
Zhu, Xiao-Lei;Hao, Ge-Fei;Zhna, Chang-Guo;Yang, Guang-Fu
* （ 期刊：
Journal of Chemical Information and Modeling ,2009年49(8):1936-1943 ISSN：1549-9596
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Zhu, Xiao-Lei; Hao, Ge-Fei] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.;[Zhan, Chang-Guo] Univ Kentucky, Dept Pharmaceut Sci, Coll Pharm, Lexington, KY 40536 USA.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.
会议名称：
International conference of molecular simulations and applied informatics technologies
会议时间：
2010-01-01
会议地点：
Wuhan(CN)
会议论文集名称：
The 5th International conference of molecular simulations and applied informatics technologies : [Life science articles proceedings]
摘要：
Grass weed populations resistant to acetyl-CoA carboxylase-inhibiting (ACCase;EC 6.4.1.2) herbicides represent a major problem for the sustainable development of modern agriculture. In the present study, extensive computational simulations, including homology modeling, molecular dynamics (MD) simulations, and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) calculations, have been carried out to uncover the detailed molecular mechanism of Alopecurus myosuroides resistance to clodinafop, a commercial herbicide targeting ACCase. All the computational model and energetic results indicated that W374C, I388N, D425G, and G443A mutations have great effects on the conformational change of the binding pocket and the hydrogen-bonding interactions. The n-n interaction between ligand and the residue of Phe377 and Tyr161′, playing an important contribution to the binding affinity, were decreased after mutations. In addition, the hydrogen-bonding interactions between clodinafop and the residues (He 158' and Ala54′) disappeared or decreased significantly upon mutation. As a result, the mutant-type ACCase has a lower affinity for the inhibitor binding than the wild-type enzyme, which accounts for the molecular basis of herbicidal resistance. The structural and mechanistic insights obtained from the present study will provide a valuable clue for future designing of a promising inhibitor to reduce drug resistance associated with both active and nonactive site mutations. ©2009 American Chemical Society.
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英文
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Understanding the mechanism of drug resistance due to a codon deletion in protoporphyrinogen oxidase through computational modeling
作者：
Hao, Ge-Fei;Zhu, Xiao-Lei;Ji, Feng-Qin;Zhang, Li;Yang, Guang-Fu
* （ ;...
期刊：
JOURNAL OF PHYSICAL CHEMISTRY B ,2009年113(14):4865-4875 ISSN：1520-6106
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Zhu, Xiao-Lei; Ji, Feng-Qin; Zhang, Li; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Zhan, Chang-Guo] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
会议名称：
International conference of molecular simulations and applied informatics technologies
会议时间：
2010-01-01
会议地点：
Wuhan(CN)
会议论文集名称：
The 5th International conference of molecular simulations and applied informatics technologies : [Life science articles proceedings]
摘要：
Protoporphyrinogen oxidase (PPO;EC 1.3.3.4) is the last common enzyme for the enzymatic transformation of protoporphyrinogen-IX to protoporphyrin-IX, which is the key common intermediate leading to heme and chlorophyll. Hence, PPO has been identified as one of the most importance action targets for the treatment of some important diseases including cancer and variegated porphyria (VP). In the agricultural field, PPO inhibitors have been used as herbicides for many years. Recently, a unique drug resistance was found to be associated with a nonactive site residue (Gly210) deletion rather than substitution in A. tuberculatus PPO. In the present study, extensive computational simulations, including homology modeling, molecular dynamics (MD) simulations, and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) calculations, have been carried out to uncover the detailed molecular mechanism of drug resistance associated with Gly210 deletion. Although Gly210 in the wild-type A. tuberculatus PPO has no direct interaction with the inhibitors, all the computational models and energetic results indicated that Gly210 deletion has great effects on the hydrogen-bonding network and the conformational change of the binding pocket. An interchain hydrogen bond between Gly210 with Ser424, playing an important role in stabilizing the local conformation of the wild-type enzyme, disappeared after Gly210 deletion. As a result, the mutant-type PPO has a lower affinity than the wild-type enzyme, which accounts for the molecular mechanism of drug resistance. The structural and mechanistic insights obtained from the present study provide a new starting point for future rational design of novel PPO inhibitors to overcome drug resistance associated with Gly210 deletion. ©2009 American Chemical Society.
