Design, syntheses and 3D-QSAR studies of novel N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyrrol-2-ones as protoporphyrinogen oxidase inhibitors
作者：
Zhang, Li;Tan, Yin;Wang, Neng-Xue;Wu, Qiong-You;Xi, Zhen* ;...
期刊：
Bioorganic & Medicinal Chemistry ,2010年18(22):7948-7956 ISSN：0968-0896
通讯作者：
Xi, Zhen
作者机构：
[Yang, Guang-Fu; Wang, Neng-Xue; Wu, Qiong-You; Zhang, Li; 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：
CoMFA;Herbicide;N-Phenyl pyrrolidin-2-one;N-Phenyl-1H-pyrrol-2-one;Protoporphyrinogen oxidase
摘要：
The characteristics of low application rates, good crop selectivity, low residue and environmental safety exhibited by Protoporphyrinogen oxidase (PPO, EC 1.3.3.4)-inhibiting herbicides have attracted a world-wide research interests. As continuation of our research work on the development of new PPO inhibitors, a series of mono-carbonyl analogues of cyclic imides, N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyrrol-2-ones, were designed and synthesized based on previously established DFT-QSAR results. The PPO inhibition activities of 29 newly synthesized compounds were tested and a predictive comparative molecular field analysis (CoMFA) model was established with the conventional correlation coefficient r2 = 0.980 and the cross-validated coefficient q2 = 0.518. According to the CoMFA model, the substituent effects on the PPO inhibition activity were explained reasonably. Further greenhouse assay showed that 2-(4-chloro-2-fluoro-5-propoxy-phenyl)-2,3,4,5,6,7- hexahydro-isoindol-1-one (C6, ki = 0.095 μM) and 2-(5-allyloxy-4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-isoindol-1-one (C7, ki = 0.12 μM) displayed excellent post-emergency herbicidal activity at the concentration of 150 g.ai/ha against seven tested weeds. Due to their high PPO inhibition effect and broad spectrum herbicidal activity, these two compounds have the potential for further study on crop selectivity and field trial. These results confirmed once again that only one of the carbonyl groups of cyclic imides is essential to the PPO inhibition activity. © 2010 Elsevier Ltd. All rights reserved.
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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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Design, Synthesis, and 3D-QSAR Analysis of Novel 1,3,4-Oxadiazol-2(3H)-ones as Protoporphyrinogen Oxidase Inhibitors
作者：
Li-Li Jiang;Ying Tan;Xiao-Lei Zhu;Zhi-Fang Wang;Yang Zuo;...
期刊：
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY ,2010年58(5):2643-2651 ISSN：0021-8561
通讯作者：
Zhen Xi
作者机构：
[Guang-Fu Yang; Yang Zuo; Xiao-Lei Zhu; Li-Li Jiang; Zhi-Fang Wang; Qiong Chen; Ying Tan] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan 430079, Peoples R China.;[Zhen Xi; Zhi-Fang Wang; Ying Tan] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
通讯机构：
[Zhen Xi] N;Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
关键词：
Protoporphyrinogen oxidase;1,3,4-oxadiazol-2(3H)-ones;benzothiazole;herbicide
摘要：
Protoporphyrlnogen oxidase (PPO, EC 1.3.3.4) has been Identified as one of the most significant action targets for a large chemically diverse family of herbicides that exhibit some Interesting characteristics, such as low use rate, low toxicity to mammals, and low environmental Impact. As a continuation of research work on the development of new PPO Inhibitors, some benzothlazole analogues of oxadlargyl, an Important PPO-lnhlbltlng commercial herbicide, were designed and synthesized by ring-closing of the substltuents at the C-4 and C-5 positions. The bloassay results Indicated that the series 8, 9, and 10 have good PPO Inhibition activity with k l values ranging from 0.25 to 18.63 μM. Most Interestingly, 9I, ethyl 2-((5-(5-fert-butyl-2-oxo-1,3,4-oxadlazol- 2(3H)-yl)-6fluorobenzothlazol-2-yl)sulfanyl) propanoate, was Identified as the most promising candidate due to Its high PPO Inhibition effect (k l 1.42 ,μM) and broad spectrum postemergence herbicidal activity at the concentration of 37.5 g of al/ha. © 2009 American Chemical Society.
