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Journal of Chemical Information and Modeling

Charly Empereur-Mot, Jean-François Zagury, Matthieu Montes
Screening Explorer is a web-based application that allows for an intuitive evaluation of the results of screening experiments using complementary metrics in the field. The usual evaluation of screening results implies the separate generation and apprehension of the ROC, Predictiveness and enrichment curves and their global metrics. Similarly, partial metrics need to be calculated repeatedly for different fractions of a dataset and there exists no handy tool that allows reading partial metrics simultaneously on different charts...
November 3, 2016: Journal of Chemical Information and Modeling
Johannes G E M Fraaije, Jan van Male, Paul Becherer, Rubèn Serral Gracià
We calibrate coarse-grained interaction potentials suitable for screening large datasets in top-down fashion. Three new algorithms are introduced: (i) automated decomposition of molecules into coarse-grained units (fragmentation), (ii) Coarse-Grained Hypernetted Chain - Reference Interaction Site Model (CG HNC-RISM) as an intermediate proxy for Dissipative Particle Dynamics (DPD), and (iii) an algorithm for calibrating DPD parameters using activity coefficient models. We find that fragment distribution follows Zipf and Heap scaling laws...
November 2, 2016: Journal of Chemical Information and Modeling
Dheivya Thiagarajan, Dinesh P Mehta
Isomer networks provide a mechanism to understand and interpret relationships between organic molecules with applications in medicinal chemistry and drug design. The extraction of isomer networks is a time and data-intensive computation (e.g., we have experimentally determined the space required for the computation of a set of 25 isomers of Nicotine to be 205 MB. Extrapolating this, we have projected the computation to require 8 TB of storage for a set of 1,050,219 isomers of nicotine). In this paper we describe our efforts to improve the network extraction process by using the symmetry present in most molecules to reduce runtime and memory and streamlining the algorithm used for the detection of duplicate dnNames...
November 1, 2016: Journal of Chemical Information and Modeling
Jingheng Wu, Sixiang Wen, Yiwei Zhou, Hui Chao, Yong Shen
Ferrochelatase catalyzes the insertion of ferrous iron into protoporphyrin IX, the terminal step in heme biosynthesis. Some disputes in its mechanism remain unsolved, especially for human ferrochelatase. In this paper, the high-level quantum mechanical/molecular mechanics (QM/MM) and free-energy studies have performed to address these controversial issues including the iron-binding site, the optimal reaction path, the substrate porphyrin distortion and the presence of sitting-atop (SAT) complex. Our results reveal that the ferrous ion is probably at the binding site coordinating with Met76, while His263 plays the role of proton acceptor...
November 1, 2016: Journal of Chemical Information and Modeling
Michelle Lynn Hall, David Calkins, Woody Sherman
With the continued rise of phenotypic and genotypic-based screening projects, computational methods to analyze, process, and ultimately make predictions in this field take on growing importance. Here we show how automated machine learning workflows can produce models that are predictive of differential gene expression as a function of a compound structure using data from A673 cells as a proof of principle. In particular, we present predictive models with an average accuracy of greater than 70% across a highly diverse ca...
October 31, 2016: Journal of Chemical Information and Modeling
Ping Qian, Hao-Bo Guo, Yufei Yue, Liang Wang, Xiaohan Yang, Hong Guo
No abstract text is available yet for this article.
October 28, 2016: Journal of Chemical Information and Modeling
Robert P Sheridan
Several papers have appeared in which a ligand efficiency index instead of pIC50 is used as the activity in QSAR. The claim is that better fits and predictions are obtained with ligand efficiency. We show on both public-domain and in-house data sets that the apparent superiority is a statistical artifact that occurs when ligand efficiency indices are correlated with the physical property included in their definition (number of non-hydrogens, ALOGP, TPSA, etc.) and when the property is easier to predict than the original pIC50...
October 28, 2016: Journal of Chemical Information and Modeling
Arkadii I Lin, Timur Ismailovich Madzhidov, Olga Klimchuk, Ramil I Nugmanov, Igor S Antipin, Alexandre Varnek
: In this paper we report a new method of assessment of protective groups (PGs) reactivity as a function of reaction conditions (catalyst, solvent) using raw reaction data. It is based on intuitive similarity principle for chemical reactions: similar reactions proceed under similar conditions. Techni-cally, reaction similarity can be assessed using the Condensed Graph of Reaction (CGR) approach rep-resenting an ensemble of reactants and products as one sole molecular graph, i.e., as a pseudomolecule for which molecular descriptors or fingerprints can be calculated...
