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Journal of Computer-aided Molecular Design

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https://www.readbyqxmd.com/read/27909938/blowing-a-breath-of-fresh-share-on-data
#1
Wendy A Warr
No abstract text is available yet for this article.
December 1, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27900588/modeling-informatics-at-vertex-pharmaceuticals-incorporated-our-philosophy-for-sustained-impact
#2
Georgia McGaughey, W Patrick Walters
Molecular modelers and informaticians have the unique opportunity to integrate cross-functional data using a myriad of tools, methods and visuals to generate information. Using their drug discovery expertise, information is transformed to knowledge that impacts drug discovery. These insights are often times formulated locally and then applied more broadly, which influence the discovery of new medicines. This is particularly true in an organization where the members are exposed to projects throughout an organization, such as in the case of the global Modeling & Informatics group at Vertex Pharmaceuticals...
November 29, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27878643/the-evolution-of-drug-design-at-merck-research-laboratories
#3
Frank K Brown, Edward C Sherer, Scott A Johnson, M Katharine Holloway, Bradley S Sherborne
On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc...
November 23, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27848066/molecular-mechanism-of-r-bicalutamide-switching-from-androgen-receptor-antagonist-to-agonist-induced-by-amino-acid-mutations-using-molecular-dynamics-simulations-and-free-energy-calculation
#4
Hongli Liu, Rui Han, Jiazhong Li, Huanxiang Liu, Lifang Zheng
R-bicalutamide, a first generation antiandrogen, was used to treat prostate cancer for decades. Although it is very effective at the beginning, resistance appears after 2-3 years of treatment. Mutation of androgen receptor (AR) is considered a main reason for drug resistance. It is reported that AR W741C, W741L, W741C_T877A, T877A, F876L, F876L_T877A and L701H mutations can convert R-bicalutamide from AR antagonist to agonist, but the switching mechanisms are not clear. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GBSA) calculations were performed to analyze the interaction mechanisms between R-bicalutamide and wild type/mutant ARs...
November 15, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27830428/empowering-pharmacoinformatics-by-linked-life-science-data
#5
Daria Goldmann, Barbara Zdrazil, Daniela Digles, Gerhard F Ecker
With the public availability of large data sources such as ChEMBLdb and the Open PHACTS Discovery Platform, retrieval of data sets for certain protein targets of interest with consistent assay conditions is no longer a time consuming process. Especially the use of workflow engines such as KNIME or Pipeline Pilot allows complex queries and enables to simultaneously search for several targets. Data can then directly be used as input to various ligand- and structure-based studies. In this contribution, using in-house projects on P-gp inhibition, transporter selectivity, and TRPV1 modulation we outline how the incorporation of linked life science data in the daily execution of projects allowed to expand our approaches from conventional Hansch analysis to complex, integrated multilayer models...
November 9, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27815770/erratum-to-a-combined-treatment-of-hydration-and-dynamical-effects-for-the-modeling-of-host-guest-binding-thermodynamics-the-sampl5-blinded-challenge
#6
Rajat Kumar Pal, Kamran Haider, Divya Kaur, William Flynn, Junchao Xia, Ronald M Levy, Tetiana Taran, Lauren Wickstrom, Tom Kurtzman, Emilio Gallicchio
No abstract text is available yet for this article.
November 4, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27804014/computer-aided-drug-discovery-research-at-a-global-contract-research-organization
#7
Douglas B Kitchen
Computer-aided drug discovery started at Albany Molecular Research, Inc in 1997. Over nearly 20 years the role of cheminformatics and computational chemistry has grown throughout the pharmaceutical industry and at AMRI. This paper will describe the infrastructure and roles of CADD throughout drug discovery and some of the lessons learned regarding the success of several methods. Various contributions provided by computational chemistry and cheminformatics in chemical library design, hit triage, hit-to-lead and lead optimization are discussed...
November 1, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27798721/tools-techniques-organisation-and-culture-of-the-cadd-group-at-sygnature-discovery
#8
Steve A St-Gallay, Colin P Sambrook-Smith
Computer-aided drug design encompasses a wide variety of tools and techniques, and can be implemented with a range of organisational structures and focus in different organisations. Here we outline the computational chemistry skills within Sygnature Discovery, along with the software and hardware at our disposal, and briefly discuss the methods that are not employed and why. The goal of the group is to provide support for design and analysis in order to improve the quality of compounds synthesised and reduce the timelines of drug discovery projects, and we reveal how this is achieved at Sygnature...