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Supramolecular rhombic grids formed from bimolecular building blocks
作者：
She, Neng-Fang
（ ;Gao, Meng;Meng, Xiang-Gao;Yang, Guang-Fu
（ ;Elemans, Johannes A A W;...
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY ,2009年131(33):11695-11697 ISSN：0002-7863
作者机构：
[She, Neng-Fang; Yang, Guang-Fu; Wu, An-Xin; Gao, Meng; Meng, Xiang-Gao] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Elemans, Johannes A A W] Radboud Univ Nijmegen, Inst Mol & Mat, NL-6525 ED Nijmegen, Netherlands.;[Isaacs, Lyle] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA.
通讯机构：
[Wu, An-Xin] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
摘要：
(Figure Presented) A programmed assembly process produces rhombic grid networks from compounds L1-L4 in the crystal by π-π stacking interactions that generate a bimolecular grid synthon, which undergoes further NH⋯N hydrogen-bond-mediated assembly. © 2009 American Chemical Society.
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Binding interaction analysis of the active site and its inhibitors for neuraminidase (N1 subtype) of human influenza virus by the integration of molecular docking, FMO calculation and 3D-QSAR CoMFA modeling
作者：
Zhang, Qingye;Yang, Jiaoyan;Liang, Kun;Feng, Lingling
（ ;Li, Sanpin;...
期刊：
Journal of Chemical Information and Modeling ,2008年48(9):1802-1812 ISSN：1549-9596
通讯作者：
Wan, Jian
作者机构：
[Yang, Guangfu; Feng, Lingling; Li, Sanpin; Zhang, Qingye; Wan, Jian; Liang, Kun] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xu, Xin] Xiamen Univ, Coll Chem & Chem Engn, Ctr Theoret Chem, State Key Lab Phys Chem Solid Surfaces, Xiamen 361005, Peoples R China.;[Yang, Shao; Liu, Deli; Yang, Jiaoyan] Cent China Normal Univ, Coll Life Sci, Wuhan 430079, Peoples R China.
通讯机构：
[Wan, Jian] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
摘要：
Recently, the worldwide spread of A/H5N1 avian influenza with high virulence has highlighted the potential threat of human influenza pandemic. Tamiflu and Relenza are currently the only two anti-influenza drugs targeting the neuraminidase (NA) enzyme of human influenza virus. Reports of the emergence of drug resistance further make the development of new potent anti-influenza inhibitors a priority. The X-ray crystallographic study of A/H5N1 avian influenza NA subtypes (Russell, R. J. Nature 2006, 443, 45-49) has demonstrated that there exist two genetically distinct groups, group-1 (N1, N4, N5 and N8) andgroup-2 (N2, N3, N6, N7 and N9), whose conformations are substantially different The detailed comparison of their active sites has established, heretofore, the most accurate and solid molecular basis of structure and mechanism for the development of new anti-influenza drugs. In the present study, a rhree-dimensiooal structure of N1 subtype of human influenza type A virus (N1hA) has been generated by homology modeling using the X-ray crystallographic structure of Nl subtype of avian influenza virus (N1aA) as the template. Binding interaction analysis between the active site and its inhibitors has been performed by combining ab initio fragment molecular orbital (FMO) calculations and three-dimensional quantitative structure-activity relationship with comparative molecular field analysis (3D-QSAR CoMFA) modeling. Integrated with docking-based 3D-QSAR CoMFA modeling, molecular surface property (electrostatic and steric) mapping and FMO pair interaction analysis, a set of new receptor-ligand binding models and bioaffinity predictive models for rational design and virtual screening of more potent inhibitors of N1hA are established. In addition, the flexibility of the loop-150 of N1hA and N1aA has been examined by a series of molecular dynamics simulations. ©2008 American Chemical Society.
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A capillary electrophoresis assay for recombinant Bacillus subtilis protoporphyrinogen oxidase
作者：
Ying Tan;Lu Sun;Zhen Xi;Guang-Fu Yang
（ ;Dong-Qing Jiang;...
