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Journal of Chemical Information and Modeling

Ari Hardianto, Fei Liu, Shoba Ranganathan
(-)-Balanol is an ATP mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with little selectivity. While PKA is known as a tumour promoter, PKC isozymes can be tumour promoters or suppressors. In particular, PKCε is frequently involved in tumorigenesis and a potential target for anticancer drugs. We recently reported that stereospecific fluorination of balanol yielded a balanoid with enhanced selectivity for PKCε over other PKC isozymes and PKA, although the global fluorine effect behind the selectivity enhancement is not fully understood...
January 17, 2018: Journal of Chemical Information and Modeling
Sergio Decherchi, Giovanni Bottegoni, Andrea Spitaleri, Walter Rocchia, Andrea Cavalli
In this paper, we introduce the BiKi Life Sciences suite. This software makes it easy for computational medicinal chemists to run ad hoc molecular dynamics protocols in a novel and task-oriented environment; as a notebook, BiKi keeps memory of any activity together with dependencies among them. It offers unique accelerated protein-ligand binding/unbinding methods, and other useful tools to gain actionable knowledge from MD simulations and to simplify the drug discovery process.
January 17, 2018: Journal of Chemical Information and Modeling
Mark Howard Barley, Nicholas J Turner, Royston Goodacre
The ability to model the activity of a protein using Quantitative Structure Activity Relationships (QSAR) requires descriptors for the 20 naturally coded amino acids. In this work we show that by modifying some established descriptors we were able to model the activity data of 140 mutants of the enzyme epoxide hydrolase with improved accuracy. These new descriptors (referred to as Physical descriptors) also gave very good results when tested against a series of four dipeptide datasets. The Physical descriptors encode the amino acids using only two orthogonal scales: the first is strongly linked to hydrophillicity/hydrophobicity, and the second to the volume of the amino acid residue...
January 16, 2018: Journal of Chemical Information and Modeling
Ali Bakiri, Jane Hubert, Romain Reynaud, Carole Lambert, Agathe Martinez, Jean-Hugues Renault, Jean-Marc Nuzillard
A new in silico method is introduced for the dereplication of natural metabolite mixtures based on HMBC and HSQC spectra that inform about short-range and long-range H-C correlations occurring in the carbon skeleton of individual chemical entities. Starting from the HMBC spectrum of a metabolite mixture, an algorithm was developed in order to recover individualized HMBC footprints of the mixture constituents. The collected H-C correlations are represented by a network of NMR peaks connected each other when sharing either a 1H or 13C chemical shift value...
January 10, 2018: Journal of Chemical Information and Modeling
Gregor Urban, Niranjan Subrahmanya, Pierre Baldi
Deep learning methods applied to problems in chemoinformatics often require the use of recursive neural networks to handle data with graphical structure and variable size. We present a useful classification of recursive neural networks approaches into two classes, the Inner and Outer approach. The inner approach uses recursion inside the underlying graph, to essentially 'crawl' the edges of the graph, while the outer approach uses recursion outside the underlying graph, to aggregate information over progressively longer distances in an orthogonal direction...
January 10, 2018: Journal of Chemical Information and Modeling
Chimno Ihuoma Nnadi, Meredith L Jenkins, Daniel R Gentile, Leslie A Bateman, Daniel Zaidman, Trent E Balius, Daniel K Nomura, John E Burke, Kevan M Shokat, Nir London
The success of targeted covalent inhibitors in the global pharmaceutical industry has led to a resurgence of covalent drug discovery. However, covalent inhibitor design for flexible binding sites remains a difficult task due to lack of methodological development. Here, we compared covalent docking to empirical electrophile screening, against the highly dynamic target K-RasG12C. While the overall hit-rate of both methods was comparable, we were able to rapidly progress a docking hit to a potent irreversible covalent inhibitor that modifies the inactive, GDP-bound state of K-RasG12C...
January 10, 2018: Journal of Chemical Information and Modeling
Huanyu Chu, Haiyan Liu
To construct backbone structures of high designability is a primary aspect of computational protein design. We report here a side chain-independent statistical energy that aims at realistic modeling of through-space packing of polypeptide backbones. To mitigate the lack of explicit amino acid side chains, the model treats the inter-backbone site packing as being dependent on peptide local conformation. In addition, new variables suitable for statistical analysis, one for relative orientation and another for distance, have been introduced to represent the inter-site geometry based on the asymmetrical tetrahedron organization of distinct chemical groups surrounding the Cα-carbon atoms...
