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Docking Simulations (docking + simulation)
Selected AbstractsThe structural comparison of the bacterial PepX and human DPP-IV reveals sites for the design of inhibitors of PepX activityFEBS JOURNAL, Issue 8 2005Pascal Rigolet X-prolyl dipeptidyl aminopeptidases (X-PDAP) are enzymes catalysing the release of dipeptides from the amino termini of polypeptides containing a proline or an alanine at the penultimate position. Involved in various mammalian regulation processes, as well as in chronic human diseases, they have been proposed to play a role in pathogenicity for Streptococci. We compared the structure of X-PDAP from Lactococcus lactis (PepX) with its human counterpart DPP-IV. Despite very different overall folds, the residues most implicated for X-PDAP activity are conserved in the same positions and orientations in both enzymes, thus defining a structural signature for the X-PDAP specificity that crosses the species frontiers of evolution. Starting from this observation, we tested some inhibitors of DPP-IV on PepX activity, for which no specific inhibitor is known. We thus found that PepX was highly sensitive to valine-pyrrolidide with a KI of 9.3 µm, close to that reported in DPP-IV inhibition. We finally used the structure of PepX from L. lactis as a template for computer-based homology modeling of PepX from the pathogenic Streptococcus gordonii. Docking simulations of valine-pyrrolidide into the active site of PepX led to the identification of key residues for a rational drug design against PepX from Streptococci. These results could have applications in human health giving new perspectives to the struggle against pathogens. [source] The specificity of alcohol dehydrogenase with cis -retinoidsFEBS JOURNAL, Issue 9 2004Activity with 11- cis -retinol, localization in retina Studies in knockout mice support the involvement of alcohol dehydrogenases ADH1 and ADH4 in retinoid metabolism, although kinetics with retinoids are not known for the mouse enzymes. Moreover, a role of alcohol dehydrogenase (ADH) in the eye retinoid interconversions cannot be ascertained due to the lack of information on the kinetics with 11- cis -retinoids. We report here the kinetics of human ADH1B1, ADH1B2, ADH4, and mouse ADH1 and ADH4 with all- trans -, 7- cis -, 9- cis -, 11- cis - and 13- cis -isomers of retinol and retinal. These retinoids are substrates for all enzymes tested, except the 13- cis isomers which are not used by ADH1. In general, human and mouse ADH4 exhibit similar activity, higher than that of ADH1, while mouse ADH1 is more efficient than the homologous human enzymes. All tested ADHs use 11- cis -retinoids efficiently. ADH4 shows much higher kcat/Km values for 11- cis -retinol oxidation than for 11- cis -retinal reduction, a unique property among mammalian ADHs for any alcohol/aldehyde substrate pair. Docking simulations and the kinetic properties of the human ADH4 M141L mutant demonstrated that residue 141, in the middle region of the active site, is essential for such ADH4 specificity. The distinct kinetics of ADH4 with 11- cis -retinol, its wide specificity with retinol isomers and its immunolocalization in several retinal cell layers, including pigment epithelium, support a role of this enzyme in the various retinol oxidations that occur in the retina. Cytosolic ADH4 activity may complement the isomer-specific microsomal enzymes involved in photopigment regeneration and retinoic acid synthesis. [source] Caffeine inhibition of ionotropic glycine receptorsTHE JOURNAL OF PHYSIOLOGY, Issue 16 2009Lei Duan We found that caffeine is a structural analogue of strychnine and a competitive antagonist at ionotropic glycine receptors (GlyRs). Docking simulations indicate that caffeine and strychnine may bind to similar sites at the GlyR. The R131A GlyR mutation, which reduces strychnine antagonism without suppressing activation by glycine, also reduces caffeine antagonism. GlyR subtypes have differing caffeine sensitivity. Tested against the EC50 of each GlyR subtype, the order of caffeine potency (IC50) is: ,2, (248 ± 32 ,m) ,,3, (255 ± 16 ,m) > ,4, (517 ± 50 ,m) > ,1,(837 ± 132 ,m). However, because the ,3, GlyR is more than 3-fold less sensitive to glycine than any of the other GlyR subtypes, this receptor is most effectively blocked by caffeine. The glycine dose,response curves and the effects of caffeine indicate that amphibian retinal ganglion cells do not express a plethora of GlyR subtypes and are dominated by the ,1, GlyR. Comparing the effects of caffeine on glycinergic spontaneous and evoked IPSCs indicates that evoked release