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Journal of Chemical Information and Modeling

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https://www.readbyqxmd.com/read/28346786/break-down-in-order-to-build-up-decomposing-small-molecules-for-fragment-based-drug-design-with-emolfrag
#1
Tairan Liu, Misagh Naderi, Chris Alvin, Supratik Mukhopadhyay, Michal Brylinski
Constructing high-quality libraries of molecular building blocks is essential for successful fragment-based drug discovery. In this communication, we describe eMolFrag, a new open-source software to decompose organic compounds into non-redundant fragments retaining molecular connectivity information. Given a collection of molecules, eMolFrag generates a set of unique fragments comprising larger moieties, bricks, and smaller linkers connecting bricks. These building blocks can subsequently be used to construct virtual screening libraries for targeted drug discovery...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28345935/targeting-self-binding-peptides-as-a-novel-strategy-to-regulate-protein-activity-and-function-a-case-study-on-the-proto-oncogene-tyrosine-protein-kinase-c-src
#2
Zhengya Bai, Shasha Hou, Shilei Zhang, Zhongyan Li, Peng Zhou
Previously, we have reported a new biomolecular phenomenon spanning between protein folding and binding, termed as self-binding peptides (SBPs), where a short peptide segment in monomeric protein functions as molecular switch by dynamically binding to/unbinding from its cognate domain in the monomer (Yang C, Zhang S, He P, Wang C, Huang J, Zhou P. Self-binding peptides: folding or binding? J. Chem. Inf. MODEL: 2015, 55: 329-342). Here, we attempt to raise the SBP as a new class of druggable targets to regulate the biological activity and function of proteins...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28345931/predictable-conformational-diversity-in-foldamers-of-sugar-amino-acids
#3
Dora K Menyhard, Ilona Hudaky, Imre Jákli, György Juhász, András Perczel
Systematic conformational search was carried out for monomers and homohexamers of furanoid β-amino acids: cis-(S,R) and trans-(S,S) stereoisomers of aminocyclopentane carboxylic acid (ACPC), two different aminofuranuronic-acids (AFU(α) and AFU(β)), their isopropylidene derivatives (AFU(ip)) as well as the key intermediate β-aminotetrahydrofurancarboxylic acid (ATFC). Stereochemistry of the building blocks was chosen to match with that of natural sugar amino acid (xylose and ribose) precursors. Results show that hexamers of cis furanoid β-amino acids show great variability: while hydrophobic cyclopentane (cis(ACPC)6), and hydrophilic (cisXylAFU(α/β))6 foldamers favor two different zigzagged conformation as hexamers, the backbone fold turns into a helix in case of (cisATFC)6 (10-helix) and (cisAFU(ip))6 (14-helix)...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28345910/pycgtool-automated-generation-of-coarse-grained-molecular-dynamics-models-from-atomistic-trajectories
#4
James A Graham, Jonathan W Essex, Syma Khalid
Development of coarse-grained (CG) molecular dynamics models is often a laborious process which commonly relies upon approximations to similar models, rather than systematic parametrisation. PyCGTOOL automates much of the construction of CG models via calculation of both equilibrium values and force constants of internal coordinates directly from atomistic molecular dynamics simulation trajectories. The derivation of bespoke parameters from atomistic simulations improves the quality of the CG model compared to the use of generic parameters derived from other molecules, while automation greatly reduces the time required...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28345905/metatox-web-application-for-predicting-structure-and-toxicity-of-xenobiotics-metabolites
#5
Anastasia V Rudik, Vladislav M Bezhentsev, Alexander V Dmitriev, Dmitry S Druzhilovskiy, Alexey A Lagunin, Dmitry A Filimonov, Vladimir V Poroikov
A new freely available web-application MetaTox (http://www.way2drug.com/mg) for prediction of xenobiotic's metabolism and calculation toxicity of metabolites based on the structural formula of chemicals has been developed. MetaTox predicts metabolites, which are formed by nine classes of reactions (aliphatic and aromatic hydroxylation, N- and O-glucuronidation, N-, S- and C-oxidation, and N- and O-dealkylation). The calculation of probability for generated metabolites is based on analyses of "structure-biotransformation reactions" and "structure-modified atoms" relationships using a Bayesian approach...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28345904/ligand-selectivity-mechanism-and-conformational-changes-in-guanine-riboswitch-by-molecular-dynamics-simulations-and-free-energy-calculations