January 9, 2018: Journal of Chemical Information and Modeling
Kedi Wu, Guo-Wei Wei
The understanding of toxicity is of paramount importance to human health and environmental protection. Quantitative toxicity analysis has become a new standard in the field. This work introduces element specific persistent homology (ESPH), an algebraic topology approach, for quantitative toxicity prediction. ESPH retains crucial chemical information during the topological abstraction of geometric complexity and provides a representation of small molecules that cannot be obtained by any other method. To investigate the representability and predictive power of ESPH for small molecules, ancillary descriptors have also been developed based on physical models...
January 9, 2018: Journal of Chemical Information and Modeling
José Jiménez Luna, Miha Skalic, Gerard Martinez-Rosell, Gianni De Fabritiis
Accurately predicting protein-ligand binding affinities is an important problem in computational chemistry since it can substantially accelerate drug discovery for virtual screening and lead optimization. We propose here a fast machine-learning approach for predicting binding affinities using state-of-the-art 3D convolutional neural networks and compare this approach to other machine-learning and scoring methods using several diverse datasets. The results for the standard PDBbind (v.2016) core test-set are state-of-the-art with a Pearson's correlation coefficient of 0...
January 8, 2018: Journal of Chemical Information and Modeling
Soumya Lipsa Rath, Huihui Liu, Susumu Okazaki, Wataru Shinoda
Around 270 million individuals currently live with Hepatitis B Virus (HBV) infection. Heteroaryldihydropyrimidines (HAPs) are a family of antivirals that target the HBV capsid protein and induce aberrant self-assembly. The capsids formed resemble the native capsid structure, but are unable to propagate the virus progeny due to lack of RNA/DNA. Under normal conditions, self-assembly is initiated by the viral genome. The mode of action of HAPs, however, remains largely unknown. Here, using molecular dynamics simulations, we attempted to understand HAP action by comparing the dynamics of capsid proteins with and without HAPs...
January 8, 2018: Journal of Chemical Information and Modeling
Connor W Coley, Luke Rogers, William H Green, Klavs F Jensen
Several definitions of molecular complexity exist to facilitate prioritization of lead compounds, to identify diversity-inducing and complexifying reactions, and to guide retrosynthetic searches. In this work, we focus on synthetic complexity and reformalize its definition to correlate with the expected number of reaction steps required to produce a target molecule, with implicit knowledge about what compounds are reasonable starting materials. We train a neural network model on twelve million reactions from the Reaxys database to impose a pairwise inequality constraint enforcing the premise of this definition: that on average, the products of published chemical reactions should be more synthetically complex than their corresponding reactants...
January 8, 2018: Journal of Chemical Information and Modeling
Axel Rudling, Adolfo Orro, Jens Carlsson
Water plays a major role in ligand binding and is attracting increasing attention in structure-based drug design. Water molecules can make large contributions to binding affinity by bridging protein-ligand interactions or by being displaced upon complex formation, but these phenomena are challenging to model at the molecular level. Here, networks of ordered water molecules in protein binding sites were analyzed by clustering of molecular dynamics (MD) simulation trajectories. Locations of ordered waters (hydration sites) were first identified from simulations of high resolution crystal structures of 13 protein-ligand complexes...
January 8, 2018: Journal of Chemical Information and Modeling
Stephen Joseph Capuzzi, Thomas Thornton, Kammy Liu, Nancy Baker, Wai In Lam, Colin O'Banion, Eugene N Muratov, Diane Pozefsky, Alexander Tropsha
Elucidation of the mechanistic relationships between drugs, their targets, and diseases is at the core of modern drug discovery research. Thousands of studies relevant to the drug-target-disease (DTD) triangle have been published and annotated in the Medline/PubMed database. Mining this database affords rapid identification of all published studies that confirm connections between vertices of this triangle or enable new inferences of such connections. To this end, we describe the development of Chemotext, a publicly-available Web server that mines the entire compendium of published literature in PubMed annotated by Medline Subject Heading (MeSH) terms...