October 26, 2016: Journal of Chemical Information and Modeling
Wojciech Pulawski, Michal Jamroz, Michal Kolinski, Andrzej Kolinski, Sebastian Kmiecik
The CABS coarse-grained model is a well-established tool for modeling globular proteins (predicting their structure, dynamics and interactions). Here we introduce an extension of CABS representation and force field (CABS-membrane) to the modeling of the effect of biological membrane environment on the structure of membrane proteins. We validate the CABS-membrane model in folding simulations of 10 short helical membrane proteins not using any knowledge about their structure. The simulations start from random protein conformations placed outside the membrane environment and allow for full flexibility of the modeled proteins during their spontaneous insertion into the membrane...
October 24, 2016: Journal of Chemical Information and Modeling
Shufang Yang, Ran Wang, Guang Wan, Zhimin Wu, Shujuan Guo, Xingxing Dai, Xinyuan Shi, Yanjiang Qiao
Menthol is a widely used penetration enhancer in clinical medicine due to its high efficiency and relative safety. However, details of the penetration enhancement mechanism of menthol on molecular level is rarely involved in the discussion. In this work, the penetration enhancement (PE) mechanism of menthol is explored by a multiscale method containing molecular dynamics simulations, in vitro penetration experiments and transmission electron microscopy. Osthole is chosen to be the tested drug due to its common-using in external preparations and its representative-accompanying with menthol as a PE in the preparations...
October 21, 2016: Journal of Chemical Information and Modeling
Jonathan David Tyzack, Peter A Hunt, Matthew D Segall
We describe methods for predicting Cytochrome P450 (CYP) metabolism incorporating both pathway-specific reactivity and isoform-specific accessibility considerations. Semi-empirical quantum mechanical (QM) simulations, parameterized using experimental data and ab initio calculations, estimate the reactivity of each potential site of metabolism in the context of the whole molecule. Ligand-based models, trained using high quality regioselectivity data, correct for orientation and steric effects of the different CYP isoform binding pockets...
October 18, 2016: Journal of Chemical Information and Modeling
James McDonagh, David S Palmer, Tanja Van Mourik, John B O Mitchell
We compare a range of computational methods for the prediction of sublimation thermodynamics (enthalpy, entropy and free energy of sublimation). These include a model from theoretical chemistry that utilizes crystal lattice energy minimization (with the DMACRYS program) and QSPR models generated by both machine learning (Random Forest and Support Vector Machines) and regression (Partial Least Squares) methods. Using these methods we investigate the predictability of the enthalpy, entropy and free energy of sublimation, with consideration of whether such a method may be able to improve solubility prediction schemes...
October 17, 2016: Journal of Chemical Information and Modeling
Peter Sadowski, David R Fooshee, Niranjan Subrahmanya, Pierre Baldi
We demonstrate how machine learning (ML) and quantum mechanical (QM) methods can be used in two-way synergy to build chemical reaction expert systems. The proposed ML approach to reaction prediction identifies electron sources and sinks among the reactants, and then ranks all source-sink pairs. This is used to address a major bottleneck of QM calculations by providing a prioritized list of mechanistic reaction steps. QM modeling can then be used to compute the transition states and activation energies of the top-ranked reactions, providing additional or improved examples of ranked source-sink pairs...
October 17, 2016: Journal of Chemical Information and Modeling
Magdalena Anna Mozolewska, Pawel Krupa, Bartlomiej Zaborowski, Adam Liwo, Jooyoung Lee, Keehyoung Joo, Cezary Czaplewski
Recently, we developed a new approach to protein-structure prediction, which combines template-based modeling with the physics-based coarse-grained UNited RESidue (UNRES) force field. In this approach, restrained multiplexed replica exchange molecular dynamics (MREMD) simulations with UNRES, with the C(α)-distance and virtual-bond-dihedral-angle restraints derived from knowledge-based models are carried out. In this work, we report a test of this approach in the 11th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction (CASP11), in which we used the template-based models from early-stage predictions by the LEE group CASP11 server (group 038, called 'nns'), and further improvement of the method...
