Search results for " docking"
showing 10 items of 226 documents
Structural determinants of resveratrol for cell proliferation inhibition potency: experimental and docking studies of new analogs.
2010
International audience; Resveratrol is the subject of intense research because of the abundance of this compound in the human diet and as one of the most valuable natural chemopreventive agents. Further advances require new resveratrol analogs be used to identify the structural determinants of resveratrol for the inhibition potency of cell proliferation by comparing experimental and docking studies. Therefore, we synthesized new trans/(E)- and cis/(Z)-resveratrol - analogs not reported to date - by modifying the hydroxylation pattern of resveratrol and a double bond geometry. We included them in a larger panel of 14 molecules, including (Z)-3,5,4'-trimethoxystilbene, the most powerful molec…
Pyrazolobenzotriazinones Derivatives as COX Inhibitors: Synthesis Biological Activity and Molecular Modeling Studies
2010
Pyrazolylbenzotriazinones are endowed with structural analogy with the COX-2 selective inhibitor celecoxib. Considering that our research group has long been interested in the 3-pyrazolyl-substituted benzotriazinones as anti-inflammatory agents, six new pyrazolylbenzotriazinone derivatives 16a-c and 18a-c have been prepared by reacting the opportune ethyl 5-(2-aminobenzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxylate or 5-(2-aminobenzamido)-1-(pyridin-2-yl)-1H-pyrazole-4-carboxyic acid with sodium nitrite in glacial acetic acid. The biological studies revealed a good pharmacological profile for some pyrazolylbenzotriazinones and, in the case of the ethyl 5-(4-oxo-1,2,3-benzotriazin-3(4H)-y…
Phosphonic Acid Analogs of Fluorophenylalanines as Inhibitors of Human and Porcine Aminopeptidases N: Validation of the Importance of the Substitutio…
2020
International audience; A library of phosphonic acid analogs of phenylalanine substituted with fluorine, chlorine and trifluoromethyl moieties on the aromatic ring was synthesized and evaluated for inhibitory activity against human (hAPN) and porcine (pAPN) aminopeptidases. Fluorogenic screening indicated that these analogs are micromolar or submicromolar inhibitors, both enzymes being more active against hAPN. In order to better understand the mode of the action of the most active compounds, molecular modeling was used. It confirmed that aminophosphonic portion of the enzyme is bound nearly identically in the case of all the studied compounds, whereas the difference in activity results fro…
DNA minor groove binders: an overview on molecular modeling and QSAR approaches
2007
Molecular recognition of DNA by small molecules and proteins is a fundamental problem in structural biology and drug design. Understanding of recognition in both sequence-selective and sequence neutral ways at the level of successful prediction of binding modes and site selectivity will be instrumental for improvements in the design and synthesis of new molecules as potent and selective gene-regulatory drugs. Minor groove is the target of a large number of non-covalent binding agents. DNA binding with specific sequences, mostly AT, takes place by means of a combination of directed hydrogen bonding to base pair edges, van der Waals interactions with the minor groove walls and generalized ele…
2NH and 3OH are crucial structural requirements in sphingomyelin for sticholysin II binding and pore formation in bilayer membranes.
2013
AbstractSticholysin II (StnII) is a pore-forming toxin from the sea anemone Stichodactyla heliantus which belongs to the large actinoporin family. The toxin binds to sphingomyelin (SM) containing membranes, and shows high binding specificity for this lipid. In this study, we have examined the role of the hydrogen bonding groups of the SM long-chain base (i.e., the 2NH and the 3OH) for StnII recognition. We prepared methylated SM-analogs which had reduced hydrogen bonding capability from 2NH and 3OH. Both surface plasmon resonance experiments, and isothermal titration calorimetry measurements indicated that StnII failed to bind to bilayers containing methylated SM-analogs, whereas clear bind…
In-silico screening of new potential Bcl-2/Bcl-xl inhibitors as apoptosis modulators
2008
One of the major problems in the fight against cancer is drug-resistance, which, at a molecular level, can be acquired through mutations able to deactivate apoptosis. In particular, proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-xl and Bcl-2, are overexpressed in many tumours. The development of new inhibitors of these proteins as potential anticancer therapeutics represents a new frontier. In this work, we carried out an in-silico screening of compounds from a free database of more than 2 million structures (ZINC database), which allowed us to identify 17 sulfonamide derivatives as new potential inhibitors; thes…
Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: Inhibition kinetics and docking studies
2014
NS2B-NS3 is a serine protease of the Dengue virus considered a key target in the search for new antiviral drugs. In this study flavonoids were found to be inhibitors of NS2B-NS3 proteases of the Dengue virus serotypes 2 and 3 with IC50 values ranging from 15 to 44 μM. Agathisflavone (1) and myricetin (4) turned out to be noncompetitive inhibitors of dengue virus serotype 2 NS2B-NS3 protease with Ki values of 11 and 4.7 μM, respectively. Docking studies propose a binding mode of the flavonoids in a specific allosteric binding site of the enzyme. Analysis of biomolecular interactions of quercetin (5) with NT647-NHS-labeled Dengue virus serotype 3 NS2B-NS3 protease by microscale thermophoresis…
On the Applicability of Elastic Network Normal Modes in Small-Molecule Docking
2012
Incorporating backbone flexibility into protein-ligand docking is still a challenging problem. In protein-protein docking, normal mode analysis (NMA) has become increasingly popular as it can be used to describe the collective motions of a biological system, but the question of whether NMA can also be useful in predicting the conformational changes observed upon small-molecule binding has only been addressed in a few case studies. Here, we describe a large-scale study on the applicability of NMA for protein-ligand docking using 433 apo/holo pairs of the Astex data sets. On the basis of sets of the first normal modes from the apo structure, we first generated for each paired holo structure a…
Homology models of melatonin receptors: challenges and recent advances
2013
Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore …