Discovery Studio Proposal

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Molecular visualization is a key aspect of the analysis and communication of molecular modeling

studies. It enables a mechanistic understanding of a molecule’s structure to be visualized, so that key

insights can be shared between computational modeling experts and collaborating team members.

With the release of Discovery Studio 3.0, a single application provides access to both free and fully

licensed features. Convert easily from the free to the full version with the addition of a license key.

DISCOVERY STUDIO VISUALIZER

With Discovery Studio (DS) Visualizer, the following

features are available without a license:

• Visualization:

– Advanced, flexible molecular visualization tools

– 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

NEW IN DS VISUALIZER 3.0

• 2D Diagram: Create 2D

ligand-receptor interaction

diagrams directly in the free

Visualizer.

• New ‘Storyboard’ mode: 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.

DISCOVERY STUDIO® VISUALIZER 3.0

† Further information is available at accelrys.com/products/ discovery-studio/requirements/technical-requirements-300.html

DATASHEET: DISCOVERY STUDIO

2www.accelrys.com

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.

• Interact with and rapidly analyze your data using the Molecule

Window, which supports visualization, data table and hierarchy

views of the data.

• 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.

• Study proteins and nucleic acids using the Sequence Window,

enabling the viewing and comparison of the sequences,

alignments and annotations.

3D GRAPHICS AND PERFORMANCE

The DS Visualizer outputs high quality graphics ready to be used

for slideshows, posters, or any other presentation format.

• New in 3.0! Improved Graphics Performance: The Visualizer

makes use of advanced hardware acceleration to improve

handling of very large macromolecule systems.

• New in 3.0! Shading and Depth Blur: Generate ambient and

direct shadows, depth blur, atom contouring and custom

backgrounds.

• Control lighting, depth cueing and graphics quality to enhance

visualization.

• Augment 3D structure appearance with multisided surfaces

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.

• Save high quality 3D graphics as POV-Ray 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]

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)


3www.accelrys.com

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.

IMPORT, BUILD AND ANALYZE STRUCTURES

DS Visualizer handles the transfer and analysis of a variety of

data types including 2D and 3D structures, sequences and

graphics. You can download structures and sequences directly

from the PDB, or NCBI. You can also edit structures and perform

calculations to gain further insight into their molecular properties:

• Sketch, build and modify 3D structures using sketching and

fragment building tools.

• Superimpose structures based on tethers, residues or sequence

alignment.

• Manually derive pharmacophore models from small molecules

or protein-ligand complexes.

• Visualize properties of large sets of molecules with a user-

defined color scheme.

• View molecular data in multiple perspectives such as 3D

structure, sequence, chart/graph and data table.

• Alter geometric and chemical properties and monitor structural

orientations and interactions within an interactive environment.

• 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.

* 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

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.


4www.accelrys.com © 2011 Accelrys Software Inc. All brands or product names may be trademarks of their respective holders.

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DISCOVERY STUDIO 3.0 VISUALIZER: FREE VERSUS LICENSED MODE

• Free: In ‘free mode’, a limited set of functions are available,

allowing you to view and edit data files created with Discovery

Studio and other applications. You can view and edit

molecular structures, sequences, sequence alignments and

Perl scripts. Additionally, a subset of the Discovery Studio Perl

API is available.

Type Feature Free Licensed

Client

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 � �

Perl scripting � �

Files explorer view � �

Table browser for small molecule data sets � �

Protocols, jobs, parameter help, and tools explorer views �

General

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 † �

Protein

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 � �

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 † �

Ligand Design

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 �

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 �

• 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. †

† Note: Running protocols does require additional product licensing from Accelrys.

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 file is used to automate the process of CDR identification and annotation. A sequence alignment file of the best aligned hits is provided for automated loop grafting of the CDR regions.

Access to the routinely used BLAST and PSI-BLAST algorithms, to search real time databases installed behind your firewall or at the NCBI

Supporting tools that perform Phylogenetic and Evolutionary Trace analysis help you create dendrograms using hierarchical clustering methods

Generate high quality homology models quickly and accurately

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.

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Protein Modeling and Sequence Analysis in Discovery Studio 2.0

Discovery Studio

Harnessing the Power of Protein Modeling

Experimental structure determination involves difficult methods that require a significant amount of expertise and resources, and can take years to yield results. Conversely, protein modeling enables access to sensible structural models within a matter of hours, or even minutes. Template-based modeling has been shown to yield useful models in countless publications. As more and more experimental structures become available, template based protein modeling will continue to provide a greater scope of understanding to researchers, delivering accurate models quickly and efficiently. Protein Modeling and Sequence Analysis solutions in Discovery Studio provide the necessary set of tools for the construction of molecular structures, as well as macromolecular docking, in an easy to use customizable graphical user interface suitable for novice and expert users.

