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The enoyl-ACP reductase gene, fabI1, of Sinorhizobium meliloti is involved in salt tolerance, swarming mobility and nodulation efficiency
Ying Liu,JiaBi Zhu,GuanQiao Yu,HuaSong Zou
Chinese Science Bulletin , 2010, DOI: 10.1007/s11434-009-0721-2
Abstract: Our previous work showed that an enoyl-ACP reductase gene fabI1 of Sinorhizobium meliloti was down-regulated in the nifA mutant nodule bacteria. To gain a better understanding of fabI1 gene, a single site insertion mutant was constructed in this study. The fabI1 mutant was retarded in cell growth, and its ability to grow on media with high concentration of NaCl was reduced. In addition, the mutant was completely defective in swarming phenotype. During symbiosis, the fabI1 mutant had delayed nodule formation on host plants. Despite the fact that FabI1 protein showed 66% identity with another enoyl-ACP reductase FabI2 in S. meliloti, defects in fabI1 were not rescued by the plasmidborne version of fabI2. This indicated the different functions of the two FabI proteins in S. meliloti.
The enoyl-ACP reductase gene, fabI1, of Sinorhizobium meliloti is involved in salt tolerance, swarming mobility and nodulation efficiency

Ying Liu,JiaBi Zhu,GuanQiao Yu,HuaSong Zou,

科学通报(英文版) , 2010,
Abstract: Our previous work showed that an enoyl-ACP reductase gene fabI1 of Sinorhizobium meliloti was down-regulated in the nifA mutant nodule bacteria. To gain a better understanding of fabI1 gene, a single site insertion mutant was constructed in this study. The fabI1 mutant was retarded in cell growth, and its ability to grow on media with high concentration of NaCl was reduced. In addition, the mutant was completely defective in swarming phenotype. During symbiosis, the fabI1 mutant had delayed nodule formation...
苜蓿中华根瘤菌烯脂酰ACP还原酶基因fabI1的功能研究  [PDF]
刘影,朱家璧,俞冠翘,邹华松
科学通报 , 2009,
Abstract: 我们先前的工作表明,苜蓿中华根瘤菌的烯脂酰ACP还原酶基因fabI1在nifA突变根瘤中表达水平降低.本研究构建了fabI1的定点插入突变体.与野生型相比,突变菌株的生长速度变慢,在高浓度NaCl培养基上的生长能力降低.在半固体培养基上,该突变体的涌动能力完全丧失.在共生过程中,突变菌株在宿主植物上延迟结瘤,形成根瘤的能力下降.虽然苜蓿中华根瘤菌中的烯脂酰ACP还原酶基因fabI2的序列与fabI1有66%的一致性,但fabI2不能恢复fabI1突变体的表型,揭示了这两个基因在功能上的差异.
2D QSAR, PHARMACOPHORE AND DOCKING STUDIES OF MYCOBACTERIUM TUBERCULOSIS ENOYL ACYL CARRIER PROTEIN REDUCTASE INHIBITORS
HARIPRIYA MUNIPALLI,Uday chandra kumar,Mahmood Shaik
Journal of Global Pharma Technology , 2010, DOI: 10.1234/jgpt.v2i5.176
Abstract:
Determination of the Crystal Structure and Active Residues of FabV, the Enoyl-ACP Reductase from Xanthomonas oryzae  [PDF]
He Li, Xiaoli Zhang, Lijun Bi, Jin He, Tao Jiang
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026743
Abstract: Background Enoyl-ACP reductase (ENR) catalyses the last reduction reaction in the fatty acid elongation cycle in bacteria and is a good antimicrobial target candidate. FabV is the most recently discovered class of ENR, but we lack information about the atomic structure and the key residues involved in reductase activity except for the known conserved tyrosine and lysine residues in the Y-X8-K active site motif. Methodology/Principal Findings Here we report the crystal structure of FabV from Xanthomonas oryzae (xoFabV). The crystal structure of this enzyme has been solved to 1.6 ? resolution in space group P212121. The model of xoFabV consists of one monomer in the asymmetric unit which is composed of 13 α-helices and 11 β-strands, representing a canonical Rossmann fold architecture. Structural comparison presents that the locations of the conserved tyrosine (Y236) and lysine (K245) residues in the Y-X8-K active site motif of xoFabV and the Y-X6-K motif of ecFabI are notably similar. However, the conformations of Y236 in xoFabV and Y156 in ecFabI are distinct. Structure-based site-directed mutagenesis and enzymatic activity assays reveal that in addition to the conserved Y236 and K245 in the Y-X8-K motif, Y53, D111 and Y226 are key residues implicated in the reductase activity, and F113 and T276 are also important for enzyme function. Moreover, a proposed active lysine located immediately after the Y-X8-K motif in FabV from Burkholderia mallei (bmFabV) is altered to an inactive V246 in xoFabV. Conclusions/Significance We determine the first crystal structure of the FabV enzyme and identify several residues important for its enzymatic activity. These findings lay a solid foundation for the development of specific antibacterial inhibitors of the pathogenic bacteria, such as Vibrio cholerae, Burkholderia species and Xanthomonas species.
