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Journal of Computer-aided Molecular Design

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https://www.readbyqxmd.com/read/28102461/rnahelix-computational-modeling-of-nucleic-acid-structures-with-watson-crick-and-non-canonical-base-pairs
#1
Dhananjay Bhattacharyya, Sukanya Halder, Sankar Basu, Debasish Mukherjee, Prasun Kumar, Manju Bansal
Comprehensive analyses of structural features of non-canonical base pairs within a nucleic acid double helix are limited by the availability of a small number of three dimensional structures. Therefore, a procedure for model building of double helices containing any given nucleotide sequence and base pairing information, either canonical or non-canonical, is seriously needed. Here we describe a program RNAHelix, which is an updated version of our widely used software, NUCGEN. The program can regenerate duplexes using the dinucleotide step and base pair orientation parameters for a given double helical DNA or RNA sequence with defined Watson-Crick or non-Watson-Crick base pairs...
January 19, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28074360/exploring-the-stability-of-ligand-binding-modes-to-proteins-by-molecular-dynamics-simulations
#2
Kai Liu, Etsurou Watanabe, Hironori Kokubo
The binding mode prediction is of great importance to structure-based drug design. The discrimination of various binding poses of ligand generated by docking is a great challenge not only to docking score functions but also to the relatively expensive free energy calculation methods. Here we systematically analyzed the stability of various ligand poses under molecular dynamics (MD) simulation. First, a data set of 120 complexes was built based on the typical physicochemical properties of drug-like ligands. Three potential binding poses (one correct pose and two decoys) were selected for each ligand from self-docking in addition to the experimental pose...
January 10, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28070730/cadd-medicine-design-is-the-potion-that-can-cure-my-disease
#3
Eric S Manas, Darren V S Green
The acronym "CADD" is often used interchangeably to refer to "Computer Aided Drug Discovery" and "Computer Aided Drug Design". While the former definition implies the use of a computer to impact one or more aspects of discovering a drug, in this paper we contend that computational chemists are most effective when they enable teams to apply true design principles as they strive to create medicines to treat human disease. We argue that teams must bring to bear multiple sub-disciplines of computational chemistry in an integrated manner in order to utilize these principles to address the multi-objective nature of the drug discovery problem...
January 9, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28063067/dockingapp-a-user-friendly-interface-for-facilitated-docking-simulations-with-autodock-vina
#4
Elena Di Muzio, Daniele Toti, Fabio Polticelli
Molecular docking is a powerful technique that helps uncover the structural and energetic bases of the interaction between macromolecules and substrates, endogenous and exogenous ligands, and inhibitors. Moreover, this technique plays a pivotal role in accelerating the screening of large libraries of compounds for drug development purposes. The need to promote community-driven drug development efforts, especially as far as neglected diseases are concerned, calls for user-friendly tools to allow non-expert users to exploit the full potential of molecular docking...
January 6, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28054187/the-influence-of-hydrogen-bonding-on-partition-coefficients
#5
Nádia Melo Borges, Peter W Kenny, Carlos A Montanari, Igor M Prokopczyk, Jean F R Ribeiro, Josmar R Rocha, Geraldo Rodrigues Sartori
This Perspective explores how consideration of hydrogen bonding can be used to both predict and better understand partition coefficients. It is shown how polarity of both compounds and substructures can be estimated from measured alkane/water partition coefficients. When polarity is defined in this manner, hydrogen bond donors are typically less polar than hydrogen bond acceptors. Analysis of alkane/water partition coefficients in conjunction with molecular electrostatic potential calculations suggests that aromatic chloro substituents may be less lipophilic than is generally believed and that some of the effect of chloro-substitution stems from making the aromatic π-cloud less available to hydrogen bond donors...
January 4, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28028736/fast-h-drop-a-thirty-times-accelerated-version-of-h-drop-for-interactive-svm-based-prediction-of-helical-domain-linkers
#6
Tambi Richa, Soichiro Ide, Ryosuke Suzuki, Teppei Ebina, Yutaka Kuroda
Efficient and rapid prediction of domain regions from amino acid sequence information alone is often required for swift structural and functional characterization of large multi-domain proteins. Here we introduce Fast H-DROP, a thirty times accelerated version of our previously reported H-DROP (Helical Domain linker pRediction using OPtimal features), which is unique in specifically predicting helical domain linkers (boundaries). Fast H-DROP, analogously to H-DROP, uses optimum features selected from a set of 3000 ones by combining a random forest and a stepwise feature selection protocol...
December 27, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27995515/computational-chemistry-at-janssen
#7
Herman van Vlijmen, Renee L Desjarlais, Tara Mirzadegan
Computer-aided drug discovery activities at Janssen are carried out by scientists in the Computational Chemistry group of the Discovery Sciences organization. This perspective gives an overview of the organizational and operational structure, the science, internal and external collaborations, and the impact of the group on Drug Discovery at Janssen.
December 19, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27995514/the-need-for-scientific-software-engineering-in-the-pharmaceutical-industry
#8
Brock Luty, Peter W Rose
Scientific software engineering is a distinct discipline from both computational chemistry project support and research informatics. A scientific software engineer not only has a deep understanding of the science of drug discovery but also the desire, skills and time to apply good software engineering practices. A good team of scientific software engineers can create a software foundation that is maintainable, validated and robust. If done correctly, this foundation enable the organization to investigate new and novel computational ideas with a very high level of efficiency...
December 19, 2016: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27900588/modeling-informatics-at-vertex-pharmaceuticals-incorporated-our-philosophy-for-sustained-impact
#9
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
#10
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/27830428/empowering-pharmacoinformatics-by-linked-life-science-data
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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/27677749/absolute-binding-free-energy-calculations-of-cbclip-host-guest-systems-in-the-sampl5-blind-challenge
#17
Juyong Lee, Florentina Tofoleanu, Frank C Pickard, Gerhard König, Jing Huang, Ana Damjanović, Minkyung Baek, Chaok Seok, Bernard R Brooks
Herein, we report the absolute binding free energy calculations of CBClip complexes in the SAMPL5 blind challenge. Initial conformations of CBClip complexes were obtained using docking and molecular dynamics simulations. Free energy calculations were performed using thermodynamic integration (TI) with soft-core potentials and Bennett's acceptance ratio (BAR) method based on a serial insertion scheme. We compared the results obtained with TI simulations with soft-core potentials and Hamiltonian replica exchange simulations with the serial insertion method combined with the BAR method...
January 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27658802/overview-of-the-sampl5-host-guest-challenge-are-we-doing-better
#18
Jian Yin, Niel M Henriksen, David R Slochower, Michael R Shirts, Michael W Chiu, David L Mobley, Michael K Gilson
The ability to computationally predict protein-small molecule binding affinities with high accuracy would accelerate drug discovery and reduce its cost by eliminating rounds of trial-and-error synthesis and experimental evaluation of candidate ligands. As academic and industrial groups work toward this capability, there is an ongoing need for datasets that can be used to rigorously test new computational methods. Although protein-ligand data are clearly important for this purpose, their size and complexity make it difficult to obtain well-converged results and to troubleshoot computational methods...
January 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/27638809/the-sampl5-host-guest-challenge-computing-binding-free-energies-and%C3%A2-enthalpies-from-explicit-solvent-simulations-by-the-attach-pull-release-apr-method
#19
Jian Yin, Niel M Henriksen, David R Slochower, Michael K Gilson
The absolute binding free energies and binding enthalpies of twelve host-guest systems in the SAMPL5 blind challenge were computed using our attach-pull-release (APR) approach. This method has previously shown good correlations between experimental and calculated binding data in retrospective studies of cucurbit[7]uril (CB7) and β-cyclodextrin (βCD) systems. In the present work, the computed binding free energies for host octa acid (OA or OAH) and tetra-endo-methyl octa-acid (TEMOA or OAMe) with guests are in good agreement with prospective experimental data, with a coefficient of determination (R(2)) of 0...
January 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28013427/collaborating-to-improve-the-use-of-free-energy-and-other-quantitative-methods-in-drug-discovery
#20
Bradley Sherborne, Veerabahu Shanmugasundaram, Alan C Cheng, Clara D Christ, Renee L DesJarlais, Jose S Duca, Richard A Lewis, Deborah A Loughney, Eric S Manas, Georgia B McGaughey, Catherine E Peishoff, Herman van Vlijmen
In May and August, 2016, several pharmaceutical companies convened to discuss and compare experiences with Free Energy Perturbation (FEP). This unusual synchronization of interest was prompted by Schrödinger's FEP+ implementation and offered the opportunity to share fresh studies with FEP and enable broader discussions on the topic. This article summarizes key conclusions of the meetings, including a path forward of actions for this group to aid the accelerated evaluation, application and development of free energy and related quantitative, structure-based design methods...
December 2016: Journal of Computer-aided Molecular Design
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