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Journal of Chemical Information and Modeling

Nicolas Bosc, Mélaine A Kuenemann, Jérome Bécot, Marek Vavrusa, Adrien H Cerdan, Olivier Sperandio
Given the difficulties to identify chemical probes that can modulate protein-protein interactions (PPIs), actors in the field start to agree on the necessity to use PPI-tailored screening chemical collections. However, which type of scaffolds may promote the binding of compounds to PPI targets remains unclear. In this big data analysis, we have identified a list of privileged chemical substructures that are most often observed within inhibitors of PPIs. Using molecular frameworks as a way to perceive chemical substructures with the combination of an experimental and a machine-learning based predicted dataset of iPPI compounds, we propose a list of privileged substructures in the form of scaffolds and chemical moieties that can be substantially chemically functionalized and do not present any toxicophore nor Pan-assay interference (PAINS) alerts...
September 18, 2017: Journal of Chemical Information and Modeling
Jean-Rémy Marchand, Andrea Dalle Vedove, Graziano Lolli, Amedeo Caflisch
The high-throughput docking protocol called ALTA-VS (anchor-based library tailoring approach for virtual screening) was developed in 2005 for the efficient in silico screening of large libraries of compounds by preselection of only those molecules that have optimal fragments (anchors) for the protein target. Here we present an updated version of ALTA-VS with a broader range of potential applications. The evaluation of binding energy makes use of a classical force field with implicit solvent in the continuum dielectric approximation...
September 18, 2017: Journal of Chemical Information and Modeling
Christopher Lockhart, Dmitri K Klimov
Using isobaric-isothermal all-atom replica-exchange molecular dynamics (REMD) simulations, we investigated the equilibrium binding of Abeta10-40 monomers to the zwitterionic dimyristoylphosphatidylcholine (DMPC) bilayer containing cholesterol. Our previous REMD simulations, which studied binding of the same peptide to the cholesterol-free DMPC bilayer, served as a control, against which we measured the impact of cholesterol. Our findings are as follows. First, addition of cholesterol to the DMPC bilayer partially expels the Abeta peptide from the hydrophobic core and promotes its binding to bilayer polar headgroups...
September 14, 2017: Journal of Chemical Information and Modeling
Zhe Deng, Weizhong Tu, Zixin Deng, Qian-Nan Hu
The current network pharmacology study encountered a bottleneck with a lot of public data scattered in different databases. There is the lack of open-access and consolidated platform that integrates this information for systemic research. To address this issue, we have developed PhID, an integrated pharmacology database which integrates >400,000 pharmacology elements (drug, target, disease, gene, side-effect, and pathway) and >200,000 element interactions in branches of public databases. The PhID has three major applications: (1) assists scientists searching through the overwhelming amount of pharmacology elements interaction data by names, public IDs, molecule structures, or molecular sub-structures; (2) helps visualizing pharmacology elements and their interactions with a web-based network graph; (3) provides prediction of drug-target interactions through two modules: PreDPI-ki and FIM, by which users can predict drug-target interactions of the PhID entities or some drug-target pairs they interest...
September 14, 2017: Journal of Chemical Information and Modeling
Reinis Danne, Chetan Poojari, Hector Martinez-Seara, Sami Rissanen, Fabio Lolicato, Tomasz Rog, Ilpo Vattulainen
Carbohydrates constitute a structurally and functionally diverse group of biological and macromolecules. In cells they are involved in, e.g., energy storage, signaling, and cell-cell recognition. All of these phenomena take place in atomistic scales, thus atomistic simulation would be the method of choice to explore how carbohydrates function. However, the progress in the field is limited by the lack of appropriate tools for preparing carbohydrate structures and related topology files for the simulation models...
September 14, 2017: Journal of Chemical Information and Modeling
Kai Liu, Hironori Kokubo
Docking has become an indispensable approach in drug discovery research to predict the binding mode of a ligand. One great challenge in docking is to efficiently refine the correct pose from various putative docking poses through score functions. We recently examined the stability of self-docking poses under molecular dynamics (MD) simulations and showed that equilibrium MD simulations have some capability to discriminate between correct and decoy poses. Here, we have extended our previous work to cross-docking studies for practical applications...
September 13, 2017: Journal of Chemical Information and Modeling
Jagna Witek, Bettina G Keller, Markus Blatter, Axel Meissner, Trixie Wagner, Sereina Riniker
No abstract text is available yet for this article.
