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Journal of Chemical Information and Modeling

Lucia Romero, Jordi Cano, Julio Gomis-Tena, Beatriz Trenor, Ferran Sanz, Manuel Pastor, Javier Saiz
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 simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue...
March 16, 2018: Journal of Chemical Information and Modeling
Samiul M Ansari, David S Palmer
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. MODEL: , 2017, 57, 1652-1666] Here we extend this idea by introducing probe atoms into the 3DRISM solvent model in order to directly capture other molecular interactions in addition to those related to hydration/dehydration...
March 15, 2018: Journal of Chemical Information and Modeling
Ramin Ekhteiari Salmas, Philip Seeman, Matthias Stein, Serdar Durdagi
The active (D2HighR) and inactive (D2LowR) states of dimeric dopamine D2 receptor (D2R) models were investigated to clarify the binding mechanisms of the dopamine agonist bromocriptine, using Molecular Dynamics (MD) simulation. The aim of this comprehensive study was to investigate the critical effects of bromocriptine binding on each distinct receptor conformation. The different binding modes of the bromocriptine ligand in the active and inactive states have a significant effect on the conformational changes of the receptor...
March 14, 2018: Journal of Chemical Information and Modeling
Yossa Dwi Hartono, You Xu, Andrey Karshikoff, Lennart Nilsson, Alessandra Villa
The protonation states for nucleic acid bases are difficult to assess experimentally. In the context of triplex DNA, the protonation state of cytidine in the third strand is particularly important, because it needs to be protonated in order to form Hoogsteen hydrogen bonds. A sugar modification, locked nucleic acid (LNA), is widely used in triplex forming oligonucleotides to target sites in the human genome. In this study, the parameters for LNA are developed in line with the CHARMM nucleic acid force field and validated towards the available structural experimental data...
March 14, 2018: Journal of Chemical Information and Modeling
Ma'mon M Hatmal, Mutasem O Taha
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-ergy relaxation of predetermined set of randomly deformed complexes generated from the targeted crystallographic structure...
March 12, 2018: Journal of Chemical Information and Modeling
Tifang Miao, Qinghua Deng, Hui Gao, Xianliang Fu, Shuang Li
Theoretical studies on DNA-cleavage properties of [Cu(bba)(diimine)] 1-4 have been carried out using density functional theory (DFT) and docking methods. The optimized structures of Cu(II) complexes were docked into DNA, glutathiones (GSH) and ascorbic acids (VC) so that the corresponding docking models were obtained. To explore DNA-cleavage properties of Cu(II) complexes, the docking models of complexes with GSH and VC were further optimized using DFT method, while the docking models of complexes with DNA were optimized using QM/MM method because DNA is a supramolecular system...
March 12, 2018: Journal of Chemical Information and Modeling
Dušan Petrović, Ansgar Bokel, Matthew Allan, Vlada B Urlacher, Birgit Strodel
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 workflow that uses enhanced-sampling Hamiltonian replica exchange (HREX) MD and focuses on quantifying the substrate binding for suggesting the mutations to be made...
March 9, 2018: Journal of Chemical Information and Modeling
Xiaozheng Zhang, Fengchao Cui, Hongqian Chen, Tianshu Zhang, Kecheng Yang, Yibo Wang, Zhenyan Jiang, Kenner C Rice, Linda R Watkins, Mark R Hutchinson, Yunqi Li, Yinghua Peng, Xiaohui Wang
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 understood, which hinders the ligand-based drug discovery...
March 8, 2018: Journal of Chemical Information and Modeling
Sereina Riniker
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 computational cost compared to polarizable force fields and in particular quantum-chemical modeling...
March 6, 2018: Journal of Chemical Information and Modeling
Jaime Rodríguez-Guerra Pedregal, Pablo Gómez-Orellana, Jean-Didier Pierre Maréchal
Electronic Supporting Information (ESI) occupies a fundamental position in the way scientists report their work. It is a key element in lightening the writing of the core manuscript and makes concise communication easier for the authors. Computational chemistry, as all fields related to structural studies of molecules, tends to generate huge amounts of data that should be inserted in the ESI. ESI reports raising from computational chemistry works generally reach tens of sheets long and include 3D depictions, coordinates, energies and other characteristics of the structures involved in the molecular process understudy...
