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Publication quality molecular images Hardware acceleration and stereo support Ligand-based design: Sketching and fragment building tools Manual pharmacophore generation Macromolecule design: View and edit molecular sequences Superimpose and edit protein structures ActiveX Control: Visualize and interact with molecules in Microsoft Office documents and Internet Explorer
Capture key scenes in the Molecule Window and save them to share with colleagues. Sequence window: Handle and align sequences with multiple chains (e.g., Antibodies). In Chain view, you can swap chain order and align independently.
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MOLECULAR VISUALIZATION
The Visualizer provides functionality for visualizing, analyzing, and sharing biological and chemical data. It allows you to view molecular data from multiple perspectives by providing the options to view data through 3D structures, sequences, and data tables.
New in 3.0! Shading and Depth Blur: Generate ambient and Interact with and rapidly analyze your data using the Molecule Window, which supports visualization, data table and hierarchy views of the data. Control lighting, depth cueing and graphics quality to enhance View and manipulate publication quality 3D molecular structures ranging from atomic-level to large macromolecular complexes. Generate a variety of charts such as 3D point plots, heat maps and Ramachandran plots to analyze your data. Scroll through sets of molecules with the help of navigation keys, easily managing complex libraries. Manage large data sets with ease using the integrated browser in the Molecule window. Visualize structures in different colors by property of interest. Augment 3D structure appearance with multisided surfaces Study proteins and nucleic acids using the Sequence Window, enabling the viewing and comparison of the sequences, alignments and annotations. and isosurfaces and apply material appearances (e.g., metallic or plastic) to create graphics that are polished, professional and ready for presentation. Export jpg, .jpeg, .bmp and .png files.
Supported Graphics Cards The following cards are supported with DS3.0. Where applicable, hardware acceleration and hardware stereo [St] is supported: ATI FireGL V3600, V5600, V7600[St], V7700[St], V8600[St] ATI FirePro V3700, V5700, V8700[St] NVidia Quadro FX 570, 580, 1800, 3800[St], 4600[St], 4700[St], 4800[St], 5600[St], 5800[St]
visualization.
Supported Operating Systems Windows and Linux compatible: Windows: XP, Vista (32bit), Windows 7 (64 bit) Linux: Red Hat 4 (32/64 bit), Red Hat 5 (64 bit) and SUSE 10 (64 bit)
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USER FRIENDLY
Enhanced client usability: Access to DS science (tools and protocols) has been reorganized to reflect the most common workflows. The result is a major improvement in the accessibility and discoverability of science available in Discovery Studio 3.0. Accelrys .dsv file: Save your molecules exactly as seen, including display styles, surfaces, text labels and Sequence Windows in the updated .dsv file format.
Calculate solvent accessibility, RMSD and predict secondary structures within a single environment.
CUSTOMIZATION
DS Visualizer can be customized to suit your workflow: Add toolbars and buttons, shortcut keys and modify default parameter settings. Use autohide to hide dockable windows and maximize the workspace for visualization. Undock tabbed windows and manage them outside the main application window. Simplify workflows by dragging and dropping files from your desktop or file explorer. Use Perl scripting to automate molecular manipulation workflows.
ActiveX Control * DS Visualizer ActiveX Control is an integratable viewer that provides interactive 3D visualization of small molecules, proteins, nucleic acids, crystal structures and pharmacophore models. Insert interactive molecular graphics into a Microsoft PowerPoint presentation to create powerful presentations with the ability to manipulate (rotate and zoom) and analyze data. Add custom buttons or right-click options to modify the chemistry and display of the data during a presentation. Enhance web pages with dynamic 3D molecular visualization.
* DS Visualizer ActiveX Control is an independent product and is available as a separate free download with DS Visualizer. It does not require the installation of DS Visualizer
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Licensed: With the addition of a client license, all available features are exposed in the client interface, without need to upgrade or reinstall: Connect to Pipeline Pilot, enabling access to licensed scientific functionality including, macromolecule design, ligand-based design, virtual screening, ADMET prediction and more. View and customize protocols, share them with colleagues, and run them from the Discovery Studio or Pipeline Pilot client.