Protein Modeling with the renowned MODELER algorithm

New Antibody Modeling Methods

Comprehensive tool kit for protein-protein docking

A xylanases hydroxylases protein model created using the build model protocol from DS MODELER from 3 protein structure templates (1b30, 1gom and 1ta3) was verified using the Profile-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 profile 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

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Test the validity of a protein model

Use DS Protein Health to test the validity of a protein structure (full or partial) derived from modeling studies or experimental methods.

Profiles-3D Verify: a method that evaluates the likelihood that an amino acid should be present within its current environment

An interactive tool kit, that allows you to browse and correct a suggested list of structural violations which are mapped and colored to the 3D structure

Perform side chain or loop refinement on your structure

Perform accurate CHARMm-based structural refinement of loops and side chains with DS Protein Refine.

LOOPER: This algorithm has been optimized for loop refinement; it will quickly generate energy optimized variants of the structure, and provide the user with a list of proposed loop conformations that have been scored using the CHARMm Energy function

ChiRotor: an algorithm designed to refine side-chain orientations by performing a systematic search of side-chain conformations and CHARMm energy minimizations

*Both methods are considered de novo methods and have no dependency on the starting conformation of the structure

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Discovery Studio

Gain better understanding of the mechanism of action of a protein

Gain new insights about the mechanism of action by looking at the molecular structure of a protein, analyzing sequence conservation patterns within a family of proteins, and mapping conserved residues to the 3D structure with DS Protein Families

Access to the Align123 program, which is based on the CLUSTAL W technology for sequence alignments

Use of Accelrys’ proprietary 3DMA algorithm for accurate structural alignments

Additional tools like the Phylogenetic and Evolutionary Trace analysis are also accessible to help determine structural conservation of amino acids

Model Protein-Protein Interactions:

Predict protein-protein structure interactions of novel targets rapidly and accurately with DS Protein Docking.

Use of ZDOCK for rigid body docking

Access to the CHARMm based RDOCK refinement program for optimization and enhanced scoring of docked poses

Use of clustering methods to narrow the search and to help identify poses of interest that can be used for further refinement

Construct molecular fragments and perform electrostatic analysis including pK predictions

Construct simple molecular models with a robust set of tools. Whether it is, amino acids (proteins), nucleic acids (DNA/RNA), or any other organic compound, access all the tools you need with DS Biopolymer

Easy-to-use interactive builders to construct molecular models quickly and accurately.

Modeling tools commonly used in X-ray crystallography work such as real space fitting of molecules to electron-density maps, force-field based regularization of models, and more.

The DELPHI program for calculating the electrostatic distribution of charges for macromolecules.

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•Loop refinement (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.

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 pK’s, 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.

The Gold Standard in Technology

Comprehensive – From protein sequence to well-defined docked complex, Discovery Studio includes a comprehensive suite of tools to analyze your data and provide you with reliable results. Beyond protein modeling, you can generate pharmacophore models, dock and score ligands, perform QSAR analysis, and more within a single easy-to-use environment.

Proven history – The core technology has undergone over a dozen years of continuous innovation and customer driven improvement, and has demonstrated dependable performance in the pharmaceutical industry with over 100 publications.

Cutting edge – Accelrys is incorporating new scientific 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 Pipeline Pilot open operating platform, integrates protein modeling, pharmacophore analysis, and virtual screening as well as third-

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Discovery Studio

party applications for an infinitely 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.

Accelrys is Your Partner in Research

User community – Numerous protein prediction meetings such as CASP, Protein Society, and CAPRI attract hundreds of researchers from all over the world to evaluate novel methods in protein modeling and protein structure prediction.

Scientific Consulting – Accelrys has dozens of experienced Ph.D.s with expertise in implementing scientific solutions for drug design that are available for short or long-term engagements to create tailored solutions or perform modeling experiments.

Customer Support – Accelrys customers report a 98% satisfaction rate with our support team.

Committed to innovation – With over 100 Ph.D.s in the field working daily with researchers in industry and academia, Accelrys is committed to delivering cutting-edge technology to our customers.

World leading scientific advisors – Through our in-licensing agreements, partnerships, and scientific advisors, many of the world’s foremost experts in computational drug design are involved in setting our direction.