October 31, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27796615/enabling-drug-discovery-project-decisions-with-integrated-computational-chemistry-and-informatics
#9
Vickie Tsui, Daniel F Ortwine, Jeffrey M Blaney
Computational chemistry/informatics scientists and software engineers in Genentech Small Molecule Drug Discovery collaborate with experimental scientists in a therapeutic project-centric environment. Our mission is to enable and improve pre-clinical drug discovery design and decisions. Our goal is to deliver timely data, analysis, and modeling to our therapeutic project teams using best-in-class software tools. We describe our strategy, the organization of our group, and our approaches to reach this goal. We conclude with a summary of the interdisciplinary skills required for computational scientists and recommendations for their training...
October 31, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27787702/lessons-learned-from-comparing-molecular-dynamics-engines-on-the-sampl5-dataset
#10
Michael R Shirts, Christoph Klein, Jason M Swails, Jian Yin, Michael K Gilson, David L Mobley, David A Case, Ellen D Zhong
We describe our efforts to prepare common starting structures and models for the SAMPL5 blind prediction challenge. We generated the starting input files and single configuration potential energies for the host-guest in the SAMPL5 blind prediction challenge for the GROMACS, AMBER, LAMMPS, DESMOND and CHARMM molecular simulation programs. All conversions were fully automated from the originally prepared AMBER input files using a combination of the ParmEd and InterMol conversion programs. We find that the energy calculations for all molecular dynamics engines for this molecular set agree to better than 0...
October 27, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27783199/compilation-and-physicochemical-classification-analysis-of-a-diverse-herg-inhibition-database
#11
Remigijus Didziapetris, Kiril Lanevskij
A large and chemically diverse hERG inhibition data set comprised of 6690 compounds was constructed on the basis of ChEMBL bioactivity database and original publications dealing with experimental determination of hERG activities using patch-clamp and competitive displacement assays. The collected data were converted to binary format at 10 µM activity threshold and subjected to gradient boosting machine classification analysis using a minimal set of physicochemical and topological descriptors. The tested parameters involved lipophilicity (log P), ionization (pK a ), polar surface area, aromaticity, molecular size and flexibility...
October 25, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27770305/identification-of-novel-trypanosoma-cruzi-prolyl-oligopeptidase-inhibitors-by-structure-based-virtual-screening
#12
Hugo de Almeida, Vincent Leroux, Flávia Nader Motta, Philippe Grellier, Bernard Maigret, Jaime M Santana, Izabela Marques Dourado Bastos
We have previously demonstrated that the secreted prolyl oligopeptidase of Trypanosoma cruzi (POPTc80) is involved in the infection process by facilitating parasite migration through the extracellular matrix. We have built a 3D structural model where POPTc80 is formed by a catalytic α/β-hydrolase domain and a β-propeller domain, and in which the substrate docks at the inter-domain interface, suggesting a "jaw opening" gating access mechanism. This preliminary model was refined by molecular dynamics simulations and next used for a virtual screening campaign, whose predictions were tested by standard binding assays...
October 21, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27722817/combining-molecular-dynamics-simulation-and-ligand-receptor-contacts-analysis-as-a-new-approach-for-pharmacophore-modeling-beta-secretase-1-and-check-point-kinase-1-as-case-studies
#13
Ma'mon M Hatmal, Shadi Jaber, Mutasem O Taha
Ligand-based pharmacophore modeling require relatively long lists of active compounds, while a pharmacophore based on a single ligand-receptor crystallographic structure is often promiscuous. These problems prompted us to combine molecular dynamics (MD) simulation with ligand-receptor contacts analysis as means to develop valid pharmacophore model(s). The particular ligand-receptor complex is allowed to perturb over a few nano-seconds using MD simulation. Subsequently, ligand-receptor contact points (≤2.5 Å) are identified...
October 8, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27718029/predicting-binding-poses-and-affinities-for-protein-ligand-complexes-in-the-2015-d3r-grand-challenge-using-a-physical-model-with-a-statistical-parameter-estimation
#14
Sergei Grudinin, Maria Kadukova, Andreas Eisenbarth, Simon Marillet, Frédéric Cazals
The 2015 D3R Grand Challenge provided an opportunity to test our new model for the binding free energy of small molecules, as well as to assess our protocol to predict binding poses for protein-ligand complexes. Our pose predictions were ranked 3-9 for the HSP90 dataset, depending on the assessment metric. For the MAP4K dataset the ranks are very dispersed and equal to 2-35, depending on the assessment metric, which does not provide any insight into the accuracy of the method. The main success of our pose prediction protocol was the re-scoring stage using the recently developed Convex-PL potential...
