Search results for "molecular model"
showing 10 items of 274 documents
Kinetic analysis and molecular modeling of the inhibition mechanism of roneparstat (SST0001) on human heparanase
2016
Heparanase is a β-d-glucuronidase which cleaves heparan sulfate chains in the extracellular matrix and on cellular membranes. A dysregulated heparanase activity is intimately associated with cell invasion, tumor metastasis and angiogenesis, making heparanase an attractive target for the development of anticancer therapies. SST0001 (roneparstat; Sigma-Tau Research Switzerland S.A.) is a non-anticoagulant 100% N-acetylated and glycol-split heparin acting as a potent heparanase inhibitor, currently in phase I in advanced multiple myeloma. Herein, the kinetics of heparanase inhibition by roneparstat is reported. The analysis of dose-inhibition curves confirmed the high potency of roneparstat (I…
Extracellular loop 2 of G protein-coupled olfactory receptors is critical for odorant recognition
2021
International audience; G protein-coupled olfactory receptors (ORs) enable us to detect innumerous odorants. They are also ectopically expressed in non-olfactory tissues and emerging as attractive drug targets. ORs can be promiscuous or highly specific, which is part of a larger mechanism for odor discrimination. Here, we demonstrate that the OR extracellular loop 2 (ECL2) plays critical roles in OR promiscuity and specificity. Using site-directed mutagenesis and molecular modeling, we constructed 3D OR models in which ECL2 forms a lid over the orthosteric pocket. We demonstrate using molecular dynamics simulations that ECL2 controls the shape and the volume of the odorant-binding pocket, m…
Phytochemical Indicaxanthin Inhibits Colon Cancer Cell Growth and Affects the DNA Methylation Status by Influencing Epigenetically Modifying Enzyme E…
2015
<b><i>Background:</i></b> Recently, we have shown anti-proliferative and pro-apoptotic effects of indicaxanthin associated with epigenetic modulation of the onco-suppressor <i>p16</i><sup><i>INK4a</i></sup> in the human colon cancer cell line CACO2. In the present study, the epigenetic activity of indicaxanthin and the mechanisms involved were further investigated in other colorectal cancer cell lines. <b><i>Methods:</i></b> LOVO1, CACO2, HT29, HCT116, and DLD1 cells were used to evaluate the potential influence of consistent dietary concentrations of indicaxanthin on DNA methylation, and the epigenetic mech…
Hybrid Schemes Based on Quantum Mechanics/Molecular Mechanics Simulations
2011
The development of characterization techniques, advanced synthesis methods, as well as molecular modeling has transformed the study of systems in a well-established research field. The current research challenges in biocatalysis and biotransformation evolve around enzyme discovery, design, and optimization. How can we find or create enzymes that catalyze important synthetic reactions, even reactions that may not exist in nature? What is the source of enzyme catalytic power? To answer these and other related questions, the standard strategies have evolved from trial-and-error methodologies based on chemical knowledge, accumulated experience, and common sense into a clearly multidisciplinary …
Interface and Surface Properties of Short Polymers in Solution: Monte Carlo Simulations and Self-Consistent Field Theory
2000
We investigate the structure and thermodynamics of inhomogeneous polymer solutions in the framework of a coarse-grained off-lattice model. Properties of the liquidvapor interface and the packing of...
Monte Carlo simulations of polymer dynamics: Recent advances
1997
A brief review is given of applications of Monte Carlo simulations to study the dynamical properties of coarse-grained models of polymer melts, emphasizing the crossover from the Rouse model toward reptation, and the glass transition. The extent to which Monte Carlo algorithms can mimic the actual chain dynamics is critically examined, and the need for the use of coarse-grained rather than fully atomistic models for such simulations is explained. It is shown that various lattice and continuum models yield qualitatively similar results, and the behavior agrees with the findings of corresponding molecular dynamics simulations and experiments, where available. It is argued that these simulatio…
Interaction between flavour compounds and beta-lactoglobulin: approach by NMR and 2D/3D-QSAR studies of ligands
2004
author cannot archive publisher's version/PDF; International audience; Interactions between flavour compounds and beta-lactoglobulin (BLG) have been the subject of several studies, but there are no unanimous binding site explanations. In our laboratory, interactions between BLG, and two flavour compounds, beta-ionone and gamma-decalactone, were studied by 2D-NMR spectroscopy. It appears that several amino acids affected by binding of gamma-decalactone are buried in the central cavity, whereas binding of beta-ionone affects amino acids located in a groove near the outer surface of the protein. 2D/3D-QSAR studies were performed using QSAR+ module of Cerius2 and Catalyst. The QSAR equation pr…
Predicting antitrichomonal activity: A computational screening using atom-based bilinear indices and experimental proofs
2006
Existing Trichomonas vaginalis therapies are out of reach for most trichomoniasis people in developing countries and, where available, they are limited by their toxicity (mainly in pregnant women) and their cost. New antitrichomonal agents are needed to combat emerging metronidazole-resistant trichomoniasis and reduce the side effects associated with currently available drugs. Toward this end, atom-based bilinear indices, a new TOMOCOMD-CARDD molecular descriptor, and linear discriminant analysis (LDA) were used to discover novel, potent, and non-toxic lead trichomonacidal chemicals. Two discriminant functions were obtained with the use of non-stochastic and stochastic atom-type bilinear in…
A topological substructural approach for the prediction of P-glycoprotein substrates
2006
A topological substructural molecular design approach (TOPS-MODE) has been used to predict whether a given compound is a P-glycoprotein (P-gp) substrate or not. A linear discriminant model was developed to classify a data set of 163 compounds as substrates or nonsubstrates (91 substrates and 72 nonsubstrates). The final model fit the data with sensitivity of 82.42% and specificity of 79.17%, for a final accuracy of 80.98%. The model was validated through the use of an external validation set (40 compounds, 22 substrates and 18 nonsubstrates) with a 77.50% of prediction accuracy; fivefold full cross-validation (removing 40 compounds in each cycle, 80.50% of good prediction) and the predictio…
Unified Markov thermodynamics based on stochastic forms to classify drugs considering molecular structure, partition system, and biological species:
2005
Abstract To date, molecular descriptors do not commonly account for important information beyond chemical structure. The present work, attempts to extend, in this sense, the stochastic molecular descriptors (Gonzalez-Diaz, H. et al., J. Mol. Mod. 2002, 8, 237), incorporating information about the specific biphasic partition system, the biological species, and chemical structure inside the molecular descriptors. Consequently, MARCH-INSIDE molecular descriptors may be identified with time-dependent thermodynamic parameters (entropy and mean free energy) of partition process. A classification function was developed to classify data of 423 drugs and up to 14 different partition systems at the s…