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Molecular Docking (molecular + docking)
Selected AbstractsBis-8-hydroxyquinoline and bis-8-hydroxyquinaldine N -substituted amines: A single methyl group structural difference between the two heterocycles, which modulates the antiproliferative effectsJOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 3 2010Sébastien Madonna The synthesis of a series of bis-8-hydroxyquinoline- and bis-8-hydroxyquinaldine-substituted N -benzyl or thiophenyl amines and their corresponding bis-8-hydroxyquinoline is reported. In vitro growth inhibitory effects of both series have been evaluated. It has been observed that analogs from the bis-8-hydroxyquinoline series exert nanomolar range activity, whereas the antiproliferative activity of the corresponding analogs from the bis-8-hydroxyquinaldine series was found to be drastically lower. Molecular docking and chemical,physical properties account for these observed growth inhibitory differences between the two series of analogs, which differ only by the presence of a methyl group at the 2 position of the heterocyclic ring. J. Heterocyclic Chem., (2010). [source] Non-enzymatic developmental functions of acetylcholinesterase , the question of redundancyFEBS JOURNAL, Issue 20 2008Glynis Johnson Despite in vitro demonstrations of non-enzymatic morphogenetic functions in acetylcholinesterase (AChE), the AChE knockout phenotype is milder than might be expected, casting doubt upon the relevance of such functions in vivo. Functional redundancy is a possible explanation. Using in vitro findings that AChE is able to bind to laminin-111, together with detailed information about the interaction sites, as well as an epitope analysis of adhesion-inhibiting anti-AChE mAbs, we have used molecular docking and bioinformatics techniques to explore this idea, investigating structurally similar molecules that have a comparable spatiotemporal expression pattern in the embryonic nervous system. On this basis, molecules with which AChE could be redundant are the syndecans, glypicans, perlecan, the receptor tyrosine kinase Mer, and the low-density lipoprotein receptor. It is also highly likely that AChE may be redundant with the homologous neuroligins, although there is no evidence that the latter are expressed before synaptogenesis. AChE was observed to dock with Gas6, the ligand for Mer, as well as with apolipoprotein E3 (but not apolipoprotein E4), both at the same site as the laminin interaction. These findings suggest that AChE may show direct functional redundancy with one or more of these molecules; it is also possible that it may itself have a unique function in the stabilization of the basement membrane. As basement membrane molecules are characterized by multiple molecular interactions, each contributing cumulatively to the construction and stability of the network, this may account for AChE's apparently promiscuous interactions, and also for the survival of the knockout. [source] Studies of molecular docking between fibroblast growth factor and heparin using generalized simulated annealingINTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 13 2008Samuel Silva da Rocha Pita Abstract Since the middle 70s, the main molecular docking problem consists in limitations to treat adequately the degrees of freedom of protein (or a receptor) due to the energy landscape roughness and the high computational cost. Until recently, only few algorithms considering flexible simultaneously both ligand and receptor at low computational cost were developed. As a recent proposed Statistical Mechanics, generalized simulated annealing (GSA) has been employed at diverse works concerning global optimization problems. In this work, we used this method exploring the molecular docking problem taking into account the FGF-2 and heparin complex. Since the requirements of an efficient docking algorithm are accuracy and velocity, we tested the influence of GSA parameters qA (new configuration acceptance index), qV (energy surface visiting index), and qT (temperature decreasing control) on the performance of GSADOCK program. Our simulations showed that as temperature parameter qT increases, qA parameter follows this behavior in the interval ranging from 1.1 to 2.3. We found that the GSA parameters have the best performance for the qA values ranging from 1.1 to 1.3, qV values from 1.3 to 1.5, and qT values from 1.1 to 1.7. Most of good qV values were equal or next the good qT values. Finally, the implemented algorithm is trustworthy and can be employed as a tool of molecular modeling methods. The final version of the program will be free of charge and will be accessible at our home-page or could be requested to the authors for e-mail. © 2008 Wiley Periodicals, Inc. Int J Quantum Chem, 2008 [source] A new method for the gradient-based optimization of molecular complexesJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 9 2009Jan Fuhrmann Abstract We present a novel method for the local optimization of molecular complexes. This new approach is especially suited for usage in molecular docking. In molecular modeling, molecules are often described employing a compact representation to reduce the number of degrees of freedom. This compact representation is realized by fixing bond lengths and angles while permitting changes in translation, orientation, and selected dihedral angles. Gradient-based energy minimization of molecular complexes using this representation suffers from well-known singularities arising during the optimization process. We suggest an approach new in the field of structure optimization that allows to employ gradient-based optimization algorithms for such a compact representation. We propose to use exponential mapping to define the molecular orientation which facilitates calculating the orientational gradient. To avoid singularities of this parametrization, the local minimization algorithm is modified to change efficiently the orientational parameters while preserving the molecular orientation, i.e. we perform well-defined jumps on the objective function. Our approach is applicable to continuous, but not necessarily differentiable objective functions. We evaluated our new method by optimizing several ligands with an increasing number of internal degrees of freedom in the presence of large receptors. In comparison to the method of Solis and Wets in the challenging case of a non-differentiable scoring function, our proposed method leads to substantially improved results in all test cases, i.e. we obtain better scores in fewer steps for all complexes. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [source] The molecular mechanism of human group IIA phospholipase A2 inactivation by bolinaquinoneJOURNAL OF MOLECULAR RECOGNITION, Issue 6 2009Maria Chiara Monti Abstract The molecular basis of the human group IIA secretory phospholipase A2 inactivation by bolinaquinone (BLQ), a hydroxyquinone marine terpenoid, has been investigated for the comprehension of its relevant antiinflammatory properties, through the combination of spectroscopic techniques, biosensors analysis, mass spectrometry (MS) and molecular docking. Indeed, sPLA2s are well known to be implicated in the pathogenesis of inflammation such as rheumatoid arthritis, septic shock, psoriasis and asthma. Our results suggest a mechanism of competitive inhibition guided by a non-covalent molecular recognition event, disclosing the key role of the BLQ hydroxyl-quinone moiety in the chelation of the catalytic Ca2+ ion inside the enzyme active site. The understanding of the sPLA2 -IIA inactivation mechanism by BLQ could be useful for the development of a new chemical class of PLA2 inhibitors, able to specifically target the enzyme active site. Copyright © 2009 John Wiley & Sons, Ltd. [source] New mathematic model for predicting chiral separation using molecular docking: Mechanism of chiral recognition of triadimenol analoguesJOURNAL OF SEPARATION SCIENCE, JSS, Issue 14 2009Guoqing Zhang Abstract The purpose of this paper was to study the enantioseparation mechanism of triadimenol compounds by carboxymethylated (CM)-,-CD mediated CE. All the enantiomers were separated under the same experimental conditions to study the chiral recognition mechanism using a 30 mM sodium dihydrogen phosphate buffer at pH 2.2 adjusted by phosphoric acid. The inclusion courses between CM-,-CD and enantiomers were investigated by the means of molecular docking technique. It was found that there were at least three points (one hydrophobic bond and two hydrogen bonds) involved in the interaction of each enantiomer with the chiral selectors. A new mathematic model has been built up based on the results of molecular mechanics calculations, which could analyze the relationship between the resolution of enantioseparation and the interaction energy in the docking area. Comparing the results of the separation by CE, the established mathematic model demonstrated good capability to predict chiral separation of triadimenol enantiomers using CM-,-CD mediated CE. [source] Design, Synthesis, and Antifungal Activity of Novel Conformationally Restricted Triazole DerivativesARCHIV DER PHARMAZIE, Issue 12 2009Wenya Wang Abstract A series of new triazole derivatives were designed and synthesized on the basis of the active site of lanosterol 14,-demethylase from Candida albicans (CACYP51). 