March 5, 2018: Journal of Chemical Information and Modeling
Denis Bucher, Pieter Fw Stouten, Nicolas Triballeau
Water molecules play an important role in the association of drugs with their pharmaceutical targets. For this reason, calculating the energetic contribution of water is essential to make accurate predictions of compounds' affinity and selectivity. Water molecules can also modify the binding mode of compounds by forming water bridges, or stable water clusters, that stabilize a particular orientation of the ligand. Several computational methods have been developed for solvent mapping, but few studies have attempted to compare them in a drug design context...
February 28, 2018: Journal of Chemical Information and Modeling
L Mark Hall, Dennis W Hill, Kelly Bugden, Shannon Marie Cawley, Lowell Hall, Ming-Hui Chen, David F Grant
The MolFind application has been developed as a non-targeted metabolomics chemometric tool to facilitate structure identification when HPLC biofluids analysis reveals a feature of interest. Here synthetic compounds are selected and measured to form the basis of a new, more accurate, HPLC retention index model for use with MolFind. We show that relatively inexpensive synthetic screening compounds with simple structures can be used to develop an artificial neural network model that is successful in making quality predictions for human metabolites...
February 28, 2018: Journal of Chemical Information and Modeling
Panagiotis Lagarias, Eleni Vrontaki, George Lambrinidis, Dimitrios Stamatis, Marino Convertino, Gabriella Ortore, Thomas Mavromoustakos, Karl-Norbert Klotz, Antonios Kolocouris
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 structure of A2AAR and ligand-based methodologies...
February 27, 2018: Journal of Chemical Information and Modeling
Joana Magalhaes, Giannamaria Annunziato, Nina Franko, Marco Pieroni, Barbara Campanini, Agostino Bruno, Gabriele Costantino
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 characterization of ligand-target complexes that are instrumental for drug design purposes...
February 26, 2018: Journal of Chemical Information and Modeling
Gerard Martinez-Rosell, Matt J Harvey, Gianni De Fabritiis
Fragment-based drug discovery (FBDD) has become a mainstream approach in drug design because it allows the reduction of the chemical space and screening libraries while identifying fragments with high protein-ligand efficiency interactions that can later be grown into drug-like leads. In this work, we leverage high-throughput molecular dynamics (MD) simulations to screen a library of 129 fragments for a total of 5.85ms against the CXCL12 monomer, a chemokine involved in inflammation and diseases such as cancer...
February 26, 2018: Journal of Chemical Information and Modeling
Kartheek Pitta, Marimuthu Krishnan
DNA damages alter genetic information and adversely affect gene expression pathways leading to various complex genetic disorders and cancers. DNA repair proteins recognize and rectify DNA damages with high fidelity. A critical molecular event that occurs during most protein-mediated DNA repair processes is the extrusion of orphaned bases at the damaged site facilitated by specific repairing enzymes. The molecular-level understanding of the mechanism, dynamics, and energetics of base extrusion is necessary to elucidate the molecular basis of protein-mediated DNA damage repair...
February 23, 2018: Journal of Chemical Information and Modeling
Patrick Bleiziffer, Kay Schaller, Sereina Riniker
Parametrization of small organic molecules for classical molecular dynamics simulations is not trivial. The vastness of the chemical space makes approaches using building blocks challenging. The most common approach is therefore an invidual parametrization of each compound by deriving partial charges from semi-empirical or ab initio calculations and inheriting the bonded and van der Waals (Lennard-Jones) parameters from a biomolecular force field. The quality of the partial charges generated in this fashion depends on the level of the quantum-chemical calculation as well as on the extraction procedure used...
February 20, 2018: Journal of Chemical Information and Modeling
Hamid Hadi-Alijanvand, Maryam Rouhani
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 stability of protein assemblies in a quantitative and qualitative manner...
February 14, 2018: Journal of Chemical Information and Modeling
Xinxiang Wang, Di Zhang, Sheng-You Huang
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 backbone conformational entropies from experimentally determined native structures...
February 14, 2018: Journal of Chemical Information and Modeling
Emel Timucin, Osman Ugur Sezerman
Magnesium deficiency increases susceptibility of plants towards heat stress. The correlation between magnesium levels and stress response has been studied at the physiological level, albeit the molecular explanation to this relationship remains elusive. Among diverse pathways implicated in the heat stress, the abscisic acid (ABA) signal modulates the heat stress response by magnesium dependent phosphatases (PP2Cs). Exclusively, sequestration of PP2Cs by ABA receptors (PYLs) in the heterodimer form activates the stress response through ABA responsive transcription factors...
February 13, 2018: Journal of Chemical Information and Modeling
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