September 12, 2017: Journal of Chemical Information and Modeling
Jean-Patrick Francoia, Jean-Christophe Rossi, Gerald Monard, Laurent Vial
Despite the growing use of poly-l-lysine dendrigrafts in biomedical applications, a deeper understanding of the molecular level properties of these macromolecules is missing. Herein, we report a simple methodology for the construction of three-dimensional structures of poly-l-lysine dendrigrafts and the subsequent investigation of their structural features using microsecond molecular dynamics simulations. This methodology relies on the encoding of the polymers' experimental characterizations (i.e., composition, degrees of polymerization, branching ratios, charges) into alphanumeric strings that are readable by the Amber simulation package...
September 12, 2017: Journal of Chemical Information and Modeling
Therese Inhester, Eva Nittinger, Kai Sommer, Pascal Schmidt, Stefan Bietz, Matthias Rarey
Noncovalent interactions play an important role in macromolecular complexes. The assessment of molecular interactions is often based on knowledge derived from statistics on structural data. Within the last years, the available data in the Brookhaven Protein Data Bank has increased dramatically, quantitatively as well as qualitatively. This development allows the derivation of enhanced interaction models and motivates new ways of data analysis. Here, we present a method to facilitate the analysis of noncovalent interactions enabling detailed insights into the nature of molecular interactions...
September 11, 2017: Journal of Chemical Information and Modeling
Charalampos Chomenidis, Georgios Drakakis, Georgia Tsiliki, Evangelia Anagnostopoulou, Angelos Valsamis, Philip Doganis, Pantelis Sopasakis, Haralambos Sarimveis
Engineered nanomaterials (ENMs) are increasingly infiltrating our lives as a result of their applications across multiple fields. However, ENM formulations may result in the modulation of pathways and mechanisms of toxic action that endanger human health and the environment. Alternative testing methods such as in silico approaches are becoming increasingly popular for assessing the safety of ENMs, as they are cost- and time-effective. Additionally, computational approaches support the industrial safer-by-design challenge and the REACH legislation objective of reducing animal testing...
September 11, 2017: Journal of Chemical Information and Modeling
Chen Jiang, Xi Jin
Emscripten is a special open source compiler that compiles C and C++ code into JavaScript. By utilizing this compiler, some typical C/C++ chemoinformatics toolkits and libraries are quickly ported to web by us. The compiled JavaScript files have sizes similar to native programs, and from a series of constructed benchmarks, the performance of the compiled JavaScript codes is also close to that of the native codes and is better than the handwritten JavaScript codes. Therefore, we believe that Emscripten is a feasible and practical tool for reusing existing C/C++ codes on the web platform and many other chemoinformatics or molecular calculation software can also be easily ported by Emscripten...
September 7, 2017: Journal of Chemical Information and Modeling
Redona Izairi, Hiqmet Kamberaj
In this study, we compared the contributions of polar and non-polar interactions to the solvation free energy of a solute in solvent, which is decomposed into four different terms based on the nature of interactions: (i) electrostatic solvation free energy term counting for the work done to move solute charges from fixed points in some reference environment to their configuration positions in solvent; (ii) solute-solvent van der Waals dispersion interactions; (iii) change on solvent-solvent interactions and solvent entropy due to reorganization of solvent around solute cavity in solvent; and (iv) compensation of electrostatic forces acting on the dielectric surface boundary between solvent and solute...
September 7, 2017: Journal of Chemical Information and Modeling
Patricia Gomez-Gutierrez, Jaime Rubio-Martinez, Juan Jesus Perez
Given the essential role played by protein kinases in regulating cellular pathways, their dysregulation can result in the onset and/or progression of various human diseases. Structural analysis of diverse protein kinases suggests that these proteins exhibit a remarkable plasticity that allows them to adopt distinct conformations in response to interactions with other proteins, providing an opportunity for designing allosteric modulators. The present work reports the results of an in silico screening study aimed at identifying novel prospective allosteric binding sites in the paradigmatic p38α MAP kinase...