2-(2,4-Difluorophenyl)-3-(methyl-(3-phenoxyalkyl)amino)-1-(1H -1,2,4-triazol-1-yl)propan-2-ols show excellent in-vitro activity against most of the tested pathogenic fungi. The MIC80 value of compound 8a against Candida albicans is 0.01 ,M, which provides a good starting template for further structural optimization. The binding modes of the designed compounds were investigated by flexible molecular docking. The compounds interacted with CACYP51 through hydrophobic, van-der-Waals, and hydrogen-bonding interactions. [source] Quantitative Structure,Activity Relationship Models for Predicting Biological Properties, Developed by Combining Structure- and Ligand-Based Approaches: An Application to the Human Ether-a-go-go-Related Gene Potassium Channel InhibitionCHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2009Alessio Coi A strategy for developing accurate quantitative structure,activity relationship models enabling predictions of biological properties, when suitable knowledge concerning both ligands and biological target is available, was tested on a data set where molecules are characterized by high structural diversity. Such a strategy was applied to human ether-a-go-go-related gene K+ channel inhibition and consists of a combination of ligand- and structure-based approaches, which can be carried out whenever the three-dimensional structure of the target macromolecule is known or may be modeled with good accuracy. Molecular conformations of ligands were obtained by means of molecular docking, performed in a previously built theoretical model of the channel pore, so that descriptors depending upon the three-dimensional molecular structure were properly computed. A modification of the directed sphere-exclusion algorithm was developed and exploited to properly splitting the whole dataset into Training/Test set pairs. Molecular descriptors, computed by means of the codessa program, were used for the search of reliable quantitative structure,activity relationship models that were subsequently identified through a rigorous validation analysis. Finally, pIC50 values of a prediction set, external to the initial dataset, were predicted and the results confirmed the high predictive power of the model within a quite wide chemical space. [source] Research Article: pso@autodock: A Fast Flexible Molecular Docking Program Based on Swarm IntelligenceCHEMICAL BIOLOGY & DRUG DESIGN, Issue 6 2007Vigneshwaran Namasivayam On the quest of novel therapeutics, molecular docking methods have proven to be valuable tools for screening large libraries of compounds determining the interactions of potential drugs with the target proteins. A widely used docking approach is the simulation of the docking process guided by a binding energy function. On the basis of the molecular docking program autodock, we present pso@autodock as a tool for fast flexible molecular docking. Our novel Particle Swarm Optimization (PSO) algorithms varCPSO and varCPSO-ls are suited for rapid docking of highly flexible ligands. Thus, a ligand with 23 rotatable bonds was successfully docked within as few as 100 000 computing steps (rmsd = 0.87 Ĺ), which corresponds to only 10% of the computing time demanded by autodock. In comparison to other docking techniques as gold 3.0, dock 6.0, flexx 2.2.0, autodock 3.05, and sodock, pso@autodock provides the smallest rmsd values for 12 in 37 protein,ligand complexes. The average rmsd value of 1.4 Ĺ is significantly lower then those obtained with the other docking programs, which are all above 2.0 Ĺ. Thus, pso@autodock is suggested as a highly efficient docking program in terms of speed and quality for flexible peptide,protein docking and virtual screening studies. [source] ,- O -Linked Glycopeptide Mimetics: Synthesis, Conformation Analysis, and Interactions with Viscumin, a Galactoside-Binding Model LectinCHEMISTRY - A EUROPEAN JOURNAL, Issue 40 2009Jesús Jiménez-Barbero Prof. Abstract Efficient cycloaddition of a silylidene-protected galactal with a suitable heterodiene yielded the basis for a facile diastereoselective route to a glycopeptide-mimetic scaffold. Its carbohydrate part was further extended by ,1,3-linked galactosylation. The pyranose rings retain their 4C1 chair conformation, as shown by molecular modeling and NMR spectroscopy, and the typical exo -anomeric geometry was observed for the disaccharide. The expected bioactivity was ascertained by saturation-transfer-difference NMR spectroscopy by using the galactoside-specific plant toxin viscumin as a model lectin. The experimental part was complemented by molecular docking. The described synthetic route and the strategic combination of computational and experimental techniques to reveal conformational properties and bioactivity establish the prepared ,- O -linked glycopeptide mimetics as promising candidates for further exploitation of this scaffold to give O -glycans for lectin blocking and vaccination. [source] New Racemosol Derivatives as Potent Cyclooxygenase (COX) InhibitorsCHEMISTRY & BIODIVERSITY, Issue 12 2005Saiphon Songarsa Racemosol (1) and 10- O -demethylracemosol (2), natural products from Bauhinia malabaricaRoxb., exhibit potent in vitro anti-inflammatory activities against cyclooxygenase-1 and -2 (COX-1 and -2) enzymes. To investigate the structure,activity relationship (SAR) of these