#6
Guodong Hu, Aijing Ma, Ji Hua Wang
Riboswitches regulate gene expression through direct and specific interactions with small metabolite molecules. Binding of a ligand to its RNA target is high selectivity and affinity and induces conformational changes of the RNA's secondary and tertiary structure. The structural difference of two purine riboswitches aptamers is caused by only one single mutation, where cytosine 74 in the guanine riboswitch is corresponding to a uracil 74 in adenine riboswitch. Here we employed molecular dynamics (MD) simulation, molecular mechanics Poisson Boltzmann surface area (MM-PBSA) and thermodynamic integration computational methodologies to evaluate the energetic and conformational changes of ligands binding to purine riboswitches...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28301157/identification-of-the-crucial-residues-in-the-early-insertion-of-pardaxin-into-different-phospholipid-bilayers
#7
Majid Jafari, Faramarz Mehrnejad, Raheleh Aghdami, Nader Chaparzadeh, Zahra Razaghi Moghadam Kashani, Farahnoosh Doustdar
Antimicrobial peptides (AMPs) are part of the innate host defense system, and they are produced by living organisms to defend themselves against infections. Pardaxin is a cationic AMP with antimicrobial and antitumor activities that has potential to be used as a novel antibiotic or for drug delivery in cancer therapy. This peptide acts on the membrane of target cells and can lead to lysis using different mechanisms of action. Here, we conducted 4.5 μs all-atom molecular dynamics (MD) simulations to determine the critical fragments and residues of Pardaxin for early insertion into different lipid bilayers...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28287733/probing-the-binding-interactions-between-chemically-modified-sirnas-and-human-argonaute-2-using-microsecond-molecular-dynamics-simulations
#8
S Harikrishna, P I Pradeepkumar
The use of chemical modifications in small interfering RNAs (siRNAs) is warranted to impart drug-like properties. However, certain chemical modifications especially those on the sugar have deleterious effects on the RNA interference (RNAi) when they are placed at key positions in the seed region of an siRNA guide strand. In order to probe the effect of chemically modified siRNAs [(2'-O-methyl, 4'-C-aminomethyl-2'-O-methyl, 2'-O-(2-methoxyethyl), and 2'-O-benzyl] on human Argonaute 2 (hAGO2), the catalytic engine of RNAi, we have developed a model of its open conformation...
March 27, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28282119/patchsearch-a-fast-computational-method-for-off-target-detection
#9
Inès Rasolohery, Gautier Moroy, Frédéric Guyon
Many therapeutic molecules are known to bind several proteins, which can be different from the initially targeted one. Such unexpected interactions with proteins called off-targets can lead to adverse effects. Potential off-target identification is important to predict to avoid drug side effects or to discover new targets for existing drugs. We propose a new program named PatchSearch that implements local nonsequential searching for similar binding sites on protein surfaces with a controlled amount of flexibility...
March 24, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28328209/multidk-a-multiple-descriptor-multiple-kernel-approach-for-molecular-discovery-and-its-application-to-the-discovery-of-organic-flow-battery-electrolytes
#10
Sung-Jin Kim, Adrián Jinich, Alán Aspuru-Guzik
We propose a multiple descriptor multiple kernel (MultiDK) method for efficient molecular discovery using machine learning. We show that the MultiDK method improves both the speed and accuracy of molecular property prediction. We apply the method to the discovery of electrolyte molecules for aqueous redox flow batteries. Using \emph{multiple-type - as opposed to single-type - descriptors}, we obtain more relevant features for machine learning. Following the principle of 'wisdom of the crowds', the combination of multiple-type descriptors significantly boosts prediction performance...