elevates the glycine concentration at some synapses whereas summation elicits evoked IPSCs at other synapses. Caffeine serves to identify the pharmacophore of strychnine and produces near-complete inhibition of glycine receptors at concentrations commonly employed to stimulate ryanodine receptors. [source] C6-Unsubstituted Pyrazolo[3,4- d]pyrimidines Are Dual Src/Abl Inhibitors Effective against Imatinib Mesylate Resistant Chronic Myeloid Leukemia Cell LinesCHEMMEDCHEM, Issue 1 2009Maria Alessandra Santucci Dr. Abstract Docking simulations were used to predict the most favorable interaction between the T315I mutated form of Abl (invariably associated with resistance to the tyrosine kinase inhibitor imatinib mesylate, IM) and C6-unsubstituted and substituted pyrazolo[3,4- d]pyrimidines previously found to be dual Src/Abl inhibitors. Two C6-unsubstituted (1 and 2) and eight C6-substituted compounds (3,10) were selected and assayed for their effects on the Ba/F3 cell line transducing the wild-type p210Bcr,Abl construct, which is IM-sensitive, or three of the most common mutations associated with IM resistance in,vivo (T315I, Y253F, and E255K), and driven to drug resistance by saturating doses of IL-3 or by the expression of the Bcr,Abl construct coding for the p185 protein of acute lymphoblastic leukemia. Compounds 1 and 2 were active against all cell lines assayed (LD50 range: 0.7,4.3,,M), whereas C6-substituted compounds exhibited lower activity (LD50,8,,M for compound 3 toward the T315I mutant). Notably, 1 and 2 were also effective toward the T315I mutation, which is insensitive to dual Src/Abl inhibitors. The cytotoxic effects of 1 and 2 on IM-sensitive and IM-resistant Ba/F3 cells were attributable, at least in part, to their pro-apoptotic activity. Taken together, such findings suggest that C6-unsubstituted pyrazolo[3,4- d]pyrimidines may represent useful inhibitors to target IM-resistant chronic myeloid leukemia. [source] Binding site on human immunoglobulin G for the affinity ligand HWRGWVJOURNAL OF MOLECULAR RECOGNITION, Issue 3 2010Haiou Yang Abstract Affinity ligand HWRGWV has demonstrated the ability to isolate human immunoglobulin G (hIgG) from mammalian cell culture media. The ligand specifically binds hIgG through its Fc portion. This work shows that deglycosylation of hIgG has no influence on its binding to the HWRGWV ligand and the ligand does not compete with Protein A or Protein G in binding hIgG. It is suggested by the mass spectrometry (MS) data and docking simulation that HWRGWV binds to the pFc portion of hIgG and interacts with the amino acids in the loop Ser383,Asn389 (SNGQPEN) located in the CH3 domain. Subsequent modeling has suggested a possible three-dimensional minimized solution structure for the interaction of hIgG and the HWRGWV ligand. The results support the fact that a peptide as small as a hexamer can have specific interactions with large proteins such as hIgG. Copyright © 2009 John Wiley & Sons, Ltd. [source] A possible molecular mechanism of hanatoxin binding-modified gating in voltage-gated K+ -channelsJOURNAL OF MOLECULAR RECOGNITION, Issue 6 2003Kuo-Long Lou Abstract While S4 is known as the voltage sensor in voltage-gated potassium channels, the carboxyl terminus of S3 (S3C) is of particular interest concerning the site for gating modifier toxins like hanatoxin. The thus derived helical secondary structural arrangement for S3C, as well as its surrounding environment, has since been intensively and vigorously debated. Our previous structural analysis based on molecular simulation has provided sufficient information to describe reasonable docking conformation and further experimental designs (Lou et al., 2002. J. Mol. Recognit. 15: 175,179). However, if one only relies on such information, more advanced structure,functional interpretations for the roles S3C may play in the modification of gating behavior upon toxin binding will remain unknown. In order to have better understanding of the molecular details regarding this issue, we have performed the docking simulation with the S3C sequence from the hanatoxin-insensitive K+ -channel, shaker, and analyzed the conformational changes resulting from such docking. Compared with other functional data from previous studies with respect to the proximity of the S3,S4 linker region, we suggested a significant movement of drk1 S3C, but not shaker S3C, in the direction presumably towards S4, which was comprehended as a possible factor interfering with S4 translocation during drk1 gating in the presence of toxin. In combination with the discussions for structural roles of the length of the S3,S4 linker, a possible