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英文
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The Role of Phe82 and Phe351 in Auxin-Induced Substrate Perception by TIR1 Ubiquitin Ligase: A Novel Insight from Molecular Dynamics Simulations
作者：
Hao, Ge-Fei
* ;Yang, Guang-Fu
（ 期刊：
PLOS ONE ,2010年5(5):e10742 ISSN：1932-6203
通讯作者：
Hao, Ge-Fei
作者机构：
[Yang, Guang-Fu; Hao, Ge-Fei] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan, Peoples R China.
通讯机构：
[Hao, Ge-Fei] C;Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan, Peoples R China.
关键词：
Auxins;Hydrogen bonding;Free energy;Crystal structure;Molecular dynamics;Membrane proteins;Solvation;Simulation and modeling
摘要：
It is well known that Auxin plays a key role in controlling many aspects of plant growth and development. Crystal structures of Transport inhibitor response 1 (TIR1), a true receptor of auxin, were very recently determined for TIR1 alone and in complexes with auxin and different synthetic analogues and an Auxin/Indole-3-Acetic Acid (Aux/IAA) substrate peptide. However, the dynamic conformational changes of the key residues of TIR1 that take place during the auxin and substrate perception by TIR1 and the detailed mechanism of these changes are still unclear. In the present study, various computational techniques were integrated to uncover the detailed molecular mechanism of the auxin and Aux/IAA perception process; these simulations included molecular dynamics (MD) simulations on complexes and the free enzyme, the molecular mechanics Poisson Boltzmann surface area (MM-PBSA) calculations, normal mode analysis, and hydrogen bond energy (HBE) calculations. The computational simulation results provided a reasonable explanation for the structureactivity relationships of auxin and its synthetic analogues in view of energy. In addition, a more detailed model for auxin and Aux/IAA perception was also proposed, indicating that Phe82 and Phe351 played a pivotal role in Aux/IAA perception. Upon auxin binding, Phe82 underwent conformational changes to accommodate the subsequent binding of Aux/IAA. As a result, auxin enhances the TIR1-Aux/IAA interactions by acting as a "molecular glue". Besides, Phe351 acts as a "fastener" to further improve the substrate binding. The structural and mechanistic insights obtained from the present study will provide valuable clues for the future design of promising auxin analogues. © 2010 Hao, Yang.
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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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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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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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Synthesis and Biological Activity of Novel Phenyltriazolinone Derivatives
作者：
Wu, Qiongyou
* ;Wang, Guodong;Huang, Shaowei;Lin, Long;Yang, Guangfu
（ 期刊：
Molecules ,2010年15(12):9024-9034 ISSN：1420-3049
通讯作者：
Wu, Qiongyou
作者机构：
[Yang, Guangfu; Wang, Guodong; Huang, Shaowei; Lin, Long; Wu, Qiongyou] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Hubei, Peoples R China.
通讯机构：
[Wu, Qiongyou] C;Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Hubei, Peoples R China.
关键词：
phenyltriazolinones;strobilurin;herbicidal activity;protoporphyrinogen oxidase
摘要：
Phenyltriazolinones are one of the most important classes of herbicides targeting the protoporphyrinogen oxidase enzyme. A series of triazolinone derivatives containing a strobilurin pharmacophore were designed and synthesized with the aim of discovering new phenyltriazolinone analogues with high activity. The herbicidal activity of the synthesized compounds was assayed and some of the test compounds displayed moderate herbicidal activity at 150 g ai/ha.
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英文
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Syntheses and herbicidal activity of new triazolopyrimidine-2-sulfonamides as acetohydroxyacid synthase inhibitor
作者：
Chen, Chao-Nan;Chen, Qiong;Liu, Yu-Chao;Zhu, Xiao-Lei;Niu, Cong-Wei;...
