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Journal of Chemical Information and Modeling

Nils-Ole Friedrich, Agnes Meyder, Christina de Bruyn Kops, Kai Sommer, Florian Flachsenberg, Matthias Rarey, Johannes Kirchmair
We developed a cheminformatics pipeline for the fully automated selection and extraction of high-quality protein-bound ligand conformations from X-ray structural data. The pipeline evaluates the validity and accuracy of the 3D structures of small molecules according to multiple criteria, including their fit to the electron density and their physicochemical and structural properties. Using this approach, we compiled two high-quality datasets from the Protein Data Bank (PDB): a comprehensive dataset and a diversified subset of 4626 and 2912 structures, respectively...
February 16, 2017: Journal of Chemical Information and Modeling
Malika Kumarasiri, Theodosia Teo, Mingfeng Yu, Stephen Philip, Sunita K C Basnet, Hugo Albrecht, Matthew J Sykes, Peng Wang, Shudong Wang
Aberrant activity of cyclin-dependent kinase (CDK) 8 is implicated in various cancers. While CDK8-targeting anticancer drugs are highly sought-after, no CDK8 inhibitor has yet reached clinical trials. Herein a large library of drug-like molecules was computationally screened using two complementary cascades to identify potential CDK8 inhibitors. Thirty-three hits were identified to inhibit CDK8 and seven of them were active against colorectal cancer cell lines. Finally, the primary target was confirmed using three promising hits...
February 16, 2017: Journal of Chemical Information and Modeling
Sabina Podlewska, Wojciech M Czarnecki, Rafał Kafel, Andrzej J Bojarski
The growing computational abilities of various tools that are applied in the broadly understood field of computer-aided drug design have led to the extreme popularity of virtual screening in the search for new biologically active compounds. Most often, the source of such molecules consists of commercially available compound databases, but they can also be searched for within the libraries of structures generated in silico from existing ligands. Various computational combinatorial approaches are based solely on the chemical structure of compounds, using different types of substitutions for new molecules formation...
February 15, 2017: Journal of Chemical Information and Modeling
Fredrik Svensson, Ulf Norinder, Andreas Bender
High throughput screening, where thousands of molecules rapidly can be assessed for activity against a protein, has been the dominating approach in drug discovery for many years. However, these methods are costly and require much time and effort. In order to suggest an improvement to this situation we, in this study, apply an iterative screening process where an initial set of compounds are selected for screening based on molecular docking. The outcome of the initial screen is then used to classify the remaining compounds through a conformal predictor...
February 14, 2017: Journal of Chemical Information and Modeling
Ross McGuire, Stefan Verhoeven, Márton Vass, Gerrit Vriend, Iwan J P de Esch, Scott J Lusher, Rob Leurs, Lars Ridder, Albert J Kooistra, Tina Ritschel, Chris de Graaf
3D-e-Chem-VM is an open source, freely available Virtual Machine ( ) that integrates cheminformatics and bioinformatics tools for the analysis of protein-ligand interaction data. 3D-e-Chem-VM consists of software libraries, and database and workflow tools that can analyze and combine small molecule and protein structural information in a graphical programming environment. New chemical and biological data analytics tools and workflows have been developed for the efficient exploitation of structural and pharmacological protein-ligand interaction data from proteomewide databases (e...
February 14, 2017: Journal of Chemical Information and Modeling
Théau Debroise, Eugene I Shakhnovich, Nicolas Chéron
We present the third generation of our scoring function for the prediction of protein-ligand binding free energy. This function is now a hybrid between a knowledge-based potential and an empirical function. We constructed a diversified set of ~1000 complexes from the PDBBinding-CN database for the training of the function and we show that this number of complexes generate enough data to build the potential. The occurrence of 420 different types of atomic pair wise interactions is computed in up to five different ranges of distances to derive the knowledge-based part...