molecular mechanism to illustrate the hanatoxin binding-modified gating is proposed. Copyright © 2003 John Wiley & Sons, Ltd. [source] Molecular modeling of chiral-modified zeolite HY employed in enantioselective separationCHIRALITY, Issue 6 2007Siricharn S. Jirapongphan Abstract Insight into enantioselective separation utilizing chiral-modified zeolite HY could be useful in designing a chiral stationary phase for resolving pharmaceutical compounds. A model was employed to better understand the enantioseparation of valinol in zeolite HY that contains (+)-(1R;2R)-hydrobenzoin as a chiral modifier. This model incorporates the zeolite support and accounts for the flexible change. Results from grand canonical Monte Carlo and molecular dynamics simulations indicate that the associated diastereomeric complex consists of a single (+)-(1R;2R)-hydrobenzoin and a single valinol molecules located in the zeolite HY supercage. Supercage-based docking simulation predicted an enantioselectivity of 2.6 compared with that of 1.4 measured experimentally. Also, the supercage-based docking simulation demonstrated a single binding motif in the S complex, and two binding motifs in the R complex. The multiple binding modes in the R complex resulted in its lower stability. This is hypothesized to be the origin of the weaker binding between (,)-(R)-valinol and the chiral modifier, and explains why (+)-(R)-valinol is retained more in the chiral-modified zeolite system studied. Chirality, 2007. © 2007 Wiley-Liss, Inc. [source] Development of the force field parameters for phosphoimidazole and phosphohistidineJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 11 2004Yuri A. Kosinsky Abstract Phosphorylation of histidine-containing proteins is a key step in the mechanism of many phosphate transfer enzymes (kinases, phosphatases) and is the first stage in a wide variety of signal transduction cascades in bacteria, yeast, higher plants, and mammals. Studies of structural and dynamical aspects of such enzymes in the phosphorylated intermediate states are important for understanding the intimate molecular mechanisms of their functioning. Such information may be obtained via molecular dynamics and/or docking simulations, but in this case appropriate force field parameters for phosphohistidine should be explicitly defined. In the present article we describe development of the GROMOS96 force field parameters for phosphoimidazole molecule,a realistic model of the phosphohistidine side chain. The parameterization is based on the results of ab initio quantum chemical calculations with subsequent refinement and testing using molecular mechanics and molecular dynamics simulations. The set of force constants and equilibrium geometry is employed to derive force field for the phosphohistidine moiety. Resulting parameters and topology are incorporated into the molecular modeling package GROMACS and used in molecular dynamics simulations of a phosphohistidine-containing protein in explicit solvent. © 2004 Wiley Periodicals, Inc. J Comput Chem 25: 1313,1321, 2004 [source] Prenylflavonoids as Nonsteroidal Phytoestrogens and Related Structure,Activity RelationshipsCHEMMEDCHEM, Issue 4 2006Zhi-qiang Wang Abstract In the search for estrogen receptor (ER) modulators, a series of prenylflavonoids were found to be widely distributed amongst tonic herbal medicines and to possess estrogen-like activity in MCF-7/BOS cells, as evaluated by an estrogen-screening assay. Cell-cycle analysis revealed that the stimulatory effects of these compounds toward cell proliferation were elicited at the G1,S checkpoint and could significantly increase the S-phase population of MCF-7 cells under hormone-free conditions. ER-responsive gene (PS2, PgR) and protein (PgR) expression was also detected; mRNA and protein-expression levels for PS2 and PgR were up-regulated by the compounds in a dose-dependent manner. These effects could be inhibited by the pure ER antagonist ICI,182,780 ((7,-[9-{4,4,5,5,5-pentafluoropentyl}sulfinyl]nonyl)estra-1,3,5(10)-triene-3,17,-diol). It was therefore concluded that the estrogen-like effects of these prenylflavonoids were mediated primarily through ERs. Furthermore, to explore the structure,activity relationship based on the estrogen receptor and detailed molecular mechanisms among the prenylflavonoids, protein,ligand docking simulations were carried out by using the DS-MODELING software package. The binding affinity of each prenylflavonoid toward ER, was scored, and the receptor,ligand interaction was also analyzed to provide the simulation characteristics of virtual molecular recognition mechanisms. [source] | ||||||||||