期刊：
Bioorganic & Medicinal Chemistry ,2010年18(14):4897-4904 ISSN：0968-0896
通讯作者：
Xi, Zhen
作者机构：
[Yang, Guang-Fu; Zhu, Xiao-Lei; Liu, Yu-Chao; Chen, Qiong; Chen, Chao-Nan] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xi, Zhen; Niu, Cong-Wei] 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：
1,2,4-Triazolopyrimidine-2-sulfonamide;Acetohydroxyacid synthase inhibitor;Herbicide
摘要：
The triazolopyrimidine-2-sulfonanilide, discovered from preparing bioisosteres of the sulfonylurea herbicides, is an important class of acetohydroxyacid synthase (AHAS, EC 4.1.3.18) inhibitors. At least over ten triazolopyrimidine sulfonanilides have been commercialized as herbicides for the control of broadleaf weeds and grass with cereal crop selectivity. Herein, a series of triazolopyrimidine-2-sulfonanilides were designed and synthesized with the aim of discovery of new herbicides with higher activity. The assay results of the inhibition activity of the synthesized compounds against Arabidopsis thatiana AHAS indicated that some compounds showed a little higher activity against flumetsulam (FS), the first commercial triazolopyrimidine-2- sulfonanilide-type herbicide. The k i values of two promising compounds 3d and 8h are respectively, 1.61 and 1.29 μM, while that of FS is 1.85 μM. Computational simulation results indicated the ester group of compound 3d formed hydrogen bonds with the surrounding residues Arg'198 and Ser653, which accounts for its 11.5-folds higher AHAS inhibition activity than Y6610. Further green house assay showed that compound 3d has comparable herbicidal activity as FS. Even at the concentration of 37.5 g.ai/ha, 3d showed excellent herbicidal activity against Galium aparine, Cerastium arvense, Chenopodium album, Amaranthus retroflexus, and Rμmex acetasa, moderate herbicidal activity against Polygonum humifusum, Cyperus iria, and Eclipta prostrate. The combination of in vitro and in vivo assay indicated that 3d could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study. © 2010 Elsevier Ltd. All rights reserved.
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Synthesis and fungicidal activities of new 1,2,4-triazolo[1,5-a]pyrimidines
作者：
Chen, Qiong;Liu, Zu-Ming;Chen, Chao-Nan;Jiang, Li-Li;Yang, Guang-Fu
* （ 期刊：
Chemistry & Biodiversity ,2009年6(8):1254-1265 ISSN：1612-1872
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Liu, Zu-Ming; Jiang, Li-Li; Chen, Qiong; Chen, Chao-Nan] 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.
关键词：
1,2,4‐Triazolo[1,5‐a]pyrimidines;Acetohydrazides;Fungicidal activity;Agrochemicals;Qualitative structure–activity relationship (QSAR);X‐Ray crystallography
摘要：
A series of new acetohydrazone-containing 1,2,4-triazolo[1,5-a]pyrimidine derivatives were designed and synthesized for the purpose of searching for novel agrochemicals with higher fungicidal activity. Their in vitro fungicidal activities against Rhizoctonia solani were evaluated, and the most promising compound, 2-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)sulfanyl]- 2′-[(2-hydroxyphenyl)methylidene] acetohydrazide (2-17), showed a lower EC50 value (5.34 μg ml-1) than that of commercial carbendazim (EC50=7.62 μg ml-1). Additionally, compound 2-17 was also found to display broad-spectrum fungicidal activities, and its EC50 value (4.56 μg ml-1) against Botrytis cinereapers was very similar to that of carbendazim. Qualitative structure-activity relationships (QSARs) of the synthesized compounds were also discussed. © 2009 Verlag Helvetica Chimica Acta AG.
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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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Bisbenzimidazole to benzobisimidazole: from binding B-form duplex DNA to recognizing different modes of telomere G-quadruplex
作者：
Huang, Jing;Li, Guorui;Wu, Zhiguo;Song, Zhibin;Zhou, Yangyang;...
期刊：
Chemical Communications ,2009年(8):902-904 ISSN：1359-7345
通讯作者：
Zhou, Xiang
作者机构：
[Li, Guorui; Zhou, Yangyang; Huang, Jing; Song, Zhibin; Shuai, Liang; Zhou, Xiang; Wu, Zhiguo; Weng, Xiaocheng] Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.;[Yang, Guangfu] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ, Coll Chem, Wuhan, Peoples R China.
通讯机构：
[Zhou, Xiang] W;Wuhan Univ, Coll Chem & Mol Sci, Wuhan 430072, Peoples R China.
摘要：
A bisbenzimidazole was discovered to bind helix DNA, while related benzobisimidazole derivatives were found to bind and induce different G-quadruplex isomers.
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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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Bioactive conformation analysis of cyclic imides as protoporphyrinogen oxidase inhibitor by combining DFT calculations, QSAR and molecular dynamic simulations
作者：
Zhang, Li;Hao, Ge-Fei;Tan, Yin;Xi, Zhen* ;Huang, Ming-Zhi;...
期刊：
Bioorganic & Medicinal Chemistry ,2009年17(14):4935-4942 ISSN：0968-0896
通讯作者：
Xi, Zhen
作者机构：
[Yang, Guang-Fu; Zhang, Li; Tan, Yin; Hao, Ge-Fei] Cent China Normal Univ, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Xi, Zhen; Tan, Yin] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.;[Huang, Ming-Zhi] Hunan Res Inst Chem Ind, Changsha 410007, Hunan, 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：
Bioactive conformation;DFT;Molecular dynamic simulations;PPO;QSAR
摘要：
Bioactive conformation of drugs is one of the key points for understanding the ligand-receptor interactions. In the present study, by combining density functional theory-based (DFT-based) conformation analysis with quantitative structure-activity relationship analysis (QSAR), we developed successfully a new approach (DFT/QSAR) to carry out bioactive conformation analyses for a series of 25 cyclic imide derivatives as protoporphyrinogen oxidase (PPO) inhibitors. Further potential energy surface scan, molecular docking and molecular dynamic simulation calculations validated that the DFT/QSAR-derived conformation is indeed very similar to the 'real' bioactive conformation. We believe the DFT/QSAR approach provides a simple alternative for the bioactive conformation of small molecules, especially in the case that the three-dimensional structure of protein is unknown. © 2009 Elsevier Ltd. All rights reserved.
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Synthesis and antitumor activity of novel dithiocarbamate substituted chromones
作者：
Huang, Wei;Ding, Yu;Miao, Yan;Liu, Ming-Zhen;Li, Yan* ;...
期刊：
European Journal of Medicinal Chemistry ,2009年44(9):3687-3696 ISSN：0223-5234
通讯作者：
Li, Yan
作者机构：
[Yang, Guang-Fu; Huang, Wei; Miao, Yan; Liu, Ming-Zhen; Ding, Yu] Cent China Normal Univ, Coll Chem, Minist Educ, Key Lab Pesticide & Chem Biol, Wuhan 430079, Peoples R China.;[Li, Yan] Wuhan Univ, Zhongnan Hosp, Ctr Canc, Wuhan 430072, Peoples R China.
通讯机构：
[Li, Yan] W;Wuhan Univ, Zhongnan Hosp, Ctr Canc, Wuhan 430072, Peoples R China.
关键词：
Flavonoids;Chromone;Dithiocarbamate;Antitumor activity
摘要：
A series of chromone derivatives bearing diverse dithiocarbamate moieties were designed and synthesized via a three-component reaction protocol. Their in vitro antitumor activities were evaluated by MTT method against HCCLM-7, Hela, MDA-MB-435S, SW-480, Hep-2 and MCF-7. Two compounds (3-chloro-4-oxo-4H-chromen-2-yl)methyl piperidine-1-carbodithioate (Iq) and (6-chloro-4-oxo-4H-chromen-3-yl)methyl piperidine-1-carbodithioate (IIu), were identified as the most promising candidate due to their high potency and broad-spectrum. Further flow-activated cell sorting analysis revealed that compounds Iq and IIu arrest the cell cycle of SW-480 and MDA-MB-435s both in G2/M phase with dose-dependent effect and might display apoptosis-inducing effect on these tumor cell lines. © 2009 Elsevier Masson SAS. All rights reserved.