February 13, 2017: Journal of Chemical Information and Modeling
Arne Wagner, Hans-Joerg Himmel
A new tool for structural comparison is presented that combines existing and new features into a single software package. aRMSD incorporates the functions of establishing a pair-wise correlation between the atoms of two molecular structures and the calculation of the optimal rotation matrix that minimizes the RMSD between the molecules. The complexity of the Hungarian assignation problem is reduced by decomposing molecules into different subsets based on different atom or group types allowing for an efficient and robust treatment of large molecules while tolerating different substituents...
February 13, 2017: Journal of Chemical Information and Modeling
Vytautas Gapsys, Bert L de Groot
With the increase of available computational power and improvements in simulation algorithms, the alchemical molecular dynamics based free energy calculations have developed into routine usage in the field of computational structural biology. To further facilitate the usability of the alchemical methods for the amino acid mutations, we have developed a web based infrastructure for obtaining hybrid protein structures and topologies. The presented webserver allows amino acid mutation selection in five contemporary molecular mechanics force fields...
February 9, 2017: Journal of Chemical Information and Modeling
Yuwei Zhang, Zexing Cao, John Zenghui Zhang, Fei Xia
Construction of coarse-grained (CG) models for large biomolecules used for multiscale simulations demands a rigorous definition of CG sites for them. Several coarse-graining methods such as the simulated annealing and steepest descent (SASD) based on the essential dynamics coarse-graining (ED-CG) or the stepwise local iterative optimization (SLIO) based on the fluctuation maximization coarse-graining (FM-CG), were developed to do it. However, the practical applications of these methods such as SASD based on ED-CG are subject to limitations because they are too expensive...
February 9, 2017: Journal of Chemical Information and Modeling
Wei Chun Ng, Thong Leng Lim, Tiem Leong Yoon
Melting dynamics of Hafnium cluster is investigated using a novel approach based on the idea of chemical similarity index. Ground state configurations of small Hafnium clusters are first derived using Basin-Hopping and Genetic Algorithm in parallel tempering mode, employing COMB potential in energy calculator. These assumed ground state structure are verified by using Low Lying Structures (LLS) method. Melting process is carried out either by using direct heating method or prolonged simulated annealing. Melting point is identified by caloric curve...
February 8, 2017: Journal of Chemical Information and Modeling
Masaki Matsuoka, Ashutosh Kumar, Muhammad Muddassar, Akihisa Matsuyama, Minoru Yoshida, Kam Y J Zhang
The efficient application of nitrogenous fertilizers is urgently required, as their excessive and inefficient use is causing substantial economic loss and environmental pollution. A significant amount of applied nitrogen in agricultural soils is lost as nitrous oxide (N2O) in the environment due to the microbial denitrification process. The widely distributed fungus Fusarium oxysporum is a major denitrifier in agricultural soils and its denitrification activity could be targeted to reduce nitrogen loss in the form of N2O from agricultural soils...
February 8, 2017: Journal of Chemical Information and Modeling
Diego Ernesto Escalante, Kelly Gardner Aukema, Lawrence P Wackett, Alptekin Aksan
Naphthalene 1,2-dioxygenase has been computationally understudied despite the extensive experimental knowledge obtained for this enzyme, including numerous crystal structures and over 100 demonstrated substrates. In this study, we have developed a substrate prediction model that moves away from the traditional active site-centric approach to include the energetics of substrate entry into the active site. By comparison with experimental data, the accuracy of the model for predicting substrate oxidation is 92%, with a positive predictive value of 93% and a negative predictive value of 98%...
February 7, 2017: Journal of Chemical Information and Modeling
Federico Zahariev, Nuwan De Silva, Mark S Gordon, Theresa L Windus, Marilu Dick-Perez
A newly created object-oriented program for automating the process of fitting molecular-mechanics parameters to ab-initio data, termed ParFit, is presented. ParFit uses a hybrid of genetic and simplex algorithms. ParFit can simultaneously handle several molecular-mechanics parameters in multiple molecules and can also apply symmetric and anti-symmetric constraints on the optimized parameters. The simultaneous handling of several molecules enhances the transferability of the fitted parameters. ParFit is written in Python, uses a rich set of standard and non-standard Python libraries and can be run in parallel on multi-core computer systems...
