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Journal of Chemical Information and Modeling

Ya Gao, Chaomin Zhang, John Z H Zhang, Ye Mei
Intrinsically Disordered Proteins (IDPs) carry out crucial biological functions in essential biological processes of life. Due to the highly dynamic and conformationally heterogeneous nature of the disordered states of IDPs, molecular dynamics simulations are becoming an indispensable tool for the investigation of the conformational ensembles and dynamic properties of IDPs. Nevertheless, there is still no consensus on the most reliable force field in molecular dynamics simulations for IDPs hitherto. In this work, a recently proposed AMBER99SB2D force field is evaluated in modeling some disordered polypeptides and proteins by checking its ability in reproducing NMR experimental data...
January 18, 2017: Journal of Chemical Information and Modeling
Pedro Rafael Magalhães, A Sofia F Oliveira, Sara R R Campos, Claudio Manuel Soares, António M Baptista
Cytochrome c oxidase (CcO) couples the reduction of dioxygen to water with transmembrane proton pumping, which leads to the generation of an electrochemical gradient. In this study we analyze how one of the components of the electrochemical gradient, the difference in pH across the membrane, or ΔpH, influences the protonation states of residues in CcO. We modified our continuum electrostatics/Monte Carlo (CE/MC) method in order to include the ΔpH and applied it to the study of CcO, in what is, to our best knowledge, the first CE/MC study of CcO in the presence of a pH gradient...
January 18, 2017: Journal of Chemical Information and Modeling
Chen Zhang, Ling-Jun Feng, Yiyou Huang, Deyan Wu, Zhe Li, Qian Zhou, Yinuo Wu, Hai-Bin Luo
Phosphodiesterase-2A (PDE2A) is a potential therapeutic target for treatment of Alzheimer's disease and pulmonary hypertension. However, most of the current PDE2A inhibitors have moderate selectivity over other PDEs. In the present study, we described the discovery of novel PDE2A inhibitors by structure-based virtual screening combining pharmacophore model screening, molecular docking, molecular dynamics simulations, and bioassay validation. Nine hits out of 30 molecules from the SPECS database (a hit rate of 30%) inhibited PDE2A with affinity less than 50 μM...
January 18, 2017: Journal of Chemical Information and Modeling
Adam Pecina, Susanta Haldar, Jindřich Fanfrlík, René Meier, Jan Řezáč, Martin Lepšík, Pavel Hobza
We have recently introduced the "SQM/COSMO" scoring function which combines a semiempirical quantum mechanical description of noncovalent interactions at the PM6-D3H4X level and the COSMO implicit model of solvation. This approach outperformed standard scoring functions but faced challenges with a metalloprotein featuring a Zn(2+)···S(-) interaction. Here, we invoke SCC-DFTB3-D3H4, a higher-level SQM method, and observe improved behavior for the metalloprotein and high-quality results for the other systems...
January 17, 2017: Journal of Chemical Information and Modeling
Maxime Melikian, Baptiste Eluard, Gildas Bertho, Véronique Baud, Nathalie Evrard-Todeschi
NF-κB is a major transcription factor whose activation is triggered through two main activation pathways: the canonical pathway involving disruption of IκB-α/NF-κB complexes and the alternative pathway whose activation relies on the inducible proteolysis of the inhibitory protein p100. One central step controlling p100 processing consists in the interaction of the E3 ubiquitin ligase β-TrCP with p100, thereby leading to its ubiquitinylation and subsequent either complete degradation or partial proteolysis by the proteasome...
January 13, 2017: Journal of Chemical Information and Modeling
Donatella Callegari, Alessio Lodola, Daniele Pala, Silvia Rivara, Marco Mor, Andrea Rizzi, Anna Maria Capelli
The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X-ray structures are available...
January 12, 2017: Journal of Chemical Information and Modeling
Hiba Alogheli, Gustav Olanders, Wesley Schaal, Peter Brandt, Anders Karlen
In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. To address docking of these commonly large and flexible compounds, a screening and a validation set were assembled from the PDB consisting of 16 and 31 macrocycle containing protein complexes, respectively. The macrocycles were docked in Glide by rigid docking of pre-generated conformational ensembles produced by the macrocycle conformational sampling method (MCS) in Schrödinger Release 2015-3 or by direct Glide Flexible Docking after performing ring-templating...