Biological Validation and Comparison

2004 – SALIGN validation has shown much better correlation of sequence to structure alignments than traditional sequence alignment methods

2007 – ZDOCK and RDOCK have been highly successful at the world renowned CAPRI (Critical Assessment of Predicted Interactions http://capri.ebi.ac.uk/ ) meetings, and having these tools in Discovery Studio make protein-protein docking a manageable task

2007 – A quick validation of LOOPER within DS Protein Refine shows an impressive 0.44Å back-bone RMSD in the de novo modeling of a 7-residue loop (residues 55 to 61) of the commonly used example, thymidine kinase (PDB ID: 1kim). Such a low RMSD demonstrates a very high degree of accuracy for our methods and borders experimental error.

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References: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 first authors), Weng Z, RDOCK: Refinement of Rigid-body Protein Docking Predictions. Proteins, 2003, 53, 693–707

Marti-Renom, M. A., Madhusudhan, M. S. and Sali, A., “Alignment of protein sequences by their profiles”, Protein Science, 2004, 13, 1071–1087 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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The Discovery Studio Research Environment

DS Biopolymer is part of the Discovery Studio® research environment, which is a comprehensive suite of modeling and simulation solutions. Because Discovery Studio is built on SciTegic®’s Pipeline Pilot, Accelrys’ scientific operating platform, these modules are extensively integrated with many other powerful software applications that will allow you to carry out such tasks as aligning sequences, creating protein homology models, building and analyzing pharmacophore models, examining receptor ligand interactions, performing molecular mechanics, and much more.

Features

Building and Editing Macromolecular Structures

With DS Biopolymer, you can rapidly build and modify peptides, proteins and nucleic acid (DNA and RNA) structures.

Peptide and Protein StructurePolypeptide structures can be easily constructed and edited by appending, replacing, or deleting residues.

You have the ability to set charges or radii of atoms in your structure and create neutral or charged N- or C-termini.

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Biopolymer Building and Analysis in Discovery Studio

You can create secondary structures by imposing a variety of standard helices or beta strands to a desired range of residues.

Any desired nonstandard turn can be imposed by specifying the two relevant pairs of phi and psi angles.

DS Biopolymer can also fix any protein structural errors, such as incomplete side chains, or improper connectivity and bond order.

Included are tools that allow you to generate protein reports and create hydrophobicity plots.

Nucleic Acid StructureYou rapidly can create single-, double-, and triple-stranded DNA molecules in A-, B-, or Z-form using standard helix parameters.

Single- or double-stranded RNA and DNA-RNA hybrid molecules in A-form can be constructed with standard helix parameters.

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Discovery Studio

The complex 3D structure of biopolymers, such as peptides, proteins and nucleic acids, are critical to their biological functions. One of the key factors that dictate the structure of a macromolecule is the electrostatic interactions among polymer residues. DS Biopolymer not only allows you to create and modify biopolymers from their basic residues building blocks, but also allows you to calculate a molecule’s electrostatic properties, including the effects of bulk solvent and ionic strength, thereby providing crucial data for rationalizing differences in the activity of macromolecules.

Powerful and versatile Poisson-Boltzman electrostatic potentials and solvation energies

Easy-to-use tools for building and modifying proteins, peptides and nucleic acids

DS Biopolymer was used to create and type a DNA duplex in preparation for minimization and molecular dynamics.

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.

Electrostatic Analysis

DelPhi, a powerful and versatile Poisson-Boltzmann electrostatics simulation engine for calculating electrostatic potentials and solvation energies of both small- and macromolecules, 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.

The electrostatic potential changes that occur upon mutation of protein residues can be studied with DS Biopolymer

High resolution calculations are possible using focusing methods.

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.

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Discovery Studio

The total electrostatic energy for a set of charges, including the total solvation energy of each charge and between charges, is accounted for.

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.

X-ray Analysis Tools

DS Biopolymer provides tools that allow you to automatically fit your protein models and ligands into electron density maps of a specified protein-ligand complex.

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Required Software

DS Visualizer Pro Enterprise (or DS Visualizer Pro with Pipeline Pilot Server)

References:1. Honig, B., Sharp, K., Yang, A.S., J. Phys. Chem., 1993, 97, 1101.

2. Nicholls, A., and Honig, B., J. Comp. Chem., 1991, 12, 435.

3. Sharp, B., Nichols, A., Friedman, R., and Honig, B., Biochemistry, 1991, 30, 9686.

The Poisson-Boltzmann electrostatic potentials displayed on the protein surface indicated areas of positive (blue), neutral (white) and

negative (red) regions.

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 significantly 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.

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.

CHARMm-based Methods for Computational Drug Discovery

The well-established computational engine CHARMm has been fully integrated into Accelrys drug discovery applications within Discovery Studio.

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Simulation in Discovery Studio 2.0

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 flexibility during docking using CHARMm-based methods for side-chain and loop-sampling/refinement. The method is available either within the highly accurate receptor-flexible docking program, DS Flexible Docking, or as individual components.