January 4, 2018: Journal of Chemical Information and Modeling
Samira Hezaveh, An-Ping Zeng, Uwe Jandt
The pyruvate dehydrogenase complex (PDC) is a large macromolecular machine consisting of dozens of interacting enzymes that are connected and regulated by highly flexible domains, also called swinging arms. The overall structure and function of these domains and how they organize the complex function is rarely elucidated yet. This lack of structural and dynamic understanding is frequently observed in multi domain enzymatic complexes. Here we present the first full and dynamic structural model of full human PDC (hPDC), including the linking arms binding to the surrounding E1 and E3 enzymes via their binding domains with variable stoichiometries...
January 3, 2018: Journal of Chemical Information and Modeling
Sarah Graham, Richard Dayton Smith, Heather Ann Carlson
Water molecules are an important factor in protein-ligand binding. Upon binding of a ligand with a protein's surface, waters can either be displaced by the ligand or may be conserved and possibly bridge interactions between the protein and ligand. Depending on the specific interactions made by the ligand, displacing waters can yield a gain in binding affinity. The extent to which binding affinity may increase is difficult to predict, as the favorable displacement of a water molecule is dependent on the site-specific interactions made by the water and the potential ligand...
December 29, 2017: Journal of Chemical Information and Modeling
Darwin Yu Fu, Jens Meiler
Incorporating experimental restraints is a powerful method of increasing accuracy in computational protein small molecule docking simulations models. Different algorithms integrate distinct forms of biochemical data during the docking and/or scoring stages. These so-called hybrid methods make use of receptor-based information such as nuclear magnetic resonance (NMR) restraints or small molecule-based information such as structure-activity relationships (SAR). A third class of methods directly interrogates contacts between the protein receptor and the small molecule...
December 29, 2017: Journal of Chemical Information and Modeling
Paweł Krupa, Anna Hałabis, Wioletta Żmudzińska, Stanisław Ołdziej, Harold A Scheraga, Adam Liwo
No abstract text is available yet for this article.
December 28, 2017: Journal of Chemical Information and Modeling
Dimitra Danai Varsou, Georgia Tsiliki, Penny Nymark, Pekka Kohonen, Roland Grafstrom, Haralambos Sarimveis
We present toxFlow, a web-application developed for enrichment analysis of omics data coupled with read-across toxicity prediction. A sequential analysis workflow is suggested where users can filter omics data using enrichment scores and incorporate their findings into a correlation-based read-across technique for predicting the toxicity of a substance based on its analogs. Either embedded or in-house gene signature libraries can be used for enrichment analysis. The suggested approach can be used for toxicity prediction of diverse chemical entities, however this article focuses on the multi-perspective characterization of nanoparticles and selects their neighbors based on both physicochemical and biological similarity criteria...
December 27, 2017: Journal of Chemical Information and Modeling
Andrew Vincent Yeager, Kathryn Humphries, Ellen Farmer, Gene Cline, Billy Miller
Optimizing DNA polymerases for a broad range of tasks requires an understanding of the factors influencing polymerase fidelity, but many details of polymerase behavior remain unknown, especially in the presence of mismatched nascent base pairs. Using molecular dynamics, the large fragment of Bacillus stearothermophilus DNA polymerase I is simulated in the presence of all sixteen possible standard nucleoside triphosphate-template (dNTP-dN) pairs, including four Watson-Crick pairs and twelve mismatches. The pre-catalytic steps of nucleotide addition from nucleotide insertion to immediately preceding catalysis are explored using three starting structures representing different stages of nucleotide addition...
December 27, 2017: Journal of Chemical Information and Modeling
Souvik Sinha, Atanu Maity, Shubhra Ghosh Dastidar
Activation of the pro-apoptotic BAX protein, a BCl-2 family member, is known to trigger the apoptosis by forming pores in the mitochondrial outer membrane (MOM). While in the cytosol, release of its transmembrane C-terminal helix (called α9 helix) from a well-characterized binding pocket (BC groove) and subsequent permeabilization of MOM is understood to be the initiating events of the activation. In concern of what initiates the BAX activation, so far one plausible suggestion has been that the transient attachment of BH3-only peptide on a distal site from BC groove triggers the activation process...
December 26, 2017: Journal of Chemical Information and Modeling
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