Type
Feature
Supported on Windows 7, Vista, XP and Red Hat Linux 4.0, 5.0, and SUSE 10 New! Welcome Page with quick access to files and information Custom short-cut keys and toolbars
Free
Licensed
Client
Perl scripting Files explorer view Table browser for small molecule data sets Protocols, jobs, parameter help, and tools explorer views Unified Molecule Window with 3D view and associated hierarchy and data table views Create multiple sided surfaces and isosurfaces for enhanced molecular visualization Access to charts, including 2D (line and point), 3D point plots, heat maps, histograms and more New! Force field typing for generation of parameter and topology files used in molecular simulations New! Constraints and restraints setup for molecular simulations New! Molecular Dynamics Simulations Superimpose structures based on tethers, residues, sequence alignment New! Superimpose structures based on molecular overlay functionality RMS calculations Transformation matrix and center of geometry Calculate basic molecular properties New! Launch protocols from the toolbar Molecular Builders for peptides and nucleic acids New! Access to Side-Chain Rotamer conformations and interaction analysis New! Structure superimposition by alignment New! Structure and Sequence alignment Support for a variety of sequence-structure formats Sequence windows Secondary structure prediction
General
Protein
Graphing functionality, including Ramachandran and contact plots New! Contour and display X-ray electron density maps 3D pointer to navigate structures and place 3D labels New! Basic tools to edit X-ray structures New! Build and refine X-ray Structure Place and refine X-ray Ligand Structure Dendrogram toolbar Access protocols to prepare, minimize and refine protein structures, generate protein reports and validate protein structures View two-dimensional chemistry Sketch 3D molecules Modify or build custom 3D small molecules using a tool panel of pre-defined fragments New! Type atoms to prepare molecules prior to energy calculations New! Modify conformations using a tool panel to perform Dreiding minimization, coordinate kick, and torsion kick Analyze molecular dynamics trajectories based on RMSD, close contacts and hydrogen bonds
Ligand Design
Calculate molecular energy and perform energy minimization using CHARMm force field Analyze complexes New! Monitor Pi-Pi, Cation-Pi, and Sigma-Pi interactions Generate 2D receptor-ligand interaction plots New! Define, display and edit ligand binding sites New! Manually generate pharmacophore (Catalyst) queries Automatically generate and analyze pharmacophore models
Note: Running protocols does require additional product licensing from Accelrys.
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2011 Accelrys Software Inc. All brands or product names may be trademarks of their respective holders.
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Discovery Studio
Accelrys Science
Search for homologs using sequence similarity
Elucidate biological function by searching for homologs using sequence similarity methods with DS Sequence Analysis
New functionality in the area of Antibody Modeling: a pre-compiled CDR information data le is used to automate the process of CDR identication and annotation. A sequence alignment le of the best aligned hits is provided for automated loop grafting of the CDR regions. Access to the routinely used BLAST and PSIBLAST algorithms, to search real time databases installed behind your rewall or at the NCBI Supporting tools that perform Phylogenetic and Evolutionary Trace analysis help you create dendrograms using hierarchical clustering methods
A xylanases hydroxylases protein model created using the build model protocol from DS MODELER from 3 protein structure templates (1b30, 1gom and 1ta3) was veried using the Prole-3D verify method. Blue (high verify scores) and red (low verify scores) residues in the protein ribbon display correspond to valid and invalid regions, respectively.
The gold-standard engine for automatically generating high quality homology models using spatial restraints A new method for improving the sequence alignment in low homology cases by using the SALIGN method which uses sequence prole information. Loop modeling using the DOPE energy function. The DOPE function represents an improved energy function from potentials extracted from on a library of non-redundant high resolution crystal structures, and has been shown to provide higher quality models Inclusion of important ligand information during the homology modeling building process Creation of mutants for site directed mutagenesis studies
Use DS MODELER to quickly construct high quality alignments and build a collection of homology models for further analysis. Further your research with modern molecular modeling in silico based methods by using DS MODELER in conjunction with simulations and structure based design tools in Discovery Studio.
Discovery Studio
Loop renement (protocol) and protein validation (Protein Health tool panel) was performed on a protein model generated from a sequence with unknown structure. The stick representation of the best loop is shown above.
Discovery Studio
A brand new algorithm which estimates the protonation state of titratable amino acids within the protein quickly and accurately. This method is based on the Generalized Born model for charge estimation, and accurately predicts pKs, pH titration curves, and overall energy of folding. This new tool has been long overdue and will certainly enable users to study macromolecular modeling in a brand new way.
party applications for an innitely extensible virtual discovery platform. Well-tested applications including CHARMm, MODELER, Catalyst, and others are accessible in the graphical DS environment, the Pipeline Pilot scripting and protocol development environment, and from command-line prompts. Parallel Computing The DS 2.0 platform is optimized to take advantage of grid and cluster computing as well as multi-core processors to rapidly process large tasks.