January 12, 2017: Journal of Chemical Information and Modeling
Michael Schauperl, Paul Czodrowski, Julian E Fuchs, Roland G Huber, Birgit J Waldner, Maren Podewitz, Christian Kramer, Klaus R Liedl
The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor β receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKA calculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes...
January 12, 2017: Journal of Chemical Information and Modeling
Jenny Pirillo, Gloria Mazzone, Nino Russo, Luca Bertini
Guanine and guanosine derivatives have long been in use as anticancer drugs and recently have been proposed also as photosensitizers in photodynamic therapy. By means of density functional theory and its time-dependent formulation, the potential power as UVA chemotherapeutic agents has been investigated computing the photophysical properties (absorption spectra, excitation energies, and spin-orbit matrix elements) of sulfur, selenium, and tellurium-substituted deoxyguanosines. Different pathways for the population of the lowest triplet state have been considered...
January 12, 2017: Journal of Chemical Information and Modeling
Fenglei Cao, Joshua D Deetz, Huai Sun
The free energy based Lennard-Jones 12-6 (FE-12-6) coarse-grained (CG) force field developed for alkanes1 has been extended to model small molecules of light hydrocarbons (methane, ethane, propane, butane, and isobutane), nitrogen, oxygen, and carbon dioxide. The adjustable parameters of the FE-12-6 potential are determined by fitting against experimental vapor-liquid equilibrium (VLE) curves and heat of vaporization (HOV) data for pure substance liquids. Simulations using the optimized FE-12-6 parameters correctly reproduced experimental measures of the VLE, HOV, density, vapor pressure, compressibility, critical point, and surface tension for pure substances over a wide range of thermodynamic states...
January 11, 2017: Journal of Chemical Information and Modeling
Marcus Wieder, Arthur Garon, Ugo Perricone, Stefan Boresch, Thomas Seidel, Anna Maria Almerico, Thierry Langer
We present a new approach that incorporates flexibility based on extensive MD simulations of protein-ligand complexes into structure based pharmacophore modeling and virtual screening. The approach uses the multiple coordinate sets saved during the MD simulations and generates for each frame a pharmacophore model. Pharmacophore models with the same pharmacophore features are pooled. In this way the high number of pharmacophore models that results from the MD simulation is reduced to only a few hundred representative pharmacophore models...
January 10, 2017: Journal of Chemical Information and Modeling
Neha Rana, Jason M Conley, Monica Soto-Velasquez, Francisco Leon, Stephen J Cutler, Val J Watts, Markus A Lill
Adenylyl cyclase 2 (AC2) is one of nine membrane-bound isoforms of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important second messenger molecule. Up-regulation of AC2 is linked to cancers like pancreatic and small intestinal neuroendocrine tumors (NETs). The structures of the various isoforms of adenylyl cyclases are highly homologous, posing a significant challenge to drug discovery efforts for an effective, isoform-selective modulator of AC2. In a previous study, a screen identified a potential isoform-selective and non-competitive inhibitor of AC2, SKF83566...
January 9, 2017: Journal of Chemical Information and Modeling
Marie Zgarbova, Petr Jurecka, Filip Lankas, Thomas E Cheatham, Jiri Sponer, Michal Otyepka
Reliable representation of the B-DNA base pair step twist is one of the crucial requirements for theoretical modeling of DNA supercoiling and other biologically relevant phenomena in B-DNA. It has long been suspected that the twist is inaccurately described by current empirical force fields. Unfortunately, comparison of simulation results with experiments is not straightforward owing to the presence of BII backbone substates, whose populations may differ between experimental and simulation ensembles. In this work, we provide a comprehensive view of the effect of BII substates on the overall B-DNA helix twist and show how to reliably compare twist values between experiment and simulation in two scenarios...
January 6, 2017: Journal of Chemical Information and Modeling
G Goret, B Aoun, E Pellegrini
The MDANSE software-Molecular Dynamics Analysis of Neutron Scattering Experiments-is presented. It is an interactive application for postprocessing molecular dynamics (MD) simulations. Given the widespread use of MD simulations in material and biomolecular sciences to get a better insight for experimental techniques such as thermal neutron scattering (TNS), the development of MDANSE has focused on providing a user-friendly, interactive, graphical user interface for analyzing many trajectories in the same session and running several analyses simultaneously independently of the interface...