February 7, 2017: Journal of Chemical Information and Modeling
Eleni Kotsampasakou, Gerhard F Ecker
Cholestasis represents one out of three types of drug induced liver injury (DILI), which comprises a major challenge in drug development. In this study we applied a two-class classification scheme based on k-nearest neighbors in order to predict cholestasis, using a set of 93 2D physicochemical descriptors and predictions of selected hepatic transporters' inhibition (BSEP, BCRP, P-gp, OATP1B1 and OATP1B3). In order to assess the potential contribution of transporter inhibition, we compared whether the inclusion of the transporters' inhibition predictions contributes to a significant increase in model performance in comparison to the plain use of the 93 2D physicochemical descriptors...
February 7, 2017: Journal of Chemical Information and Modeling
Weilin Zhang, Jianfeng Pei, Luhua Lai
Designing drugs that can simultaneously interact with multiple targets is a promising approach for treating complicated diseases. Compared to using combinations of single target drugs, multi-target drugs have advantages of higher efficacy, improved safety profile, and simpler administration. Many in silico methods have been developed to approach different aspects of this polypharmacology-guided drug design, particularly for drug repurposing and multi-target drug design. In this review, we summarize recent progress in computational multi-target drug design and discuss their advantages and limitations...
February 6, 2017: Journal of Chemical Information and Modeling
Stephen Joseph Capuzzi, Eugene N Muratov, Alexander Tropsha
The use of substructural alerts to identify Pan-Assay INterference compoundS (PAINS) has become a common component of the triage process in biological screening campaigns. These alerts, however, were originally derived from a proprietary library tested in just six assays measuring protein-protein interaction (PPI) inhibition using the AlphaScreen detection technology only; moreover, 68% (328 out of the 480 alerts) were derived from four or fewer compounds. In an effort to assess the reliability of these alerts as indicators of pan-assay interference, we performed a large-scale analysis of the impact of PAINS alerts on compound promiscuity in bioassays using publicly available data in PubChem...
February 6, 2017: Journal of Chemical Information and Modeling
Donatella Callegari, Alessio Lodola, Daniele Pala, Silvia Rivara, Marco Mor, Andrea Rizzi, Anna Maria Capelli
No abstract text is available yet for this article.
February 2, 2017: Journal of Chemical Information and Modeling
Florian Flachsenberg, Niek Andresen, Matthias Rarey
Many cheminformatics applications like aromaticity detection, SMARTS matching, or the calculation of atomic coordinates require a chemically meaningful perception of the molecular ring topology. The unique ring families (URFs) were recently introduced as a unique, polynomial, and chemically meaningful description of the ring topology. Here we present the first open-source implementation of the URF concept for ring perception. The C library RingDecomposerLib is easy to use, portable, well-documented, and thoroughly tested...
February 2, 2017: Journal of Chemical Information and Modeling
Sreya Mukherjee, Aleksandra Karolak, Marjolaine Debant, Paul Buscaglia, Yves Renaudineau, Olivier Mignen, Wayne Charles Guida, Wesley H Brooks
Calcium is involved in important intracellular processes, such as intracellular signaling from cell membrane receptors to the nucleus. Typically calcium levels are kept at less than 100 nM in the nucleus and cytosol but some calcium is stored in the endoplasmic reticulum (ER) lumen for rapid release to activate intracellular calcium-dependent functions. Stromal Interacting Molecule 1 (STIM1) plays a critical role in early sensing of changes in the ER's calcium level, especially when there is a sudden release of stored calcium from the ER...
February 2, 2017: Journal of Chemical Information and Modeling
Hiba Alogheli, Gustav Olanders, Wesley Schaal, Peter Brandt, Anders Karlén
In recent years, there has been an increased interest in using macrocyclic compounds for drug discovery and development. For docking of these commonly large and flexible compounds to be addressed, 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 pregenerated 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...
February 2, 2017: Journal of Chemical Information and Modeling
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