Further refine the accuracy of docked poses with physics-based scoring functions available with DS CHARMm (MM-PBSA, MM-GBSA and LIE).

A Complete Simulation Package for Macromolecules

Perform molecular mechanics and dynamics calculations using DS CHARMm, the gold standard for computational simulation.

Access the most validated implicit solvent models, minimization methods and production schemes ever assembled in one integrated, visual environment.

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Discovery Studio

The Power of SimulationInteractions between macromolecules and ligands, cofactors, membrane surfaces, metal ions, etc. are fundamental to biomolecular processes. Computational simulation of biomolecular systems helps in the understanding of these processes by providing a visual representation of the molecular geometries, spatial alignments, and energetics that contribute to molecular interactions.

The powerful set of CHARMm-based molecular mechanics and molecular dynamics-based methods available in Discovery Studio® (DS) enable simulation of all types of biomolecular systems. Well-validated forcefields ensure reliable results. The output trajectory files can be efficiently analyzed in a high-throughput and graphical manner using a set of user-friendly analysis tools. The simulation tools are further integrated with industry-standard protein modeling, docking, scoring and pharmacophore tools within the single, unified environment of Discovery Studio.

A comprehensive suite of solutions for simulating macromolecules, ligands, cofactors, membrane surfaces, and metal ions for drug discovery research

Unprecedented customization capabilities for simulation workflows

Industry-standard simulation engine, force fields, and implicit solvent models

Industry-Standard Force Fields in a Unified, Graphical Interface

Access the most comprehensive collection of protein and small-molecule force fields explicitly developed for drug discovery research. Discovery Studio now provides easy, graphical access to the following industry-standard force fields: CHARMm, charmm(19,22,27), MMFF, and CFF.

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Discovery Studio

Figure 2: Quickly prepare your molecular system for simulation and analyze the results using a rich set of interactive tools

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 infinitely 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 specific hydrogen bonds during simulation (B); and calculate pairwise Cα RMS deviations between frames in the trajectory (C).

The Gold Standard in TechnologyComprehensive – From molecular mechanics and molecular dynamics to a complete set of analysis tools including trajectory clustering, normal modes, radius of gyration and Principle Component Analysis, Discovery Studio provides a complete suite of tools that are optimized for computational drug discovery research.

Longest standing – Accelrys has been providing cutting-edge solutions in simulation and force fields that have seen continued innovation, improvement and dependable performance in the pharmaceutical industry for over 25 years.

Easy to use interface – DS 2.0 provides a powerful and intuitive user interface. DS 2.0 can be deployed either as 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.

Accelrys is Your Partner in ResearchUser community – With over a thousand registered users, the academic CHARMM community continues to seed development and usages of the CHARMm engine that is the core of Accelrys’ Life Science solutions.




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References: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 affinity” J. Med. Chem., 2005, 48(13), 4332-45.Nimlos, MR at al. “Molecular modeling suggests induced fit 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 DatasheetSpassov, 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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Validation2005 – CHARMm-based MM-PBSA scoring of docked poses correctly identified 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 significant 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 field of bio-fuel synthesis.3

2007 – A publication that describes the method and validation results on a CHARMm-based protein side chain sampling and refinement 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

Accelrys Science

A Rational Approach to Flexible Docking (New in Discovery Studio 2.0)

Leverage the proven strength of CHARMm and efficient 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 flexible docking in which the docking of small molecules is influenced by existing low-energy conformations of side chains in the active site.

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 GBORN-based pK estimation algorithm in DS CHARMm.

Docking Tools Optimized for vHTS Applications

Maximize the probability of identifying actives by using two docking methods during a vHTS experiment. Studies show that a single vHTS docking program does not give accurate results across different protein families2. Accelrys provides two well-validated vHTS applications within the Discovery Studio environment: the shape-based docking program DS LigandFit and the

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Structure Based Design in Discovery Studio A comprehensive suite of solutions for small-molecule docking

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.

Industry-Validated De Novo Ligand Generation and Optimization

Rapidly identify drug-like scaffolds with DS Ludi, a de novo drug discovery application that uses interaction sites in the receptor binding pocket to place and score fragments from fragment libraries.

Reduce lead discovery time by generating complete, drug-like molecules with DS De Novo Evolution by linking and growing fragments onto a scaffold using linear, evolutionary or combinatorial methods5.

A Comprehensive Suite of Scoring Tools

Prioritize docking hits by performing rapid, high-throughput scoring of thousands of docked poses with the well-validated set of scores available in DS LigandScore.