March 22, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28263066/wurcs-2-0-update-to-encapsulate-ambiguous-carbohydrate-structures
#11
Masaaki Matsubara, Kiyoko F Aoki-Kinoshita, Nobuyuki P Aoki, Issaku Yamada, Hisashi Narimatsu
Accurate representation of structural ambiguity is important for storing carbohydrate structures containing varying levels of ambiguity in the literature and databases. Although many representations for carbohydrates have been developed in the past, a generalized but discrete representation format did not exist. We had previously developed the Web3 Unique Representation of Carbohydrate Structures (WURCS) in an attempt to define a generalizable and unique linear representation for carbohydrate structures. However, it lacked sufficient rules to uniquely describe ambiguous structures...
March 22, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28322559/identification-of-novel-inhibitors-of-leishmania-donovani-%C3%AE-glutamylcysteine-synthetase-using-structure-based-virtual-screening-docking-molecular-dynamics-simulation-and-in-vitro-studies
#12
Pragati Agnihotri, Arjun Kumar Mishra, Shikha Mishra, Vijay Kumar Sirohi, Amogh A Sahasrabuddhe, J Venkatesh Pratap
Trypansomatids maintain their redox balance by the trypanothione based redox system, enzymes of which exhibit differences from mammalian homologues. γ-glutamylcysteine synthetase (Gcs) is an essential enzyme of this pathway performing the first and rate limiting step. L-buthionine-S,R-sulfoximine (BSO), a specific inhibitor of Gcs induces toxicity in hosts infected with T. brucei underlining for novel Gcs inhibitors. The present study reports identification of Ld Gcs inhibitors using computational approaches and their experimental validation...
March 21, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28319380/evaluation-and-characterization-of-trk-kinase-inhibitors-for-the-treatment-of-pain-reliable-binding-affinity-predictions-from-theory-and-computation
#13
Shunzhou Wan, Agastya P Bhati, Sarah Skerratt, Kiyoyuki Omoto, Veerabahu Shanmugasundaram, Sharan K Bagal, Peter Vivian Coveney
Optimisation of ligand binding affinity to the target protein of interest is a primary objective in small-molecule drug discovery. Until now, the prediction of binding affinities by computational methods has not been widely applied in the drug discovery process, mainly due to its lack of accuracy and reproducibility, as well as the long turnaround times required to obtain results. Herein, we report on a collaborative study that compares tropomyosin receptor kinase A (TrkA) binding affinity predictions using two recently formulated fast computational approaches - namely ESMACS (Enhanced Sampling of Molecular dynamics with Approximation of Continuum Solvent) and TIES (Thermodynamic Integration with Enhanced Sampling) - to experimentally derived TrkA binding affinities for a set of Pfizer pan-Trk compounds...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28318252/molecular-dynamics-in-mixed-solvents-reveals-protein-ligand-interactions-improves-docking-and-allows-accurate-binding-free-energy-predictions
#14
Juan Pablo Arcon, Lucas A Alfredo Defelipe, Carlos Pablo Modenutti, Elias Daniel Lopez, Daniel Alvarez-Garcia, Xavier Barril, Adrian Gustavo Turjanski, Marcelo A Marti
One of the most important biological processes at the molecular level is the formation of protein-ligand complexes. Therefore, determining their structure and underlying key interactions is of paramount relevance and has direct applications in drug development. Due to its low cost relative to its experimental sibling, Molecular Dynamics (MD) simulations in the presence of different solvent probes mimicking specific type of interactions have been increasingly used to analyze protein binding sites and reveal protein-ligand interaction hot spots...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28318251/molecular-simulation-studies-on-the-binding-selectivity-of-type-i-inhibitors-in-the-complexes-with-ros1-versus-alk
#15
Yuanxin Tian, Yonghuan Yu, Yudong Shen, Hua Wan, Shan Chang, Tingting Zhang, Shanhe Wan, Jiajie Zhang
ROS1 and ALK are promising targets of anti-cancer drugs for non small cell lung cancer. Since they have 49% amide acid sequence homology in the kinases domain and 77% identity at the ATP binding area, some ALK inhibitors also showed some significant responses for ROS1 in the clinical trial, such as the type-I binding inhibitor crizotinib and PF-06463922. As a newly therapeutic target, selective ROS1 inhibitor is relative rarely. Moreover, the molecular basis for the selectivity of ROS1 versus ALK still remains unclear...