期刊：
Analytical Biochemistry ,2008年383(2):200-204 ISSN：0003-2697
通讯作者：
Xi, Zhen
作者机构：
[Zhen Xi; Xing Yang; Lu Sun; Ying Tan; He-Yang Li] Nankai Univ, State Key Lab Element Organ Chem, Tianjin 300071, Peoples R China.;[Zhen Xi; Xing Yang; Lu Sun; Ying Tan; He-Yang Li] Nankai Univ, Dept Biol Chem, Tianjin 300071, Peoples R China.;[Guang-Fu Yang; Ying Tan] Cent China Normal Univ, Key Lab Pesticide & Chem Biol Minist Educat, Coll Chem, Wuhan 430079, Peoples R China.;[Dong-Qing Jiang; Xiu-Ping Yan] Nankai Univ, Res Ctr Analyt Sci, Coll Chem, Tianjin 300071, Peoples R China.
通讯机构：
[Xi, Zhen] N;Nankai Univ, State Key Lab Element Organ Chem, Tianjin 300071, Peoples R China.
关键词：
Capillary electrophoresis;FAD;Herbicide;Kinetics;Protoporphyrinogen oxidase
摘要：
Protoporphyrinogen oxidase (PPO) is a flavin adenine dinucleotide (FAD)-containing enzyme in the tetrapyrrole biosynthetic pathway that leads to the formation of both heme and chlorophylls, which has been identified as one of the most important action targets of commercial herbicides. The literature reports gave different PPO-catalytic kinetic parameters for the substrate protoporphyrinogen IX (Km of 0.1 to 10.4 μM) with different sources of PPO using fluorescent or HPLC methods. Herein we assayed the enzymatic activity of recombinant Bacillus subtilis PPO by using capillary electrophoresis (CE), a method with high separation efficiency, easy automation, and low sample consumption. The Michaelis constant and maximum reaction velocity were determined as 7.0 ± 0.6 μM and 0.38 ± 0.02 μmol min-1 μg-1, respectively. The interaction between PPO and acifluorfen, a commercial PPO-inhibiting herbicide, was measured as the inhibition constant 186.9 ± 9.3 μM{cyrillic}. The relationship between cofactor FAD and PPO activity can also be quantitatively studied by this CE method. The CE method used here should also be a convenient, reliable method for PPO study. © 2008 Elsevier Inc. All rights reserved.
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Synthesis and oxidation-induced DNA cross-linking capabilities of bis(catechol) quaternary ammonium derivatives
作者：
Song, Zhibin;Weng, Xiaocheng;Weng, Liwei;Huang, Jing;Wang, Xiaolin;...
期刊：
CHEMISTRY-A EUROPEAN JOURNAL ,2008年14(19):5751-5754 ISSN：0947-6539
通讯作者：
Zhou, Xiang
作者机构：
[Zhou, Yangyang; Weng, Liwei; Song, Zhibin; Huang, Jing; Wang, Xiaolin; Zhou, Xiang; Bai, Minghui; Weng, Xiaocheng] Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.;[Yang, Guangfu] Huazhong Normal Univ, Coll Chem, Wuhan 430072, Peoples R China.
通讯机构：
[Zhou, Xiang] W;Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.
关键词：
catechol;DNA damage;enzymes;oxidation;quinones
摘要：
A study was conducted to demonstrate the synthesis of a number of DNA crosslinking agents, such as bis(catechol) quaternary ammonium derives. It was found that these agents can crosslink DNA through an o-quinone intermediate, induced by oxidation. It was also found that these compounds are composed of two catechol monomers, acting as DNA cross-linking units and are joined by different linkers that act as DNA binding units. Positive charged linkers and quaternary ammonium derivatives were used in the study, to achieve high affinity to DNA. Aliphatic and aromatic chains were investigated, to determine their ability in performing favorable cross-linking reactions and to determine the relationship between agent flexibility and DNA cross-linking abilities.
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Rational design based on bioactive conformation analysis of pyrimidinylbenzoates as acetohydroxyacid synthase inhibitors by integrating molecular docking, CoMFA, CoMSIA, and DFT calculations
作者：
He, Yan-Zhen;Li, Yuan-Xiang;Zhu, Xiao-Lei;Xi, Zhen* ;Niu, Congwei;...
期刊：
Journal of Chemical Information and Modeling ,2007年47(6):2335-2344 ISSN：1549-9596
通讯作者：
Xi, Zhen
作者机构：
[Xi, Zhen] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;Nankai Univ, State Key Lab Elemento Organ Chem, Tianjin 300071, Peoples R China.