Refine the accuracy of docked poses further with physics-based scoring functions available with CHARMm (MM-PBSA, MM-GBSA and LIE).

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Discovery Studio

The Power of Structure Based Design

Structure Based Design is a powerful method for rapidly identifying new lead compounds when a receptor structure is available. In the early stages of drug discovery, virtual high throughput screening (vHTS) can lead to increased efficiency by helping to prioritize compounds in a library and by reducing library size. During the lead optimization stage, accurate docking methods, efficient de novo design methods, and accurate physics-based scoring can yield high-confidence compounds that are more likely to be active in vivo.

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.

Rational and fast receptor-flexible docking

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


Comprehensive – From a realistic and fast flexible docking method to industry-validated de novo ligand design and optimization, Discovery Studio provides a complete suite of tools for structure based design.

Longest Standing – Accelrys has been providing cutting-edge solutions in simulation, docking and scoring that have seen continued innovation, improvement and dependable performance in the pharmaceutical industry for over 25 years.

Easy to use interface – DS 2.0 provides a powerful and intuitive user interface. DS 2.0 can be deployed either as a 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.

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 third-party applications for an infinitely 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.


User community – With over a thousand registered users, the academic CHARMM community continues to seed development and usage of the CHARMm engine that is at the core of Accelrys SBD solutions.



Committed to innovation – With over 100 Ph.D.s in the field working daily with researchers in industry and academia, Accelrys is committed to delivering cutting-edge technology to our customers

Validation

2007 – Cross-docking experiments with the new receptor-flexible docking method DS Flexible Docking on 21 receptors spanning diverse protein families shows consistently accurate results with all ligands docked within a 2Å RMSD to X-ray poses.1

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References: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_workflow_app_note.pdfRisal, 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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2007 – Docking validation against the new AstexDiverse dataset shows that CDOCKER docks 94% of ligands to within 2 Å of X-ray pose, while LibDock docks 91% to within 2 Å.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 identified 39 compounds that were docked into the receptor using LigandFit. The final 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 coefficient (r=0.60) between experimental pIC50 values and top-ranked rescores of 30 poses of each compound”.9

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 efficient implementations of semi-empirical quantum mechanical methods to rapidly calculate highly accurate electronic properties for thousands of candidate compounds.

Advanced Modeling Tools for Easy Analysis of Complex Data in DS QSAR

Easily apply modeling techniques such as Bayesian models, multiple linear regression, Partial Least Squares (PLS), Genetic Functional Analysis and more.

Extend the basic functionality of the package by adding an advanced neural network component and quantum mechanical based descriptors.

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QSAR and Library Design in Discovery Studio

Powerful, Customizable, and Easily Accessible SAR Tools in DS QSAR

Integrated Discovery Studio environment provides easy access to QSAR tools along side library design and other tools.

Using the Pipeline Pilot Platform, QSAR models can easily be deployed to and shared among large groups of chemists.

Advanced 3D graphing and molecular data views guide users in drawing conclusions from complex data.

Easily Design Targeted Chemical Libraries with DS Library Design

Maximize multiple properties simultaneously using Pareto Optimization methods.

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.

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Discovery Studio

The Power of QSAR and Library Design

The ultimate objective of many computational modeling studies is to identify compounds that could potentially become new drugs. With appropriate molecular descriptors, the large quantity of relatively easily available data inherent in chemical libraries can be mined, analyzed and used to select compounds that can become drug leads.

DS QSAR provides easy access to the hundreds of molecular descriptors, proven in biological systems to correlate with activity. The streamlined Discovery Studio® (DS) interface presents 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 specifically tailored for chemical library design to guide optimal library design.

Advanced tools for creating optimal chemical libraries

Pareto Optimization for simultaneous multivariable enhancement

An extensive set of QSAR descriptors and seamless integration of additional data into QSAR models


Comprehensive – The QSAR and library design tools in Discovery Studio include hundreds of useful descriptors, multiple well validated model building techniques and tools specially tailored for custom library selection and design. These packages can easily be augmented with powerful add-ons for rapidly generating quantum mechanical based descriptors and advanced modeling techniques.

Proven history – The core technology has undergone over a dozen years of continuous innovation and customer driven improvement, and has demonstrated dependable performance in the pharmaceutical industry with dozens of publications.



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 third-party applications for an infinitely 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.


User community – Accelrys scientific forums and presentations at scientific meetings world-wide provide opportunities for Accelrys users to exchange ideas and share new research.

Scientific consulting – Accelrys has dozens of experienced Ph.D.s with expertise in implementing scientific solutions for drug design that are available for short or long-term engagements to create tailored solutions or perform modeling experiments.

