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PubMed Journal Database | Journal of chemical information and modeling RSS

08:30 EDT 24th May 2018 | BioPortfolio

The US National Library of Medicine and National Institutes of Health manage PubMed.gov which comprises of more than 21 million records, papers, reports for biomedical literature, including MEDLINE, life science and medical journals, articles, reviews, reports and  books.  BioPortfolio aims to publish relevant information on published papers, clinical trials and news associated with users selected topics.

For example view all recent relevant publications on Epigenetics and associated publications and clincial trials.

Showing PubMed Articles 1–25 of 439 from Journal of chemical information and modeling

Resolution Measurement From a Single Reconstructed Cryo-EM Density Map With Multi-Scale Spectral Analysis.

As a relatively new technology to solve the 3D structure of a protein or protein complex, the Single-Particle Reconstruction (SPR) of cryo-EM images shows much superiority and is in a rapidly developing stage. Resolution measurement in SPR, which evaluates the quality of a reconstructed 3D density map, plays a critical role for promoting methodology development of SPR and structural biology. Due to there is no benchmark map in a new structure generation, how to realize the resolution estimation of a new map...

Computational Prediction and Analysis for Tyrosine Post-Translational Modifications via Elastic Net.

The tyrosine residue has been identified as suffering three major post-translational modifications (PTMs) including nitration, sulfation, and phosphorylation, which could be involved in different physiological and pathological processes. Multiple tyrosine residues of the whole protein may be modified concurrently, where PTM of a single tyrosine may affect modification of other neighboring tyrosine residues. Hence, it is significant and beneficial to predict nitration, sulfation, and phosphorylation of tyros...

Determining the Relative Binding Affinity of Ricin Toxin A (RTA) Inhibitors by Using Molecular Docking and Non-Equilibrium Work.

Ricin is a ribosome-inactivating protein (RIP-type2) consisting of two subunits, Ricin Toxin A (RTA) and Ricin Toxin B (RTB). Due to its cytotoxicity, ricin has worried world authorities for its potential use as a chemical weapon; therefore, its inhibition is of great biotechnological interest. RTA is the target for inhibitor synthesis and pterin derivatives are promising candidates to inhibit it. In this study, we used a combination of molecular docking approach and fast steered molecular dynamics in order...

WarpEngine, a flexible platform for distributed computing implemented in the VEGA program and specially targeted for Virtual Screening studies.

The manuscript describes WarpEngine, a novel platform implemented within the VEGA ZZ suite of software for performing distributed simulations both in local and wide area networks. Despite being tailored for structure-based virtual screening campaigns, WarpEngine possesses the required flexibility to carry out distributed calculations utilizing various pieces of software, which can be easily encapsulated within this platform without changing their source codes. WarpEngine takes advantages of all cheminformat...

Hierarchical Flexible Peptide Docking by Conformer Generation and Ensemble Docking of Peptides.

Given the importance of peptide-mediated protein interactions in cellular processes, protein- peptide docking has received increasing attention. Here, we have developed a Hierarchical flexible Peptide Docking approach through fast generation and ensemble docking of peptide conformations, which is referred to as HPepDock. Tested on the LEADS-PEP benchmark data set of 53 diverse complexes with peptides of 3 to 12 residues, HpepDock performed significantly better than the 11 docking protocols of five small-mol...

CypReact: A Software Tool for in silico Reactant Prediction for Human Cytochrome P450 Enzymes.

In silico metabolism prediction requires first predicting whether a specific molecule will interact with one or more specific metabolizing enzymes, then predicting the result of each enzymatic reaction. Here, we provide a computational tool, CypReact, for performing this first task of reactant prediction. Specically, CypReact takes as input an arbitrary molecule (specied as a SMILES string or a standard SDF file), and any one of the nine of the most important human cytochrome P450 (CYP450) enzymes -- CYP1A2...

Modelling Kinase Inhibition Using Highly Confident Data Sets.

Protein kinases form a consistent class of promising drug targets, and several efforts have been made to predict the activity of small-molecules against a representative part of the kinome. This study continues our previous work (Bora, A.; Avram, S.; Ciucanu, I.; Raica, M.; Avram, S., Predictive Models for Fast and Effective Profiling of Kinase Inhibitors. J. Chem. Inf.

Conformal Regression for QSAR Modelling - Quantifying Prediction Uncertainty.