January 6, 2017: Journal of Chemical Information and Modeling
Dawid Warszycki, Manuel Rueda, Stefan Mordalski, Kurt Kristiansen, Grzegorz Satała, Krzysztof Rataj, Zdzisław Chilmonczyk, Ingebrigt Sylte, Ruben Abagyan, Andrzej J Bojarski
Despite its remarkable importance in the arena of drug design, serotonin 1A receptor (5-HT1A) has been elusive to the x-ray crystallography community. This lack of direct structural information not only hampers our knowledge regarding the binding modes of many popular ligands (including endogenous neurotransmitter - serotonin), but also limits the search for more potent compounds. In this paper we shed new light on the 3D pharmacological properties of the 5-HT1A receptor by using a ligand-guided approach (ALiBERO) grounded in the Internal Coordinate Mechanics (ICM) docking platform...
January 5, 2017: Journal of Chemical Information and Modeling
Elke Haensele, Nawel Mele, Marija Miljak, Christopher M Read, David C Whitley, Lee Banting, Carla Delepee, Jana Sopková-de Oliveira Santos, Alban Lepailleur, Ronan Bureau, Jonathan W Essex, Timothy Clark
Conformation and dynamics of the vasoconstrictive peptides human urotensin-II (UII) and urotensin related peptide (URP) have been investigated by both unrestrained and enhanced-sampling molecular-dynamics (MD) simulations and NMR spectroscopy. These peptides are natural ligands of the G-protein coupled urotensin II receptor (UTR) and have been linked to mammalian pathophysiology. UII and URP cannot be characterized by a single structure but exist as an equilibrium of two main classes of ring-conformations, open and folded, with rapidly interchanging subtypes ...
January 5, 2017: Journal of Chemical Information and Modeling
Florent Hédin, Krystel El Hage, Markus Meuwly
No abstract text is available yet for this article.
January 5, 2017: Journal of Chemical Information and Modeling
Stephen Joseph Capuzzi, Ian Sang-June Kim, Wai In Lam, Thomas E Thornton, Eugene N Muratov, Diane Pozefsky, Alexander Tropsha
The enormous increase in the amount of publicly available chemical genomics data and the growing emphasis on data sharing and open science mandates that cheminformaticians make their models publicly available for broad use by the scientific community. Chembench is one of the first publicly-accessible, integrated cheminformatics Web portals. It has been extensively used by researchers from different fields for curation, visualization, analysis, and modeling of chemogenomics data. Since its launch in 2008, Chembench has been accessed more than 1 million times by more than 5K users from a total of 98 countries...
January 3, 2017: Journal of Chemical Information and Modeling
Nicolas Bosc, Berthold Wroblowski, Christophe Meyer, Pascal Bonnet
So far, 518 protein kinases have been identified in the human genome. They share a common mechanism of protein phosphorylation and are involved in many critical biological processes of eukaryotic cells. Deregulation of the kinase phosphorylation function induces severe illnesses such as cancer, diabetes, or inflammatory diseases. Many actors in the pharmaceutical domain have made significant efforts to design potent and selective protein kinase inhibitors as new potential drugs. Because the ATP binding site is highly conserved in the protein kinase family, the design of selective inhibitors remains a challenge and has negatively impacted the progression of drug candidates to late-stage clinical development...
January 3, 2017: Journal of Chemical Information and Modeling
Florbela Pereira, Kaixia Xiao, Diogo A R S Latino, Chengcheng Wu, Qingyou Zhang, Joao Aires-de-Sousa
Machine learning algorithms were explored for the fast estimation of HOMO and LUMO orbital energies calculated by DFT B3LYP, on the basis of molecular descriptors exclusively based on connectivity. The whole project involved the retrieval and generation of molecular structures, quantum chemical calculations for a database with >111 000 structures, development of new molecular descriptors, and training/validation of machine learning models. Several machine learning algorithms were screened, and an applicability domain was defined based on Euclidean distances to the training set...
December 29, 2016: Journal of Chemical Information and Modeling
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