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Design and synthesis of N-2,6-difluorophenyl-5-methoxyl-1,2,4-triazolo[1,5-a]-pyrimidine-2-sulfonamide as acetohydroxyacid synthase inhibitor
作者：
Chen, Chao-Nan;Lv, Li-Li;Ji, Feng-Qin;Chen, Qiong;Xu, Hui;...
期刊：
Bioorganic & Medicinal Chemistry ,2009年17(8):3011-3017 ISSN：0968-0896
通讯作者：
Yang, Guang-Fu
作者机构：
[Yang, Guang-Fu; Ji, Feng-Qin; Lv, Li-Li; Chen, Qiong; Xu, Hui; Chen, Chao-Nan] Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol, Minist Educ, Wuhan 430079, Peoples R China.;[Xi, Zhen; Niu, Cong-Wei] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin 300071, Peoples R China.
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.
关键词：
Triazolopyrimidine-2-sulfonamide;Herbicide;Acetohydroxyacid synthase inhibitor
摘要：
Triazolopyrimidine-2-sulfonamide belongs to a herbicide group called acetohydroxyacid synthase inhibitors. With the aim to discover new triazolopyrimidine sulfonanilide compounds with high herbicidal activity and faster degradation rate in soil, the methyl group of Flumetsulam (FS) was modified into a methoxy group to produce a new herbicidal compound, N-2,6-difluorophenyl-5-methoxy-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (experimental code: Y6610). The enzymatic kinetic results indicated that compound Y6610 and FS have ki values of 3.31 × 10-6 M and 3.60 × 10-7 M against Arabidopsis thaliana AHAS, respectively. The 10-fold lower enzyme-inhibiting activity of Y6610 was explained rationally by further computational simulations and binding free energy calculations. In addition, compound Y6610 was found to display the same level in vivo post-emergent herbicidal activity as FS against some broad-leaf weeds and good safety to rice, maize, and wheat at the dosages of 75-300 g ai/ha. Further determination of the half-lives in soil revealed that the half-life in soil of Y6610 is 3.9 days shorter than that of FS. The experimental results herein showed that compound Y6610 could be regarded as a new potential acetohydroxyacid synthase-inhibiting herbicide candidate for further study. © 2009 Elsevier Ltd. All rights reserved.
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Bis(benzimidazole)pyridine derivative as a new class of G-quadruplex inducing and stabilizing ligand
作者：
Li, Guorui;Huang, Jing;Zhang, Ming;Zhou, Yangyang;Zhang, Dan;...
期刊：
Chemical Communications ,2008年(38):4564-4566 ISSN：1359-7345
通讯作者：
Zhou, Xiang
作者机构：
[Li, Guorui; Zhou, Yangyang; Huang, Jing; Zhou, Xiang; Zhang, Dan; Wu, Zhiguo; Zhang, Ming; Wang, Shaoru; Weng, Xiaocheng] Wuhan Univ, Coll Chem & Mol Sci, Minist Educ Res, Key Lab Biomed,State Key Lab Virol, Wuhan 430072, Peoples R China.;[Yang, Guangfu; Zhou, Xiang] Cent China Normal Univ, Key Lab Pesticide & Chem Biol, Minist Educ Res, Coll Chem, Wuhan 430079, Peoples R China.
通讯机构：
[Zhou, Xiang] W;Wuhan Univ, Coll Chem & Mol Sci, Minist Educ Res, Key Lab Biomed,State Key Lab Virol, Wuhan 430072, Peoples R China.
摘要：
Two new bis(benzimidazole)aryl derivatives have been prepared and one of them has been shown to induce and stabilize formation of a G-quadruplex.
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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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