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작성일 : 09-06-22 12:09
[Tripos] Scientific Publications 2009
 글쓴이 : 티앤제이테크 (210.♡.60.176)
조회 : 15,055  
   http://www.tripos.com/index.php?family=modules,SimplePage,the_angle [2797]
● Discovery of Novel Myc#Max Heterodimer Disruptors with a Three-Dimensional Pharmacophore Model
Gabriela Mustata, Ariele Viacava Follis, Dalia I. Hammoudeh, Steven J. Metallo, Huabo Wang, Edward V. Prochownik, John S. Lazo, Ivet Bahar
Journal of Medicinal Chemistry 2009 [Epub ahead of print]

A three-dimensional pharmacophore model was generated utilizing a set of known inhibitors of c-Myc-Max heterodimer formation. The model successfully identified a set of structurally diverse compounds with potential inhibitory activity against c-Myc. Nine compounds were tested in vitro, and four displayed affinities in the micromolar range and growth inhibitory activity against c-Myc-overexpressing cells. These studies demonstrate the applicability of pharmacophore modeling to the identification of novel and potentially more puissant inhibitors of the c-Myc oncoprotein.
Link to full article (subscription to ACS journal required)


● Homology modeling of human α1β2γ2 and house fly β3 GABA receptor channels and Surflex-docking of fipronil
Cheng J, Ju XL, Chen XY, Liu GY
J Mol Model. 2009 [Epub ahead of print]

To further explore the mechanism of selective binding of the representative gamma-aminobutyric acid receptors (GABARs) noncompetitive antagonist (NCA) fipronil to insect over mammalian GABARs, three-dimensional models of human alpha1beta2gamma2 and house fly beta3 GABAR were generated by homology modeling, using the cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) of Torpedo marmorata as a template. Fipronil was docked into the putative binding site of the human alpha1beta2gamma2 and house fly beta3 receptors by Surflex-docking, and the calculated docking energies are in agreement with experimental results. The GABA receptor antagonist fipronil exhibited higher potency with house fly beta3 GABAR than with human alpha1beta2gamma2 GABAR. Furthermore, analyses of Surflex-docking suggest that the H-bond interaction of fipronil with Ala2 and Thr6 in the second transmembrane segment (TM2) of these GABARs plays a relatively important role in ligand selective binding. The different subunit assemblies of human alpha1beta2gamma2 and house fly beta3 GABARs may result in differential selectivity for fipronil.
Link to full article (subscription to ACS journal required)


● Octahydrophenanthrene-2,7-diol Analogues as Dissociated Glucocorticoid Receptor Agonists: Discovery and Lead Exploration
Robinson RP, Buckbinder L, Haugeto AI, McNiff PA, Millham ML, Reese MR, Schaefer JF, Abramov YA, Bordner J, Chantigny YA, Kleinman EF, Laird ER, Morgan BP, Murray JC, Salter ED, Wessel MD, Yocum SA.
J Med Chem. 2009 52(6):1731-43

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.
Link to full article (subscription to ACS journal required)
[이 게시물은 티앤제이테크님에 의해 2011-06-14 14:19:54 게시판에서 복사 됨]