March 20, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28316236/webmolcs-a-web-based-interface-for-visualizing-molecules-in-3d-chemical-spaces
#16
Mahendra Awale, Daniel Probst, Jean-Louis Reymond
The concept of chemical space provides a convenient framework to analyze large collections of molecules by placing them in property spaces where distances represent similarities. Here we report webMolCS, a new type of web-based interface visualizing up to 5000 user-defined molecules in six different 3D chemical spaces obtained by principal component analysis or similarity mapping of multi-dimensional property spaces describing composition (MQN: 42D Molecular Quantum Numbers, SMIfp: 34D SMILES fingerprint), shapes and pharmacophores (APfp: 20D atom pair fingerprint, Xfp: 55D category extended atom pair fingerprint), and substructures (Sfp: 1024D binary substructure fingerprint, ECfp4: 1024D extended connectivity fingerprint)...
March 19, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28257198/shared-consensus-machine-learning-models-for-predicting-blood-stage-malaria-inhibition
#17
Andreas Verras, Chris L Waller, Peter Gedeck, Darren V S Green, Thierry Kogej, Anandkumar Raichurkar, Manoranjan Panda, Anang Shelat, Julie Clark, Kip Guy, George Papadatos, Jeremy Burrows
The development of new antimalarial therapies is essential, and lowering the barrier of entry for the screening and discovery of new lead compound classes can spur drug development at organizations that may not have large compound screening libraries or resources to conduct high-throughput screens. Machine learning models have been long established to be more robust and have a larger domain of applicability with larger training sets. Screens over multiple data sets to find compounds with potential malaria blood stage inhibitory activity have been used to generate multiple Bayesian models...
March 17, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28301154/consistent-principal-component-modes-from-molecular-dynamics-simulations-of-proteins
#18
Rodrigo Cossio-Pérez, Juliana Palma, Gustavo Pierdominici-Sottile
Principal component analysis is a technique widely used for studying the movements of proteins using data collected from molecular dynamics simulations. In spite of its extensive use the technique has a serious drawback: equivalent simulations do not afford the same PC-modes. In this article we show that concatenating equivalent trajectories and calculating the PC-modes from the concatenated one significantly enhances the reproducibility of the results. Moreover, the consistency of the modes can be systematically improved by adding more individual trajectories to the concatenated one...
March 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28301150/discovery-of-new-sirt2-inhibitors-by-utilizing-a-consensus-docking-scoring-strategy-and-structure-activity-relationship-analysis
#19
Shen-Zhen Huang, Chun-Li Song, Xiang Wang, Guo Zhang, Yan-Lin Wang, Xiao-Juan Jiang, Qi-Zheng Sun, Lu-Yi Huang, Rong Xiang, Yi-Guo Hu, Lin-Li Li, Sheng-Yong Yang
SIRT2, which is a NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase, has been demonstrated to play an important role in the occurrence and development of a variety of diseases such as cancer, ischemia-reperfusion, and neurodegenerative diseases. Small molecule inhibitors of SIRT2 are thought as potential interfering agents for relevant diseases. Discovery of SIRT2 inhibitor has attracted much attention recently. In this investigation, we first adopted a consensus docking/scoring strategy to screen for novel SIRT2 inhibitors...
March 16, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28257573/toward-understanding-the-cold-hot-and-neutral-nature-of-chinese-medicines-using-in-silico-mode-of-action-analysis
#20
Xianjun Fu, Lewis H Mervin, Xuebo Li, Huayun Yu, Jiaoyang Li, Siti Zuraidah Mohamad Zobir, Azedine Zoufir, Yang Zhou, Yongmei Song, Zhenguo Wang, Andreas Bender
One important, however, poorly understood, concept of Traditional Chinese Medicine (TCM) is that of hot, cold, and neutral nature of its bioactive principles. To advance the field, in this study, we analyzed compound-nature pairs from TCM on a large scale (>23 000 structures) via chemical space visualizations to understand its physicochemical domain and in silico target prediction to understand differences related to their modes-of-action (MoA) against proteins. We found that overall TCM natures spread into different subclusters with specific molecular patterns, as opposed to forming coherent global groups...
March 16, 2017: Journal of Chemical Information and Modeling
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