Discovery Studio
References:
1. 2. 3. 4. 5. 6. 7. 8. 9. Brooks,B.R.,Bruccoleri,R.E.,Olafson,B.D.,States,D.J.,Swaminathan,S.,and Karplus, M., CHARMM: A program for macromolecular energy, minimization, and dynamics calculations, J. Comput. Chem., 1983, 4, 187-217. Chen R, Li L, Weng Z, ZDOCK: An Initial-stage Protein-Docking Algorithm. Proteins, 2003, 52, 80 87 Eswar, N., Eramian, D., Webb, B., Shen, M., Sali. A. Protein Structure Modeling With MODELLER. Current Protocols in Bioinformatics John Wiley & Sons, Inc., 2006, Supplement 15, 5.6.1-5.6.30 Li L, Chen R (joint rst authors), Weng Z, RDOCK: Renement of Rigid-body Protein Docking Predictions. Proteins, 2003, 53, 693707 Marti-Renom, M. A., Madhusudhan, M. S. and Sali, A., Alignment of protein sequences by their proles, Protein Science, 2004, 13, 10711087 Morea, V., Lesk, A., and Tramontano, A. Antibody Modeling: Implications for Engineering and Design, METHODS, 2000, 20, 267. Sali, A., Pottertone, L., Yuan, F., van Vlijmen, H., and Karplus, M., Evaluation of comparative protein modeling by MODELLER, Proteins, 1995, 23, 318. Spassov, V., Yan, L. and Flook, P. The Dominant Role of Side-chain Backbone Interactions in Structural Realization of Amino-acid Code. ChiRotor: a Side-chain Prediction Algorithm Based on Side-chain Backbone Interactions, Protein Science, 2007 Spassov, V., Yan, L., and Flook, P., LOOPER: A Molecular Mechanics Based Algorithm for Protein Loop Prediction. Manuscript in preparation.
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Discovery Studio
Easy-to-use tools for building and modifying proteins, peptides and nucleic acids
Features
Building and Editing Macromolecular Structures
With DS Biopolymer, you can rapidly build and modify peptides, proteins and nucleic acid (DNA and RNA) structures.
Discovery Studio
You can further modify your structure with tools for ligating two nucleic acid molecules together, and for adding caps and primes to the 5 end.
The total electrostatic energy for a set of charges, including the total solvation energy of each charge and between charges, is accounted for.
Electrostatic Analysis
DelPhi, a powerful and versatile PoissonBoltzmann electrostatics simulation engine for calculating electrostatic potentials and solvation energies of both small- and macro- molecules, is available within DS Biopolymer. Shape and electrostatic properties often determine the function of small- and macro-molecules. DS Biopolymer provides sophisticated tools for examining such properties, without resorting to inappropriate dielectric models or including explicit solvent. The effects of the presence or absence of solvent are taken into account, both of which may result in a different calculation for the electrostatic potential of a macromolecule.
DelPhi calculations can reproduce experimental results where Colulombic models fail.
The powerful visualization capabilities of Discovery Studio allow you to view electrostatic potential grids generated by DelPhi as solid, triangle or quad mesh, or volume isosurfaces. This enables you to evaluate the shape and the extent of electrostatic potentials in and around a protein.
Required Software
DS Visualizer Pro Enterprise (or DS Visualizer Pro with Pipeline Pilot Server)
The electrostatic potential changes that occur upon mutation of protein residues can be studied with DS Biopolymer
The Poisson-Boltzmann electrostatic potentials displayed on the protein surface indicated areas of positive (blue), neutral (white) and negative (red) regions.
By treating macromolecules and solvent as separate dielectric domains, DelPhi can rigorously account for the effect of molecular shape on solvation, substrate binding, and electrostatic interactions.
References:
1. 2. 3. Honig, B., Sharp, K., Yang, A.S., J. Phys. Chem., 1993, 97, 1101. Nicholls, A., and Honig, B., J. Comp. Chem., 1991, 12, 435. Sharp, B., Nichols, A., Friedman, R., and Honig, B., Biochemistry, 1991, 30, 9686.