molecules, we prepared and fully characterized 17 derivatives by functionalizing one, two, or all three OH group(s) of 2 (Scheme). Both the size and polarity of the substituents as well as the substitution pattern in compounds 3a,q were found to be critical for anti-inflammatory activity. The orientation of the drugs and their mode of binding were studied by molecular docking based on the known 3D structure of the complex between COX-2 and the drug SC-558. Whereas the monoacetoxy derivative 3h exhibited an equally potent inhibitory activity towards both COX-1 and -2 (Table,1), its diacetoxy congener 3i was slightly more selective toward COX-2. In vivo anti-inflammatory tests showed that 3i and 2 are slightly more active than the reference compound phenylbutazone (Table,2). [source] Toward a Consensus Model of the hERG Potassium ChannelCHEMMEDCHEM, Issue 3 2010Anna Stary Dr. Abstract Malfunction of hERG potassium channels, due to inherited mutations or inhibition by drugs, can cause long QT syndrome, which can lead to life-threatening arrhythmias. A three-dimensional structure of hERG is a prerequisite to understand the molecular basis of hERG malfunction. To achieve a consensus model, we carried out an extensive analysis of hERG models based on various alignments of helix,S5. We analyzed seven models using a combination of conventional geometry/packing/normality validation methods as well as molecular dynamics simulations and molecular docking. A synthetic test set with the X-ray crystal structure of Kv1.2 with artificially shifted S5 sequences modeled into the structure served as a reference case. We docked the known hERG inhibitors (+)-cisapride, (S)-terfenadine, and MK-499 into the hERG models and simulation snapshots. None of the single analyses unambiguously identified a preferred model, but the combination of all three revealed that there is only one model that fulfils all quality criteria. This model is confirmed by a recent mutation scanning experiment (P. Ju, G. Pages, R.,P. Riek, P.,C. Chen, A.,M. Torres, P.,S. Bansal, S. Kuyucak, P.,W. Kuchel, J.,I. Vandenberg, J. Biol. Chem. 2009, 284, 1000,1008).1We expect the modeled structure to be useful as a basis both for computational studies of channel function and kinetics as well as the design of experiments. [source] Computational Studies to Discover a New NR2B/NMDA Receptor Antagonist and Evaluation of Pharmacological ProfileCHEMMEDCHEM, Issue 10 2008Rosaria Gitto Prof. Abstract The ionotropic glutamate NMDA/NR2B receptor and its interaction with ifenprodil-like noncompetitive ligands were investigated by a combined ligand-based and target-based approach. First, we generated 3D pharmacophore hypotheses and identified common chemical features that are shared by a training set of well-known NR2B antagonists. The binding mode of the most representative ligand was also studied by molecular docking. Because the docking results and the suggested 3D pharmacophore model were in good agreement, we obtained new information about the NR2B ifenprodil site. The best pharmacophoric hypothesis was used as a query for in,silico screening; this allowed the identification of new "hit". We synthesized "hit-compound" analogues, and some of the molecules showed significant activity both in binding and functional assay as well as in,vivo anticonvulsant efficacy in DBA/2 mice. The most active derivatives also exhibited neuroprotective effects against glutamate-induced toxicity in HCN-1A cells. [source] Structure,Activity Studies on Suramin Analogues as Inhibitors of NAD+ -Dependent Histone Deacetylases (Sirtuins)CHEMMEDCHEM, Issue 10 2007Johannes Trapp Dr. Abstract Suramin is a symmetric polyanionic naphthylurea originally used for the treatment of trypanosomiasis and onchocerciasis. Suramin and diverse analogues exhibit a broad range of biological actions in,vitro and in,vivo, including, among others, antiproliferative and antiviral activity. Suramin derivatives usually target purinergic binding sites. Class,III histone deacetylases (sirtuins) are amidohydrolases that require nicotinamide adenine dinucleotide (NAD+) as a cofactor for their catalytic mechanism. Deacetylation of the target proteins leads to a change in conformation and alters the activity of the proteins in question. Suramin was reported to inhibit human sirtuin,1 (SIRT1). We tested a diverse set of suramin analogues to elucidate the inhibition of the NAD+ -dependent histone deacetylases SIRT1 and SIRT2 and discovered selective inhibitors of human sirtuins with potency in the two-digit nanomolar range. In addition, the structural requirements for the binding of suramin derivatives to sirtuins were investigated by molecular docking. The recently published X-ray crystal structure of human SIRT5 in complex with suramin and the human SIRT2 structure were used to analyze the interaction mode of the novel suramin derivatives. [source] | ||||||||||