通讯机构：
[Xi, Zhen] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
摘要：
Pyrimidinylthiobenzoates constitute an important kind of herbicides targeting acetohydroxyacid synthase (AHAS, EC 2.2.1.6), which catalyze the first common step in branched-chain amino acid biosynthesis. Due to the symmetry of 4,6-dimethoxypyrimidyl, there are two kinds of conformation of pyrimidinylthiobenzoates: one's phenyl is left-extending (named conformation-L);the other's phenyl is right-extending (named conformation-R). On the basis of the assumption that 3D quantitative structure-activity relationship (QSAR) models derived from the bioactive conformation should give the best result, a strategy of density-functional-theory-based 3D-QSAR was proposed to identify the bioactive conformation of pyrimidinylthiobenzoates by integrating the techniques of molecular docking, comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), and density functional theory calculation. The combination of three criteria of q <sup>2</sup>, r<sup>2</sup>, and r<inf>pred</inf><sup>2</sup> obtained from CoMFA and CoMSIA analyses clearly indicated that conformation-R rather than conformation-L might be the bioactive conformation for pyrimidinylthiobenzoates. A further comparison between the two binding modes indicated that pyrimidinylthiobenzoates and sulfonylureas have very similar binding sites, such as Trp586, Arg380, and Pro192. However, Lys251 formed H bonds with sulfonylureas rather than pyrimidinylthiobenzoates. In addition, the orientation of phenyl groups of the two classes of compounds in the binding pocket were revealed to be opposite, which explained why the mutation of Pro192 displayed different sensitivity to sulfonylureas and pyrimidinylthiobenzoates. On the basis of the understanding of interactions between pyrimidinyl-thiobenzoates and AHAS, we designed and synthesized six 8-(4,6-dimethoxypyrimidin-2-yloxy)-4- methylphthalazin-1-one derivatives according to the 3D-QSAR models. The excellent correlation between the tested K<inf>i</inf> values against wild-type A. thaliana acetohydroxyacid synthase and the predicted IC<inf>50</inf> values demonstrated the high reliability of the established 3D-QSAR models. To our knowledge, this is the first report highlighting the binding mode of herbicidal pyrimidinylthiobenzoates, which consisted of the reported results of herbicide resistance. ©2007 American Chemical Society.
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Construction of a combinatorial library of 2-(4-oxo-4H-1-benzopyran-3-yl)-4-thiazolidinones by microwave-assisted one-pot parallel syntheses
作者：
Zhou, Zhong‐Zheng;Huang, Wei;Ji, Feng‐Qin;Ding, Ming‐Wu;Yang, Guang‐Fu
（ 期刊：
Heteroatom Chemistry ,2007年18(4):381-389 ISSN：1042-7163
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang‐Fu; Huang, Wei; Zhou, Zhong‐Zheng; Ji, Feng‐Qin; Yang, GF; Ding, Ming‐Wu] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.
摘要：
A one‐pot liquid‐phase combinatorial synthesis of 2‐(4‐oxo‐4H‐1‐benzopyran‐3‐yl)‐4‐thiazolidinones bearing diverse substituents at the 3‐position under microwave irradiation was successfully performed using 3‐formyl chromone, primary amine, and mercaptoacetic acid as reactants. Compared to an identical library generated by conventional parallel synthesis, the microwave‐assisted parallel synthesis approach dramatically decreased the reaction time from an average of 9 h to 5 min, and substantially increased the product yields. The coupling of microwave technology with liquid‐phase combinatorial synthesis constitutes a novel and particularly attractive avenue for the rapid generation of structurally diverse libraries. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:381–389, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20309
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Erratum: Formation of supramolecular permethrin/ Β-cyclodextrin nanorods ( Journal of Chemical Physics (2006) 125 (111104))
作者：
Yang, Guang-Fu
* （ ;Wang, Hong-Bo;Yang, Wen-Chao;Gao, Daquan;Zhan, Chang-Guo
期刊：
JOURNAL OF CHEMICAL PHYSICS ,2007年126(5):059902 ISSN：0021-9606
通讯作者：
Yang, Guang-Fu
（ 作者机构：
[Yang, Guang-Fu] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan, Peoples R China.;Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA.
通讯机构：
[Yang, Guang-Fu] C;Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan, Peoples R China.
关键词：
organic compounds;nanostructured materials
摘要：
This article was originally published online and print with incorrect footnotes for the first and fifth authors, Guang-Fu Yang and Chang-Guo Zhan. AIP apologizes for these errors. All online versions of the article have been corrected. Footnote b was removed, and the correct footnote for both authors appears below.
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