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A comprehensive suite of solutions for simulating macromolecules, ligands, cofactors, membrane surfaces, and metal ions for drug discovery research
Discovery Studio
Accelrys Science
Fast and Accurate Protein Ionization and pK Estimation (New in Discovery Studio 2.0)
Improve docking accuracy, protein-ligand binding energy estimation, and the stability and accuracy of protein simulations signicantly by using a GBORN-based pK estimation algorithm in DS CHARMm. The method is faster and more accurate than existing methods, taking only a few minutes per protein structure1. Use this method to explore the pH-stability of your protein, and to detect active site residues during early stages of drug discovery.
Leverage the power of CHARMm to perform small molecule docking using CDOCKER.
Minimize pre-docked poses and adjacent receptor atoms/residues using DS CHARMm or DS CHARMm Lite.
Sample receptor exibility during docking using CHARMm-based methods for side-chain and loop-sampling/renement. The method is available either within the highly accurate receptor-exible docking program, DS Flexible Docking, or as individual components.
Further rene the accuracy of docked poses with physics-based scoring functions available with DS CHARMm (MM-PBSA, MMGBSA and LIE).
Entropy Estimation for Accurate MM-PBSA/ MM-GBSA Scoring (New in Discovery Studio 2.0)
Increase the accuracy of physics-based scoring such as MM-PBSA and MM-GBSA using several DS CHARMm-based methods for estimating the translational, rotational and vibrational entropies of protein-ligand systems.
Discovery Studio
Integrated solution The DS 2.0 environment, based on the Pipeline Pilot operating platform, integrates simulation with protein modeling, pharmacophore analysis, and virtual screening as well as third-party applications for an innitely extensible virtual discovery platform. Industry-validated applications including CHARMm, MODELER, Catalyst, and others are accessible in the graphical DS environment, the Pipeline Pilot scripting and protocol development environment, as well as from the command prompt. Parallel Computing All available CHARMm-based docking and scoring experiments in Discovery Studio have been optimized to take advantage of cluster computing as well as multi-core processors to rapidly process large tasks. Fine-grain parallelization is available for CHARMm-based molecular dynamics using new HP-MPI libraries.
Figure 1: A powerful set of analysis tools allows you to calculate interaction energies between arbitrary subsets of atoms (A); monitor the formation and breakage of specic hydrogen bonds during simulation (B); and calculate pairwise C RMS deviations between frames in the trajectory (C).
Discovery Studio
Validation
2005 CHARMm-based MM-PBSA scoring of docked poses correctly identied the proper binding mode of Chk1 inhibitors that were previously missed by docking studies. This study shows that early scoring of docked poses using CHARMm can results in signicant savings in time and resources.2 2007 A CHARMm-based simulation study of the mechanism by which a biofuel-synthesizing enzyme breaks down cellulose. This study shows how CHARMm-based research can be brought to bear in the increasingly critical eld of bio-fuel synthesis.3 2007 A publication that describes the method and validation results on a CHARMm-based protein side chain sampling and renement algorithm called ChiRotor. ChiRotor and its variants are at the heart of the new Flexible Docking method4 in Discovery Studio.5 2007 A paper that describes the accurate and fast CHARMm-based loop sampling algorithm, Looper. Looper has been shown to perform better than existing loop-sampling methods, and can be easily integrated into the Discovery Studio Flexible Docking method.6
References:
1. 2. 3. 4. 5. 6. Spassov, V. et al. A fast and accurate CHARMm-based protein-ionization and pK prediction method, in preparation. Foloppe, N. et al. Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand afnity J. Med. Chem., 2005, 48(13), 4332-45. Nimlos, MR at al. Molecular modeling suggests induced t of Family I carbohydrate-binding modules with a broken-chain cellulose surface, Protein Eng. Des. Sel., 2007, 20(4), 179-87. URL to Structure Based Design Datasheet Spassov, VZ, et al. The dominant role of side-chain backbone interactions in structural realization of amino acid code. ChiRotor: a side-chain prediction algorithm based on side-chain backbone interactions, Protein Sci., 2007 , 16(3), 494-506. Spassov, VZ, et al. LOOPER: A Molecular Mechanics Based Algorithm for Protein Loop Prediction, Accepted, Protein Engineering, Design and Selection
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Discovery Studio
Industry-validated de novo ligand design and optimization CHARMm-based docking and scoring of small molecules
Choose from methods optimized for performance or accuracy, as you proceed from lead discovery to lead optimization
Discovery Studio can streamline the entire drug discovery process with its many validated tools to dock and score small molecules, and to perform de novo design of lead compounds. These tools are further integrated with industry-standard protein modeling and pharmacophore tools within a single, integrated environment.