Making predictions with an associated confidence is highly desirable as it facilitates decision making and resource prioritization. Conformal regression is a machine learning framework that allows the user to define the required confidence and delivers predictions that are guaranteed to be correct to the selected extent. In this study, we apply conformal regression to model molecular properties and bioactivity values and investigate different ways to scale the outputted prediction intervals to create as eff...

Exploration and Comparison of the Geometrical and Physico-Chemical Properties of an αC Allosteric Pocket in the Structural Kinome.

In this work, a comprehensive analysis of the local geometrical and physico-chemical properties of a type III allosteric pocket located between the regulatory αC helix and the activation loop of protein kinases was made by comparing available crystal structures in the structural kinome. We first explored the structural kinome to outline the possible conformations of this site. Subsequently we characterized the positions of co-crystallized ligands of the structural kinome with respect to the structural vari...

Most Ligand-Based Classification Benchmarks Reward Memorization Rather than Generalization.

Undetected overfitting can occur when there are significant redundancies between training and validation data. We describe AVE, a new measure of training-validation redundancy for ligand-based classification problems that accounts for the similarity amongst inactive molecules as well as active. We investigated seven widely-used benchmarks for virtual screening and classification, and show that the amount of AVE bias strongly correlates with the performance of ligand-based predictive methods irrespective of ...

Maximal Unbiased Benchmarking Data Sets for Human Chemokine Receptors and Its Comparative Analysis.

Chemokine receptors (CRs) have long been druggable targets for the treatment of inflammatory diseases and HIV-1 infection. As a powerful technique, virtual screening (VS) has been widely applied to identifying small molecule leads for modern drug targets including CRs. For rational selection of a wide variety of VS approaches, ligand enrichment assessment based on a benchmarking data set has become an indispensable practice. However, the lack of versatile benchmarking sets for the whole CRs family that are ...

Peptidic Macrocycles - Conformational Sampling and Thermodynamic Characterization.

Macrocycles are of considerable interest as highly specific drug candidates, yet they challenge standard conformer generators with their large number of rotatable bonds and conformational restrictions. Here, we present a molecular dynamics-based routine that bypasses current limitations in conformational sampling and extensively profiles the free energy landscape of peptidic macrocycles in solution. We perform accelerated molecular dynamics simulations to capture a diverse conformational ensemble. By applyi...

Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38α MAP Kinase Type-I/II/III Inhibitors.

Understanding the governing factors of fast or slow inhibitor binding/unbinding assists in developing drugs with preferred kinetic properties. For inhibitors with the same binding affinity targeting different binding sites of the same protein, the kinetic behavior can profoundly differ. In this study, we investigated unbinding kinetics and mechanisms of fast (type-I) and slow (type-II/III) binders of p38α mitogen-activated protein kinase, where the crystal structures showed that type-I and type-II/III inhi...

Virtual Screening of Novel and Selective Inhibitors of PTP1B over TCPTP Using a Bidentate Inhibition Strategy.

Protein tyrosine phosphatase 1B (PTP1B), a promising target for II diabetes, obesity and cancer therapeutics, plays an important negative role in insulin signaling pathways. However, the lack of selective over other PTPs, especially for TCPTP, is still a challenge for inhibitors development. Recent studies suggest that the second pTyr binding site, close to the catalytic domain, may elevate binding affinity while bringing selectivity to inhibitors. Inspired by these studies, a virtual screening method based...

In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk.

Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on sim...

Comparative Molecular Field Analysis using Molecular Integral Equation Theory.

Recently, Güssregen et al. used solute-solvent distribution functions calculated by the 3D Reference Interaction Site Model (3DRISM) in a 3D-QSAR approach to model activity data for a set of serine protease inhibitors; this approach was referred to as Comparative Analysis of 3D RISM MAps (CARMa). [J. Chem. Inf.

Combining Stochastic Deformation/Relaxation and Intermolecular Contacts Analysis for Extracting Pharmacophores from Ligand-Receptor Complexes.

We previously combined molecular dynamics (classical or simulated annealing) with ligand-receptor contacts analysis as means to extract valid pharmacophore model(s) from single ligand-receptor complexes. However, molecular dynamics methods are computa-tionally expensive and time consuming. Here we describe a novel method for extracting valid pharmacophore model(s) from a single crystallographic structure within reasonable time scale. The new method is based on ligand-receptor contacts analysis following en-...