October 17, 2016: Journal of Chemical Information and Modeling
Laura Guasch, Waruna Yapamudiyansel, Megan L Peach, James A Kelley, Joseph J Barchi, Marc C Nicklaus
We investigated how many cases of the same chemical sold as different products (at possibly different prices) occurred in a prototypical large aggregated database and simultaneously tested the tautomerism definitions in the chemoinformatics toolkit CACTVS. We applied the standard CACTVS tautomeric transforms plus a set of recently developed ring-chain transforms to the Aldrich Market Select (AMS) database of 6 million screening samples and building blocks. In 30 000 cases, two or more AMS products were found to be just different tautomeric forms of the same compound...
October 16, 2016: Journal of Chemical Information and Modeling
Sara Khan, Umar Farooq, Maria Kurnikova
In the present studies, we analyzed the influence of temperature on the stability and dynamics of the α subunit of tryptophan synthase (TRPS) from hyperthermophilic, mesophilic, and psychrophilic homologues at different temperatures by molecular dynamics simulations. Employing different indicators such as root-mean-square deviations, root-mean-square fluctuations, principal component analysis, and free energy landscapes, this study manifests the diverse behavior of these homologues with changes in temperature...
October 14, 2016: Journal of Chemical Information and Modeling
Elena Dolgikh, Ian A Watson, Prashant V Desai, Geri A Sawada, Stuart Morton, Timothy M Jones, Thomas J Raub
We report development and prospective validation of a QSAR model of the unbound brain-to-plasma partition coefficient, Kp,uu,brain, based on the in-house data set of ∼1000 compounds. We discuss effects of experimental variability, explore the applicability of both regression and classification approaches, and evaluate a novel, model-within-a-model approach of including P-glycoprotein efflux prediction as an additional variable. When tested on an independent test set of 91 internal compounds, incorporation of P-glycoprotein efflux information significantly improves the model performance resulting in an R(2) of 0...
October 13, 2016: Journal of Chemical Information and Modeling
Qin Wang, Simone Sciabola, Gabriela Barreiro, Xinjun Hou, Guoyun Bai, Michael J Shapiro, Frank E Koehn, Anabella Villalobos, Matthew P Jacobson
Macrocycles pose challenges for computer-aided drug design due to their conformational complexity. One fundamental challenge is identifying all low-energy conformations of the macrocyclic ring, which is important for modeling target binding, passive membrane permeation, and other conformation-dependent properties. Macrocyclic polyketides are medically and biologically important natural products characterized by structural and functional diversity. Advances in synthetic biology and semi-synthetic methods may enable creation of an even more diverse set of non-natural product polyketides for drug discovery and other applications...
October 12, 2016: Journal of Chemical Information and Modeling
Govindan Subramanian, Bharath Ramsundar, Vijay Pande, Rajiah Aldrin Denny
The binding affinities (IC50) reported for diverse structural and chemical classes of human β-secretase 1 (BACE-1) inhibitors in literature were modeled using multiple in silico ligand based modeling approaches and statistical techniques. The descriptor space encompasses simple binary molecular fingerprint, one- and two-dimensional constitutional, physicochemical, and topological descriptors, and sophisticated three-dimensional molecular fields that require appropriate structural alignments of varied chemical scaffolds in one universal chemical space...
October 10, 2016: Journal of Chemical Information and Modeling
Yu Zhang, Lirong Wang, Zhiwei Feng, Haizi Cheng, Terence Francis McGuire, Yahui Ding, Tao Cheng, Yingdai Gao, Xiang-Qun Xie
Given the capacity of self-renewal and multilineage differentiation, stem cells are promising sources for use in regenerative medicines as well as in the clinical treatment of certain hematological malignancies and degenerative diseases. Complex networks of cellular signaling pathways largely determine stem cell fate and function. Small molecules that modulate these pathways can provide important biological and pharmacological insights. However, it is still challenging to identify the specific protein targets of these compounds, to explore the changes in stem cell phenotypes induced by compound treatment and to ascertain compound mechanisms of action...
October 7, 2016: Journal of Chemical Information and Modeling
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