Accelrys Science
A Rational Approach to Flexible Docking (New in Discovery Studio 2.0)
Leverage the proven strength of CHARMm and efcient feature-based docking in the new DS Flexible Docking method that shows stellar performance across a variety of receptor targets1. Employ a realistic approach to exible docking in which the docking of small molecules is inuenced by existing low-energy conformations of side chains in the active site.
feature-based DS LibDock. The two methods have been shown to complement each other and thus ensure maximum coverage of protein families3 Further optimize docking results with CDOCKER, a CHARMm-based docking method that has been shown to give highly accurate docked poses4.
Fast and Accurate Protein Ionization and pK Estimation (New in Discovery Studio 2.0)
Improve docking accuracy and protein-ligand binding energy estimation by using a fast GBORNbased pK estimation algorithm in DS CHARMm.
Discovery Studio
Figure 1 Top-scoring pose from a cross-docking experiment (ligand from PDB ID 3ert docked into the 1err receptor) using the rational DS Flexible Docking method. The ligand induces the 3ert conformation of side chains in the 1err binding pocket.
Integrated solution The DS 2.0 environment, based on the Pipeline Pilot operating platform, integrates protein modeling, pharmacophore analysis, and virtual screening as well as thirdparty applications for an innitely extensible virtual discovery platform. Industry-validated applications including CHARMm, MODELER, Catalyst, and others are accessible in the graphical DS environment, the Pipeline Pilot scripting and protocol development environment, as well as from the command prompt. Parallel Computing All available docking and scoring experiments in Discovery Studio have been optimized to take advantage of cluster computing as well as multi-core processors to rapidly process large tasks. Fine-grain parallelization is available for CHARMm-based experiments using new HP-MPI libraries.
Discovery Studio
2007 Docking validation against the new AstexDiverse dataset shows that CDOCKER docks 94% of ligands to within 2 of X-ray pose, while LibDock docks 91% to within 2 .6 2006 Large-scale docking validation from GSK showed that LigandFit gave better enrichment of actives than all other docking programs (including Glide, FlexX, GOLD, and others) for some receptor targets.7 2007 In this study, a combined Catalyst Shape and hypothesis query was built from a KDR kinase structure and inhibitors. A database search based on Catalyst pharmacophore model identied 39 compounds that were docked into the receptor using LigandFit. The nal hit from the docking experiment inhibited KDR kinase phosphorylation in an in vitro cellular assay.8 2007 Docking validation of CDK2 inhibitors using LigandFit, GOLD and FlexX shows that, ...When predicting activities by scoring programs, the combination of docking with LigandFit/plp and scoring with LIGSCORE1_CFF gave the best correlation coefcient (r=0.60) between experimental pIC50 values and top-ranked rescores of 30 poses of each compound.9
Validation
2007 Cross-docking experiments with the new receptor-exible docking method DS Flexible Docking on 21 receptors spanning diverse protein families shows consistently accurate results with all ligands docked within a 2 RMSD to X-ray poses.
1
References:
1. 2. 3. 4. 5. 6. 7. 8. 9. Koska, J. et al. A Fully Automated Molecular Mechanics Based Induced Fit Protein-Ligand Docking Method. Submitted,, J. Med. Chem (manuscript in preparation). Warren G.L., et al. A critical assessment of docking programs and scoring functions, J. Med. Chem., 2006, 49, 5912. Rao et al, J. Chem. Inf. Model (submitted) Erickson et al. J Med Chem. 2004, 47(1), 45-55. For an Application Note covering De Novo Design and CHARMm-based MM-GBSA scoring, visit http://www.accelrys.com/ reference/cases/studies/de_novo_workow_app_note.pdf Risal, D. et al. Docking validation against the AstexDiverse Dataset: CDOCKER and LibDock are optimized for virtual High Throughput Screening applications. (in preparation) Warren, GL et al. A critical assessment of docking programs and scoring functions, J. Med. Chem. 2006, 49(20), 5912-31. Yu, H. et al. The discovery of novel vascular endothelial growth factor receptor tyrosine kinases inhibitors: pharmacophore modeling, virtual screening and docking studies Chem Biol Drug Des., 2007, 69(3), 204-11 Sato, H. Et al. Prediction of multiple binding modes of the CDK2 inhibitors, anilinopyrazoles, using the automated docking programs GOLD, FlexX, and LigandFit: an evaluation of performance, J Chem Inf Model., 2006, 46(6), 2552-62.