Combined Pharmacophore Modeling, Docking, and 3D-QSAR Studies of PLK1 Inhibitors  [PDF]
Shuai Lu,Hai-Chun Liu,Ya-Dong Chen,Hao-Liang Yuan,Shan-Liang Sun,Yi-Ping Gao,Pei Yang,Liang Zhang,Tao Lu
International Journal of Molecular Sciences , 2011, DOI: 10.3390/ijms12128713
Abstract: Polo-like kinase 1, an important enzyme with diverse biological actions in cell mitosis, is a promising target for developing novel anticancer drugs. A combined molecular docking, structure-based pharmacophore modeling and three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a set of 4,5-dihydro-1 H-pyrazolo[4,3- h]quinazoline derivatives as PLK1 inhibitors. The common substructure, molecular docking and pharmacophore-based alignment were used to develop different 3D-QSAR models. The comparative molecular field analysis (CoMFA) and comparative molecule similarity indices analysis (CoMSIA) models gave statistically significant results. These models showed good q 2 and r 2 pred values and revealed a good response to test set validation. All of the structural insights obtained from the 3D-QSAR contour maps are consistent with the available crystal structure of PLK1. The contour maps obtained from the 3D-QSAR models in combination with the structure based pharmacophore model help to better interpret the structure-activity relationship. These satisfactory results may aid the design of novel PLK1 inhibitors. This is the first report on 3D-QSAR study of PLK1 inhibitors.
AutoGPA: An Automated 3D-QSAR Method Based on Pharmacophore Alignment and Grid Potential Analysis  [PDF]
Naoyuki Asakawa,Seiichi Kobayashi,Junichi Goto,Noriaki Hirayama
International Journal of Medicinal Chemistry , 2012, DOI: 10.1155/2012/498931
Abstract: 3D-QSAR approach has been widely applied and proven to be useful in the case where no reliable crystal structure of the complex between a biologically active molecule and the receptor is available. At the same time, however, it also has highlighted the sensitivity of this approach. The main requirement of the traditional 3D-QSAR method is that molecules should be correctly overlaid in what is assumed to be the bioactive conformation. Identifying an active conformation of a flexible molecule is technically difficult. It has been a bottleneck in the application of the 3D-QSAR method. We have developed a 3D-QSAR software named AutoGPA especially based on an automatic pharmacophore alignment method in order to overcome this problem which has discouraged general medicinal chemists from applying the 3D-QSAR methods to their “real-world” problems. Applications of AutoGPA to three inhibitor-receptor systems have demonstrated that without any prior information about the three-dimensional structure of the bioactive conformations AutoGPA can automatically generate reliable 3D-QSAR models. In this paper, the concept of AutoGPA and the application results will be described. 1. Introduction There are two major types of in silico drug discovery techniques: structure-based and ligand-based techniques. Quantitative structure-activity relationship (QSAR) approach only based on biological activities and chemical structures of a series of molecules with the modest biological activities is one of the ligand-based techniques. The QSAR approach explicitly considering three-dimensional shape of molecules is called 3D-QSAR. The CoMFA method proposed by Cramer et al. [1] is one of the 3D-QSAR approaches which has been widely applied and proven that the 3D-QSAR approach is better than the traditional QSAR one. The CoMFA method is based on the idea that biological activity can be analyzed by relating the shape-dependent steric and electrostatic field of molecules to their biological activity. The results of a 3D-QSAR depend on a number of factors, each of which must be carefully considered. One of the most important considerations involves the selection of biologically active conformations and their alignment prior to the analysis. This may be relatively straightforward when one is working with a congeneric series of compounds that all have some key structural features that can be overlaid. For example, the original CoMFA paper [1] examined a series of steroid molecules which can be overlaid easily using the rigid steroid nucleus. In most cases, however, molecules of interest for
Pharmacophore Modeling and Docking Based QSAR Studies of Aryl Amidino Isoxazoline Derivatives to Design Potential FXa Inhibitors
American Journal of Bioinformatics Research , 2012, DOI: 10.5923/j.bioinformatics.20120203.01
Abstract: In order to elucidate the structural requirements for human factor Xa receptor antagonism, 72 antagonists belonging to isoxazolidine chemical class were selected from the literature and conducted molecular modeling studies. Best binding conformations were isolated by docking selected molecules into the receptor binding site. To further explore the structure-activity relationships within the considered chemical class, a pharmacophore model and QSAR analyses were developed. Pharmacophore models of these inhibitors were established by using the HipHop and HypoGen algorithms implemented in the Catalyst software package. The best quantitative pharmacophore model, which has the highest correlation coefficient (0.92), consisted of two hydrogen bond donor, a hydrophobic aromatic, and a ring aromatic feature. The model was further validated by test set and cross validation method. Molecular shape analysis (MSA) and Molecular field analysis (MFA) were used as the QSAR techniques. Two conformer-based alignment strategies were employed to construct reliable 3D-QSAR models. The docked conformer-based alignment strategy gave the best 3D-QSAR models. The best MFA and MSA models gave a cross-validated coefficient q(2) of 0.641 and 0.816, non-cross-validated r(2) values of 0.736 and 0.902, 20% out r(2) values of 0.743 and 0.871, respectively. The information obtained from molecular modelling studies was very helpful to design some novel selective inhibitors of factor Xa with desired activity.