Simulation-guided design of cytochrome P450 for chemo- and regioselective macrocyclic oxidation.

Engineering a high chemo-, regio-, and stereoselectivity is a prerequisite for enzyme usage in organic synthesis. Cytochromes P450 can oxidize a broad range of substrates, including macrocycles, which are becoming popular scaffolds for therapeutic agents. However, a large conformational space explored by macrocycles not only reduces the selectivity of oxidation, but also impairs computational enzyme design strategies based on docking and molecular dynamics (MD) simulations. We present a novel design workflo...

Dissecting the Innate Immune Recognition of Opioid Inactive Isomer (+)-Naltrexone Derived Toll-like Receptor 4 (TLR4) Antagonists.

The opioid inactive isomer (+)-naltrexone is one of the rare Toll-like receptor 4 (TLR4) antagonists with good blood-brain barrier (BBB) permeability, which is a lead with promising potential for treating neuropathic pain and drug addiction. (+)-Naltrexone targets the lipopolysaccharides (LPS) binding pocket of myeloid differentiation protein 2 (MD-2) and blocks innate immune TLR4 signaling. However, the details of the molecular interactions of (+)-naltrexone and its derivatives with MD-2 are not fully unde...

Fixed-Charge Atomistic Force Fields for Molecular Dynamics Simulations in the Condensed Phase: An Overview.

In molecular dynamics or Monte-Carlo simulations, the interactions between the particles (atoms) in the system are described by a so-called force field. The empirical functional form of classical fixed-charge force fields dates back to 1969 and remains essentially unchanged. In a fixed-charge force field, the polarization is not modeled explicitly, i.e. the effective partial charges do not change depending on conformation and environment. This simplification allows, however, a dramatic reduction in computat...

Discovery of Novel Adenosine Receptor Antagonists through a Combined Structure- and Ligand-Based Approach Followed by Molecular Dynamics Investigation of Ligand Binding Mode.

An intense effort is made by pharmaceutical and academic research laboratories to identify and develop selective antagonists for each adenosine receptor (AR) subtype as potential clinical candidates for "soft" treatment of various diseases. Crystal structures of subtypes A2A and A1ARs offer exciting opportunities for structure-based drug design. In the first part of the present work, Maybridge HitFinderTM library of 14400 compounds was utilized to apply a combination of structure-based against the crystal s...

Integration of enhanced sampling methods with Saturation Transfer Difference (STD) experiments to identify protein druggable pockets.

Saturation Transfer Difference (STD) is an NMR technique conventionally applied in drug discovery to identify ligand moieties relevant for binding to protein cavities. This is important to direct medicinal chemistry efforts in small-molecule optimization processes. However, STD does not provide any structural details about the ligand-target complex under investigation. Herein, we report the application of a new integrated approach, which combines enhanced sampling methods with STD experiments, for the chara...

A New Knowledge-based Scoring Function with Inclusion of Backbone Conformational Entropies from Protein Structures.

Accurate prediction of a protein's structure requires a reliable free energy function that consists of both enthalpic and entropic contributions. Although considerable progresses have been made in the calculation of {potential energies} in protein structure prediction, the computation for entropies of protein has lagged far behind, due to the challenge that estimation of entropies often requires expensive conformational sampling. In this study, we have used a knowledge-based approach to estimate the backbon...

Partner-Specific Prediction of Protein-Dimer Stability from Unbound Structure of Monomer.

Protein complexes play deterministic roles in the live entities in sensing, compiling, controlling, and responding to the external and internal stimuli. Thermodynamic stability is an important property of protein complexes; having knowledge about complex stability helps us to understand the basics of protein-assembly-related diseases and the mechanism of protein assembly clearly. Enormous protein-protein interactions, detected by high-throughput methods, necessitate finding fast methods for predicting the s...

Optimal HTS fingerprints definitions by using a desirability function and a genetic algorithm.

Compound biological fingerprints built on data from high throughput screening (HTS) campaigns, or HTS fingerprints, are a novel cheminformatics method of representing compounds by integrating chemical and biological activity data that is gaining momentum in its application to drug discovery, including hit expansion, target identification and virtual screening. HTS fingerprints present two major limitations, noise and missing data, which are intrinsic to the high-throughput data acquisition technologies and ...


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