Customer support – Accelrys customers report a 98% satisfaction rate with our support team.

Committed to innovation – With over 100 Ph.D.s in the field working daily with researchers in industry and academia, Accelrys is committed to delivering cutting-edge technology to our customers

World leading scientific advisors – Through our in-licensing agreements, partnerships, and scientific advisors many of the world’s foremost experts in computational drug design are involved in setting our direction.

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References:Cheg, D. et al., “Relationship of quantitative structure and pharmacokinetics in fluoroquinolone 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., “Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT”, Mol. Pharmacol, 2003, 63(3), 489-98

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Figure 2 An interactive 3D plot of the first three principal components from a Principal Component Analysis using several molecular descriptors as input. The plot can optionally be colored by a specified property.


2007 – Genetic Functional Analysis module used to study fluoroquinolone antibacterials. The results suggest specific chemical modifications and physical properties for future drug design efforts.1

2006 – Effect of 2-aminothiazole derivatives on Neuro-cell apoptosis studied using a QSAR model that has a 97% correlation to EC

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2003 – A descriptor-based QSAR model for hOCT1 predicts IC

50 values with 95% correlation to

observed data.3

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 specific features to optimize the model based on the known data.

Automatically generate structure-based pharmacophore models using DS Catalyst SBP that can easily be combined with ligand-based 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.

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Pharmacophore Modeling in Discovery Studio

Fast and Reliable Database Building and Searching

Select from three top-ranked conformational generation algorithms each optimized for different types of uses to provide the best sampling of biologically relevant small molecule conformations in DS Catalyst Conformation. This module includes the new CEASAR algorithm for rapid, highly accurate, conformation generation.

Calculate predicted fit or activity value for each compound to allow for rapid prioritization of leads and explore multiple ligand mappings to pharmacophore models with user-defined tether points for critical features with DS Catalyst Score.

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Discovery Studio

The Power of Pharmacophore Modeling

Pharmacophore modeling is a powerful method to rapidly identify new potential drugs. For the numerous therapeutically relevant drug targets with undetermined active site geometries, pharmacophore modeling provides an effective mechanism for virtual screening. Using proven pharmacophore methods, researchers can achieve astounding results from limited data.

Catalyst, the most cited and successful collection of pharmacophore modeling tools, has been re-engineered for improved usability in Discovery Studio®. In addition to classical tools, Discovery Studio integrates powerful new pharmacophore tools for fragment-based design, activity profiling and structure-based design.

Pharmacophore guided fragment-based drug discovery

Highly-accurate, rapid conformer generation with CAESAR

Add value to drug discovery in a whole new way using activity profiling

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.

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.

Cutting-Edge Pharmacophore Applications

Generate novel lead structures by fragment-based design, a new and highly actionable method for ligand design. The De Novo Ligand Builder combines the multi-dimensional property matching capabilities of pharmacophores with user-specified reagent lists to identify new chemical entities.

Compare ligands to structure-based pharmacophores from different sources to gain early insight into potential toxicities or drug targets for co-development using the Ligand Profiler in DS SBP. Leverage previously generated pharmacophores from internal sources or search high quality pharmacophore models in HypoDB from publicly available data.


Comprehensive – The Catalyst set of tools allow ligand- and structure-based pharmacophore methods to be combined to generate hypotheses. Within the same integrated environment, these hypotheses can then be extensively customized using a single set of tools, and used to search multiple databases.

Proven history – The core technology has undergone over a dozen years of continuous innovation and customer driven improvement, and has demonstrated dependable performance in the pharmaceutical industry with over 100 publications.

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Discovery Studio



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 infinitely 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.

Interactive dendrogram for easy clustering and selection of pharmacophore points


User community – Annual Catalyst user group meetings on two continents each attract over a hundred participants sharing new research and current results using Catalyst.

Scientific consulting – Accelrys has dozens of experienced Ph.D.s with expertise in implementing scientific solutions for drug design that are available for short or long-term engagements to create tailored solutions or perform modeling experiments.

Customer support – Accelrys customers report a 98% satisfaction rate with our support team.


World leading scientific advisors – Through our in-licensing agreements, partnerships, and scientific advisors, many of the world’s foremost experts in computational drug design are involved in setting our direction.

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References:Purushottamachar P., et al., “First pharmacophore-based identification 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.

Agrafiotis, DK, et al., “Conformational Sampling of Bioactive Molecules: A Comparative Study,” J. Chem. Inf. Model., 2007, 47(3),

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2007 – After screening over a quarter million compounds, 17 were selected for assay. Six of these compounds were “experimentally confirmed,” and “exhibited significant human prostate cancer LNCaP proliferation inhibitory activities.”1

2007 – Screening the NCI database, 5 compounds were selected for assay. All 5 compounds were “found to possess nanomolar to low micromolar inhibitory IC

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2007 – J&J tests internal and commercially available conformation generation algorithms. Catalyst methods outperform all other commercial methods on every metric.3

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Mapping of a tyrosine kinase inhibitor, Imatinib mesylate, derived from pharmacophore based de-novo fragment screening against known crystal structure ligand orientation.

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 Discovery Studio Research Environment

ADMET Descriptors are part of the Discovery Studio research environment, which is a comprehensive suite of modeling and simulation solutions for life science researchers. Because Discovery Studio is built on SciTegic Pipeline Pilot, Accelrys’ scientific operating platform, these modules are extensively integrated with many other powerful software applications that will allow you to carry out such tasks as aligning sequences, creating protein homology models, building and analyzing pharmacophore models, and examining receptor ligand interactions.

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 classification of absorption level2.

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ADMET Descriptors in Discovery Studio

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 25°C 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, defined 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 classification of penetration level. The model combines a confidence ellipse derived from over 800 compounds classified 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 confidence 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 flag binding at a level of 90 percent or greater and the other at 95 percent or greater. Binding

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Discovery Studio

One of the most daunting hurdles a drug candidate must pass is having favorable ADMET characteristics. ADMET refers to the absorption, distribution, metabolism, excretion, and toxicity properties of a molecule within an organism. Optimizing these properties during early drug discovery is crucial for reducing ADMET problems later in the development process1. Such early identification helps to make your research process more efficient and cost-effective by allowing you to eliminate compounds with unfavorable ADMET characteristics early on, and evaluate proposed structural refinements that are designed to improve ADMET properties, prior to resource expenditure on synthesis.

Rapid optimization for drug-like properties to reduce downstream failures

Computational prediction based solely on chemical structures

levels predicted by the marker similarities are modified 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 classified as either toxic or non-toxic, and a confidence level indicates the model’s 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.

These ADMET Descriptors in Discovery Studio can allow you to gain critical insight to help you make well-informed, smart decisions during drug development. You’ll be able to invest your time wisely, focusing on compounds with much higher probabilities for success in ADMET testing.

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Required Software

DS Visualizer Pro Enterprise (or DS Visualizer Pro with Pipeline Pilot Server)

References:

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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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% confidence limit ellipses corresponding to the Blood Brain Barrier and

Intestinal Absorption models.

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 define categories and to help assess individual chemicals.”

DS TOPKAT: A Step Beyond SAR

DS TOPKAT has been used for toxicity testing by universities, private companies and government agencies including the Amgen, Pfizer, US CDC, US NIH, and Health and Welfare Canada. The QSAR-based system generates and validates accurate, rapid assessments of chemical toxicity solely from a chemical’s molecular structure. Unique among SAR-based technologies, DS TOPKAT uses robust, cross-validated models based on experimental data of highly consistent protocol. The models are subjected to extensive diagnostics for accuracy and validity. And only DS TOPKAT uses patented Optimum Prediction Space (OPS) technology to assure that the compounds under investigation are well represented in the models. Included within DS TOPKAT are tools that allow you to easily build molecules or queries from available fragment libraries. DS TOPKAT can be used for tests including physical/chemical, environmental fate, ecotoxicity, toxicity, mutagenicity, and subchronic reproductive/developmental. DS TOPKAT is fast, cost-effective, and proven.

Predictive Toxicology in Discovery Studio

DS TOPKAT in the Discovery Studio Research Environment

DS TOPKAT is an integrated application module in Discovery Studio, which includes a comprehensive suite of modeling and simulation solutions for life science researchers. Built on SciTegic Pipeline Pilot, Accelrys’ scientific operating platform, Discovery Studio provides a flexible research environment, which allows DS TOPKAT to read multiple file formats and integrate data with many other premium application modules, which provide functionality for such tasks as molecular docking and pharmacophore modeling.

Users can access DS TOPKAT technology through multiple interfaces. In addition to being accessible through DS Visualizer Pro Enterprise, which serves as the user interface for Discovery Studio, DS TOPKAT is also available as a component for use with SciTegic Pipeline Pilot, a high-throughput data analysis and mining solution that allows you to streamline your workflows. DS TOPKAT is also available as a stand-alone command line executable for high throughput calculation and/or for integration with in-house workflows.

Discovery Studio

A structure-activity relationship (SAR) is a computer-based statistical technique that allows chemical testing based solely on a chemical’s molecular structure. It is one component of the more comprehensive Quantitative Structure Activity Relationship (QSAR), which is capable of quantifying the type of relationship identified. While there are numerous QSAR-based software programs commercially available, none offers the depth, scope, and validation tools of Accelrys’ Discovery Studio (DS) TOPKAT®.