Pharmacophore modeling and 3D-QSAR studies on substituted benzothiazole / benzimidazole analogues as DHFR inhibitors with antimycobacterial activity  [PDF]
R. Priyadarsini,Dr. C.B. Tharani,Sathya Suganya,S.Kavitha
International Journal of Pharma Sciences and Research , 2012,
Abstract: The resurgence of tuberculosis and the emergence of multidrug-resistant strains of Mycobacteria drugs has propelled the development of new structural classes of antitubercular agents. The present study was undertaken to investigate the opportunities which the enzyme dihydrofolate reductase, a promising drug target for treatmentof Mycobacterial infections offers for the development of new TB drugs. Pharmacophore models were established by using the HipHop and HypoGen algorithms implemented in the Catalyst software package. Thebest quantitative pharmacophore model, consisted of two hydrogen bond acceptor, a hydrophobic aliphatic, and a ring aromatic feature which has the highest correlation coefficient (0.93), as well as enrichment factor of 1.75 and Goodness of hit score of 0.73. Based on the pharmacophore model some leads were optimized and some of its derivatives were synthesized and analysed by following QSAR studies. About 25 compounds of substituted benzothiazole/ benzimidazole derivatives were synthesized as potent DHFR inhibitors and screened for antimycobacterial activity. To further explore the structure-activity relationships of all newly synthesized compounds, 3D-QSAR analyses were developed. MFA studies were performed with the QSAR module of Cerius2 using genetic partial least squares (G/PLS) algorithm. The predictive ability of the developed model was assessed using a training set of 25 and a test set of 5 compounds (r2pred = 0.924).The analyzed MF
Pharmacophore Modelling and 3D-QSAR Studies on -Phenylpyrazinones as Corticotropin-Releasing Factor 1 Receptor Antagonists  [PDF]
Paramjit Kaur,Vikas Sharma,Vipin Kumar
International Journal of Medicinal Chemistry , 2012, DOI: 10.1155/2012/452325
Abstract: Pharmacophore modelling-based virtual screening of compound is a ligand-based approach and is useful when the 3D structure of target is not available but a few known active compounds are known. Pharmacophore mapping studies were undertaken for a set of 50?N3-phenylpyrazinones possessing Corticotropin-releasing Factor 1 (CRF 1) antagonistic activity. Six point pharmacophores with two hydrogen bond acceptors, one hydrogen bond donor, two hydrophobic regions, and one aromatic ring as pharmacophoric features were developed. Amongst them the pharmacophore hypothesis AADHHR.47 yielded a statistically significant 3D-QSAR model with 0.803 as value and was considered to be the best pharmacophore hypothesis. The developed pharmacophore model was externally validated by predicting the activity of test set molecules. The squared predictive correlation coefficient of 0.91 was observed between experimental and predicted activity values of test set molecules. The geometry and features of pharmacophore were expected to be useful for the design of selective CRF 1 receptor antagonists. 1. Introduction Anxiety and depression are among the most common disorders seen in medical practice. The coexistence of anxiety and depression with medical illness is a topic of considerable clinical and research interest [1]. Depression is a serious mental health problem, with significant consequences in terms of human suffering, lost productivity, and even loss of life [2]. Corticotropin-releasing factor 1 (CRF 1) receptor antagonists have been sought since the stress-secreted peptide (adrenocorticotropin-releasing hypothalamic peptide) was isolated in 1981. Although evidence is mixed concerning the efficacy of CRF 1 receptor antagonist as antidepressants, CRF 1 receptor antagonist might be novel pharmacotherapies for anxiety and addiction [3]. Two well-characterized receptor subtypes, CRF 1 and CRF 2, have been identified. These G-protein-coupled receptors are widely distributed throughout the central and peripheral nervous systems [4]. Clinical evidence supports the hypothesis that overproduction of CRF 1??may underlie the pathology of depression, anxiety, and stress-related disorders and suggests that CRF 1 receptor antagonists could be useful for the treatment of these conditions [5]. To reduce the overall cost associated with the discovery and development of a new drug, the computer-aided molecular design methods have been identified as the most promising candidates to focus on the experimental efforts in modern medicinal chemistry. Pharmacophore mapping is one of the major elements
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