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Discovery Studio
An extensive set of QSAR descriptors and seamless integration of additional data into QSAR models
these descriptors and advanced modeling and visualization methods in an easy-to-use environment. DS Library Design applies these capabilities together with similarity and diversity methods specically tailored for chemical library design to guide optimal library design.
Accelrys Science
Extensive Set of Proven Descriptors to Effectively Capture Critical Properties in DS QSAR
Describe billions of structural features present in molecules using Extended Connectivity Fingerprint (ECFP) descriptors. Access traditional descriptors for basic chemical features, physical properties, ADME characteristics, and experimental data. Optionally add VAMP and DMol3 for efcient implementations of semi-empirical quantum mechanical methods to rapidly calculate highly accurate electronic properties for thousands of candidate compounds.
Prioritize chemical libraries using readily accessible metrics for diversity, similarity, and hundreds of physical and chemical properties.
Interactively customize chemical libraries to optimize the value of each member of a selected set of compounds.
Discovery Studio
Figure 1 An interactive Multiple Linear Regression QSAR model showing correlation between actual and predicted activities. Selection between the plot and table are synchronized.
Integrated solution The DS 2.0 environment, based on the Pipeline Pilot open operating platform, integrates protein modeling, pharmacophore analysis, and virtual screening as well as thirdparty applications for an innitely extensible virtual discovery platform. Well-tested applications including CHARMm, MODELER, Catalyst, and others are accessible in the graphical DS environment, the Pipeline Pilot scripting and protocol development environment and from command-line prompts. Parallel computing The DS 2.0 platform is optimized to take advantage of grid and cluster computing as well as multi-core processors to rapidly process large tasks.
Discovery Studio
Figure 2 An interactive 3D plot of the rst three principal components from a Principal Component Analysis using several molecular descriptors as input. The plot can optionally be colored by a specied property.
Customer support Accelrys customers report a 98% satisfaction rate with our support team. Committed to innovation With over 100 Ph.D.s in the eld working daily with researchers in industry and academia, Accelrys is committed to delivering cutting-edge technology to our customers World leading scientic advisors Through our in-licensing agreements, partnerships, and scientic advisors many of the worlds foremost experts in computational drug design are involved in setting our direction.
References:
1. 2. 3. Cheg, D. et al., Relationship of quantitative structure and pharmacokinetics in uoroquinolone antibacterials, World J Gastroenterol, 2007, 13(17), 2496-503 Jiang FC., et al., The design and synthesis of 2-aminothiazole derivatives and their inhibitory activity on apoptosis, Yao Xue Xue Bao, 2006, 41(8), 727-34 Bednarczyk D., et al., Inuence of molecular structure on substrate binding to the human organic cation transporter, hOCT, Mol. Pharmacol, 2003, 63(3), 489-98
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Discovery Studio
Add value to drug discovery in a whole new way using activity proling
new pharmacophore tools for fragment-based design, activity proling and structure-based design.
Accelrys Science
Experimentally Accurate Pharmacophore Models
Create optimal ligand-based pharmacophore models using two methods in DS Catalyst Hypothesis:
Common feature alignment can be especially useful when the mode-of-action for a series of compounds is unknown. Activity-based pharmacophore models correlate binding activity with specic features to optimize the model based on the known data.
Structure based pharmacophore allows you to elucidate essential features representing binding interactions from known or putative protein active site. Easily merge shape and pharmacophore features into a more selective query.
Automatically generate structure-based pharmacophore models using DS Catalyst SBP that can easily be combined with ligandbased hypotheses. Features:
Intuitive graphical interface for creating and editing customized pharmacophore features. Easily add excluded volumes observed from protein structures or derived from ligand data to better correlate the model with the steric constraints imposed by the target. Cluster features automatically with an interactive dendrogram for easy feature selection.
Discovery Studio
Integrate information-rich geometric descriptors to accelerate and add chemical diversity to pharmacophore queries using DS Catalyst Shape.
Quickly and easily create 3D databases of energetically accessible conformations of extensive compound collections with DS Catalyst DB Build.
Rapidly screen hundreds of thousands of potential drug leads with DS Catalyst DB Search using pre-designed or highly customized queries.
Interactive dendrogram for easy clustering and selection of pharmacophore points
Cutting edge Accelrys is incorporating new scientic tools to meet current pharmaceutical needs and we are continuously working with our customers to plan for future innovation. Easy to use interface DS 2.0 provides a powerful and intuitive user interface. DS 2.0 can be deployed either in a complete standalone solution for individual modelers or as part of an enterprise-level client server installation for easier protocol sharing and administration in larger modeling groups. Integrated solution The DS 2.0 environment, built on the SciTegic Pipeline Pilot open operating platform, integrates protein modeling, pharmacophore analysis, and virtual screening as well as third-party applications for an innitely extensible virtual discovery platform. Well-tested applications including CHARMm, MODELER, Catalyst, and others are accessible in the graphical DS environment, the Pipeline Pilot scripting and protocol development environment, and from command-line prompts. Parallel computing The DS 2.0 platform is optimized to take advantage of grid and cluster computing as well as multi-core processors to rapidly process large tasks.
Discovery Studio
References:
1. 2. 3. Purushottamachar P., et al., First pharmacophore-based identication of androgen receptor down-regulating agents: discovery of potent anti-prostate cancer agents, Bioorg Med Chem., 2007, 15, 3413-21. Taha MO, et al., Discovery of new potent human protein tyrosine phosphatase inhibitors via pharmacophore and QSAR analysis followed by in silico screening, J Mol Graph Model., 2007, 25, 870-84. Agraotis, DK, et al., Conformational Sampling of Bioactive Molecules: A Comparative Study, J. Chem. Inf. Model., 2007, 47(3), 1067-86
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Discovery Studio
ADMET Descriptors in Discovery Studio include models for intestinal absorption, aqueous solubility, blood brain barrier penetration, plasma protein binding, cytochrome P450 2D6 inhibition, and hepatotoxicity. With these advanced predictive tools, you can optimize your drug discovery efforts and gain critical insight early on to avoid expensive reformulation later.
The pattern recognition model underlying the method is based on calculations of logP,3 and polar surface area and is derived from a training set of 199 well-absorbed molecules with actively transported molecules removed. ADMET Aqueous Solubility: Predicts the solubility of each compound in water at 25C and reports the predicted solubility and a ranking relative to the solubilities of a set of drug molecules. A genetic partial least squares method was used to derive the model based on a training set of 784 compounds with experimentally measured solubilities. ADMET Blood Brain Barrier: Predicts the blood brain barrier penetration of a molecule, dened as the ratio of the concentrations of solute (compound) on the both sides of the membrane after oral administration, and reports the predicted penetration as well as a classication of penetration level. The model combines a condence ellipse derived from over 800 compounds classied as CNS therapeutics, and a robust regression model based on 120 compounds with measured penetration, to predict penetration values for those molecules falling within the condence ellipse. ADMET Plasma Protein Binding: Predicts whether or not a compound is likely to be highly bound to carrier proteins in the blood. Predictions are based on the similarity between the candidate molecule and two sets of marker molecules; one used to ag binding at a level of 90 percent or greater and the other at 95 percent or greater. Binding
ADMET Descriptors
ADMET Descriptors perform computational prediction based solely on the chemical structure of the molecule. Included are six models that provide a comprehensive analysis of ADMET characteristics: ADMET Absorption: Predicts Human Intestinal Absorption (HIA) after oral administration and reports a classication of absorption level .
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Discovery Studio
levels predicted by the marker similarities are modied according to conditions on calculated logP. ADMET CYP2D6 Binding: Predicts cytochrome P450 2D6 enzyme inhibition and reports whether or not a compound is likely to be an inhibitor, as well as a probability estimate for the prediction. Predictions are based on an ensemble recursive partitioning model of a training set of 100 compounds with known CYP2D6 inhibitions. ADMET Hepatotoxicity: Predicts the occurrence of dose-dependent human hepatoxicity. Compounds are classied as either toxic or non-toxic, and a condence level indicates the models likely accuracy. Predictions are based on an ensemble recursive partitioning model of 382 training compounds known to exhibit liver toxicity or to trigger dose-related elevated aminotransferase levels in more than 10 percent of the human population. DS Visualizer Pro Enterprise (or DS Visualizer Pro with Pipeline Pilot Server) These ADMET Descriptors in Discovery Studio can allow you to gain critical insight to help you make well-informed, smart decisions during drug development. Youll be able to invest your time wisely, focusing on compounds with much higher probabilities for success in ADMET testing.
Plot of Polar Surface Area (PSA) vs. LogP for a sample compounds from the the World Drug Index (WDI) database showing the 95% and 99% condence limit ellipses corresponding to the Blood Brain Barrier and Intestinal Absorption models.
Required Software
References:
1. 2. 3. Prentis, R.A., Lis, Y., and Walker, S.R., Br. J. Clin. Pharmac., 1988, 25, 387-396. Egan,W. J., Merz, K.M., Jr., and Baldwin, J. J., J. Med. Chem., 2000, 43, 3867-3877. Ghose, A. K.,Viswanadhan, V. N., Wendoloski, J. J., J. Phys. Chem., 1998, 102, 3762-3772.
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Discovery Studio
Many regulatory agencies use SAR. The US Environmental Protection Agency (EPA) has indicated its support for the use of alternative testing technologies. In particular, the Agency acknowledged that it actively encourages companies to consider alternatives such as SAR (because) SAR approaches can be used both to help dene categories and to help assess individual chemicals.
Discovery Studio
Various tasks, such as accessing a user specied sub-model, outputting result tables for reporting feature similarities and descriptor contribution to toxicity, can be enabled from the command line as well.
Platform requirements:
Windows 2000 Windows XP Red Hat Linux WS3.0 Red Hat Linux WS4.0
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ApsaraGG
http://accelrys.com/products/discovery-studio/...
Windows
x86 (32-bit)
Microsoft Windows XP Professional, SP2 and SP3 Microsoft Windows 2003 Server, SP1 and SP2 Microsoft Windows Vista, Business and Enterprise Editions, SP1
x86-64 (64-bit)
Microsoft Windows Server 2008 On Windows systems, Administration privileges are required. 64-bit Windows support is provided using 32-bit binaries.
Linux
x86 (32-bit)
Red Hat Enterprise Linux 4.0, Updates 4-7
x86-64 (64-bit)
Red Hat Enterprise Linux 4.0, Updates 4-7 Red Hat Enterprise Linux 5, Retail, Updates 1-2 SUSE Linux Enterprise 10, SP1 and SP2 Discovery Studio is optimized for the GNOME Desktop. The root password is not necessary for Linux installations. 64-bit support is provided using 32-bit binaries.
Hardware Requirements
Intel compatible processor running at 2 GHz or greater 2 GB RAM Disk space: Up to 3.9 GB available for a standard install Graphics card: NVIDIA Quadro FX or ATI FireGL cards (see Supported Graphics Cards and Drivers) A DVD-ROM drive Note. The total hard disk space required for installation can vary between 600 MB and 4.4 GB, depending on the components selected for installation. Additional space is required if system updates are necessary or additional databases are installed (which may use up to 32 GB of disk space).
Graphics Cards
The Discovery Studio Client is optimized to provide hardware-accelerated graphics with supported NVIDIA and ATI hardware when certified drivers are installed. 3D stereo support is also available with hardware that provides quad-buffered OpenGL stereo capabilities.
NVIDIA
Operating System Graphics Card Driver
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ApsaraGG
http://accelrys.com/products/discovery-studio/...
Microsoft Windows XP Microsoft Windows Vista Red Hat Enterprise Linux 4.0 Red Hat Enterprise Linux Desktop 5 (x86-64) SUSE Linux Enterprise 10 (x86-64)
540 570 1400 3700 (a) 540 570 1400 3700 (a)
182.46
ATI
Operating System Microsoft Windows XP Microsoft Windows Vista Red Hat Enterprise Linux WS 4.0 Red Hat Enterprise Linux Desktop 5 (x86-64) SUSE Linux Enterprise 10 (x86-64) Graphics Card FireGL V3600 FireGL V5100 FireGL V5600 FireGL V7200 FireGL V7600 Driver
8.583
(a) Activation of hardware stereo can be intermittent with this platform, card and driver combination. This is a known issue with all OpenGL applications. If you anticipate extensive use of stereo graphics, NVIDIA recommends that a stereoscopic override (91.31) be installed. More information on NVIDIA's 3D Stereo technology can be found here .
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