Robust cross-validated models for accurate assessment of chemical toxicity

DS TOPKAT prediction of known HIV inhibitors for Rat Inhalation

Various tasks, such as accessing a user specified sub-model, outputting result tables for reporting feature similarities and descriptor contribution to toxicity, can be enabled from the command line as well.

Defensible, Dependable Results

Accelrys also offers DS TOPKAT technology as part of its toxicity assessment service and under licensing agreements; both arrangements offer distinct benefits. Accelrys’ Contract Research Toxicity Assessment Service removes all testing and management burdens from you. Once a chemical and endpoint have been submitted for computational assessment, Accelrys’ team of toxicological experts undertakes the required test and prepares an in-depth report. Many companies prefer to use the computational toxicological assessment service, even though they may require multiple tests. For example, one major chemical company requested toxicological assessments for multiple endpoints for more than 70 chemicals. The resulting reports were completed within one month and at substantial time and cost savings when compared to conventional experimental testing. Alternatively, DS TOPKAT’s modules are available under licensing agreement, either individually or collectively. Once licensed, the software can be employed for multiple chemical assessments, slashing the cost of per-chemical testing. Using DS TOPKAT as opposed to traditional testing methods can achieve significant cost savings. Plus, while those traditional methods can take months to complete, a full chemical assessment using DS TOPKAT typically takes only a few days.

Discovery Studio

Available DS TOPKAT modules:

Rodent CarcinogenicityAmes MutagenicityRat Oral LD50

Rat Chronic LOAELDevelopmental Toxicity PotentialSkin SensitizationFathead Minnow LC50

Daphnia Magna EC50

Weight of Evidence Rodent CarcinogenicityRat Maximum Tolerated DoseAerobic BiodegradabilityEye IrritancyLog PRabbit Skin IrritancyRat Inhalation Toxicity LC50

Rat Maximum Tolerated Dose

A partial list of DS TOPKAT Clients:

AmgenBuckman Labs InternationalUS Centers for Disease Control and Prevention (CDC)Heath and Welfare CanadaUS National Cancer Institute (NCI)US National Institute for Occupational SafetyPfizerNational Institute for Public Health and Environment, Netherlands.US Environmental Protection Agency (EPA)Vertex PharmaceuticalsWalter Reed Army Institute of ResearchWyeth Pharmaceuticals.

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Platform requirements:

Windows 2000Windows XPRed Hat Linux WS3.0Red Hat Linux WS4.0

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System Requirements for Discovery Studio 2.5

Operating System Requirements

Discovery Studio 2.5 is supported on Windows and Linux.

Windows

x86 (32-bit)

Microsoft® Windows XP Professional, SP2 and SP3Microsoft Windows 2003 Server, SP1 and SP2Microsoft 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 4-7Red Hat Enterprise Linux 5, Retail, Updates 1-2SUSE® 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 isprovided using 32-bit binaries.

Hardware Requirements

Intel® compatible processor running at 2 GHz or greater2 GB RAMDisk space: Up to 3.9 GB available for a standard installGraphics 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 componentsselected for installation. Additional space is required if system updates are necessary or additional databases are installed (whichmay 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 whencertified drivers are installed. 3D stereo support is also available with hardware that provides quad-buffered OpenGL stereocapabilities.

NVIDIAOperating System Graphics Card Driver

System Requirements for Discovery Studio 2.5 ApsaraGG http://accelrys.com/products/discovery-studio/...

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Microsoft Windows XPMicrosoft Windows Vista

Quadro FX 540Quadro FX 570Quadro FX 1400Quadro FX 3700 (a)

182.46

Red Hat Enterprise Linux 4.0Red Hat Enterprise Linux Desktop 5 (x86-64)SUSE Linux Enterprise 10 (x86-64)

Quadro FX 540Quadro FX 570Quadro FX 1400Quadro FX 3700 (a)

171.06.01 (32-bit)171.06.01 (64-bit)

ATIOperating System Graphics Card DriverMicrosoft Windows XPMicrosoft Windows VistaRed Hat Enterprise Linux WS 4.0Red Hat Enterprise Linux Desktop 5 (x86-64)SUSE Linux Enterprise 10 (x86-64)

FireGL V3600FireGL V5100FireGL V5600FireGL V7200FireGL V7600

8.583

(a) Activation of hardware stereo can be intermittent with this platform, card and driver combination. This is a known issue with allOpenGL 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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Documents

Discovery Studio Proposal