September 5, 2017: Journal of Chemical Information and Modeling
Yuting Xu, Junshui Ma, Andy Liaw, Robert P Sheridan, Vladimir Svetnik
Deep neural networks (DNNs) are complex computational models that have found great success in many artificial intelligence applications, such as computer vision and natural language processing. In the past four years, DNNs also generated promising results for quantitative structure-activity relationship (QSAR) tasks. Previous work showed that DNNs can routinely make better predictions than traditional methods, such as random forests, on a diverse collection of QSAR datasets. It was also found that multi-task DNN models - those trained on and predicting multiple QSAR properties simultaneously - outperform DNNs trained separately on the individual datasets in many but not all tasks...
September 5, 2017: Journal of Chemical Information and Modeling
Jinfeng Huang, Bin Sun, Yuan Yao, Junjun Liu
The protonation state of asp dyad is significantly important in revealing enzymatic mechanism and developing drugs. However, it is hard to be determined by calculating free energy changes between possible protonation states, because the free energy changes due to protein conformational flexibility are usually much larger than that originated from the different locations of protons. Sophisticated and computationally expensive methods such as free energy perturbation, thermodynamic integration, and QM/MM are therefore usually used for this purpose...
September 5, 2017: Journal of Chemical Information and Modeling
Paweł Krupa, Anna Hałabis, Wioletta Żmudzińska, Stanisław Ołdziej, Harold A Scheraga, Adam Liwo
By using the maximum likelihood method for force-field calibration recently developed in our laboratory, which is aimed at achieving the agreement between the simulated conformational ensembles of selected training proteins and the corresponding ensembles determined experimentally at various temperatures, the physics-based coarse-grained UNRES force field for simulations of protein structure and dynamics was optimized with seven small training proteins exhibiting a variety of secondary and tertiary structures...
September 5, 2017: Journal of Chemical Information and Modeling
Prabir Khatua, Sudipta Kumar Sinha, Sanjoy Bandyopadhyay
Alzheimer's disease is caused due to aggregation of amyloid beta (Aβ) peptide into soluble oligomers and insoluble fibrils in the brain. In this study, we have performed room temperature molecular dynamics simulations to probe the size-dependent conformational features and thermodynamic stabilities of five Aβ17-42 protofilaments, namely, O5(pentamer), O8 (octamer), O10 (decamer), O12 (dodecamer), and O14 (tetradecamer). Analysis of the free energy profiles of the aggregates showed that the higher order protofilaments (O10, O12 and O14) undergo conformational transitions between two minimum energy states separated by small energy barriers, while the smaller aggregates (O5 and O8) remain in single deep minima surrounded by high barriers...
August 30, 2017: Journal of Chemical Information and Modeling
Davide Sala, Silvia Ciambellotti, Andrea Giachetti, Paola Turano, Antonio Rosato
We investigated the kinetics of the release of iron(II) ions from the internal cavity of human H ferritin as a function of pH. Extensive molecular dynamics (MD) simulations of the entire 24-mer ferritin provided atomic-level information on the release mechanism. Iron ions exit via the C3 channels. Double protonation of His residues at pH 4 facilitates the removal of the iron ligands within the channel through the formation of salt bridges, resulting in a significantly lower release energy barrier than pH 9...
August 30, 2017: Journal of Chemical Information and Modeling
Pernille Sønderby, Åsmund Rinnan, Jesper J Madsen, Pernille Harris, Jens Thostrup Bukrinski, Guenther H H J Peters
We have performed a benchmark to evaluate the relative success of using small angle X-ray scattering (SAXS) data as constrains (hereafter referred to SAXSconstrain) in the RosettaDock protocol (hereafter referred to RosettaDockSAXS). For this purpose, we have chosen 38 protein complex structures, calculated the theoretical SAXS data for the protein complexes using the program CRYSOL and used then the SAXS data as constrains. We further considered few examples where crystal structures and experimental SAXS data are available...
August 30, 2017: Journal of Chemical Information and Modeling
Ya Chen, Christina de Bruyn Kops, Johannes Kirchmair
Natural products from plants, animals, marine life, fungi, bacteria, and other organisms are an important resource for modern drug discovery. Their biological relevance and structural diversity make natural products good starting points for drug design. Natural product-based drug discovery can benefit greatly from computational approaches, which are a valuable precursor or supplementary method to in vitro testing. We present an overview of 25 virtual and 31 physical natural product libraries that are useful for applications in cheminformatics, in particular virtual screening...
August 30, 2017: Journal of Chemical Information and Modeling
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