October 7, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27718028/measuring-experimental-cyclohexane-water-distribution-coefficients-for-the-sampl5-challenge
#15
Ariën S Rustenburg, Justin Dancer, Baiwei Lin, Jianwen A Feng, Daniel F Ortwine, David L Mobley, John D Chodera
Small molecule distribution coefficients between immiscible nonaqueuous and aqueous phases-such as cyclohexane and water-measure the degree to which small molecules prefer one phase over another at a given pH. As distribution coefficients capture both thermodynamic effects (the free energy of transfer between phases) and chemical effects (protonation state and tautomer effects in aqueous solution), they provide an exacting test of the thermodynamic and chemical accuracy of physical models without the long correlation times inherent to the prediction of more complex properties of relevance to drug discovery, such as protein-ligand binding affinities...
October 7, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27714494/role-of-r292k-mutation-in-influenza-h7n9-neuraminidase-toward-oseltamivir-susceptibility-md-and-mm-pb-gb-sa-study
#16
Jiraphorn Phanich, Thanyada Rungrotmongkol, Nawee Kungwan, Supot Hannongbua
The H7N9 avian influenza virus is a novel re-assortment from at least four different strains of virus. Neuraminidase, which is a glycoprotein on the surface membrane, has been the target for drug treatment. However, some H7N9 strains that have been isolated from patient after drug treatment have a R292K mutation in neuraminidase. This substitution was found to facilitate drug resistance using protein- and virus- assays, in particular it gave a high resistance to the most commonly used drug, oseltamivir. The aim of this research is to understand the source of oseltamivir resistance using MD simulations and the MM/PB(GB)SA binding free energy approaches...
October 6, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27714493/improved-pose-and-affinity-predictions-using-different-protocols-tailored-on-the-basis-of-data-availability
#17
Philip Prathipati, Chioko Nagao, Shandar Ahmad, Kenji Mizuguchi
The D3R 2015 grand drug design challenge provided a set of blinded challenges for evaluating the applicability of our protocols for pose and affinity prediction. In the present study, we report the application of two different strategies for the two D3R protein targets HSP90 and MAP4K4. HSP90 is a well-studied target system with numerous co-crystal structures and SAR data. Furthermore the D3R HSP90 test compounds showed high structural similarity to existing HSP90 inhibitors in BindingDB. Thus, we adopted an integrated docking and scoring approach involving a combination of both pharmacophoric and heavy atom similarity alignments, local minimization and quantitative structure activity relationships modeling, resulting in the reasonable prediction of pose [with the root mean square deviation (RMSD) values of 1...
October 6, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27709317/docking-undocking-combination-applied-to-the-d3r-grand-challenge-2015
#18
Sergio Ruiz-Carmona, Xavier Barril
Novel methods for drug discovery are constantly under development and independent exercises to test and validate them for different goals are extremely useful. The drug discovery data resource (D3R) Grand Challenge 2015 offers an excellent opportunity as an external assessment and validation experiment for Computer-Aided Drug Discovery methods. The challenge comprises two protein targets and prediction tests: binding mode and ligand ranking. We have faced both of them with the same strategy: pharmacophore-guided docking followed by dynamic undocking (a new method tested experimentally here) and, where possible, critical assessment of the results based on pre-existing information...
October 5, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27699554/molecular-docking-performance-evaluated-on-the-d3r-grand-challenge-2015-drug-like-ligand-datasets
#19
Edithe Selwa, Virginie Y Martiny, Bogdan I Iorga
The D3R Grand Challenge 2015 was focused on two protein targets: Heat Shock Protein 90 (HSP90) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4). We used a protocol involving a preliminary analysis of the available data in PDB and PubChem BioAssay, and then a docking/scoring step using more computationally demanding parameters that were required to provide more reliable predictions. We could evidence that different docking software and scoring functions can behave differently on individual ligand datasets, and that the flexibility of specific binding site residues is a crucial element to provide good predictions...
October 3, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27699553/on-the-fly-estimation-of-host-guest-binding-free-energies-using-the-movable-type-method-participation-in-the-sampl5-blind-challenge
#20
Nupur Bansal, Zheng Zheng, David S Cerutti, Kenneth M Merz
We review our performance in the SAMPL5 challenge for predicting host-guest binding affinities using the movable type (MT) method. The challenge included three hosts, acyclic Cucurbit[2]uril and two octa-acids with and without methylation at the entrance to their binding cavities. Each host was associated with 6-10 guest molecules. The MT method extrapolates local energy landscapes around particular molecular states and estimates the free energy by Monte Carlo integration over these landscapes. Two blind submissions pairing MT with variants of the KECSA potential function yielded mean unsigned errors of 1...
October 3, 2016: Journal of Computer-aided Molecular Design
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