Discovery StudioLife Science Modeling and SimulationsDiscovery Studio® is a singleunifi ed, easy-to-use, graphical interface for powerful drug design and protein modeling research. Discovery Studio contains both established gold-standard applications (e.g., Catalyst, MODELER, CHARMm, etc.) with years of proven published results, as well as and cutting-edge science to address today’s drug discovery challenges. Discovery Studio is built on the SciTegic Pipeline PilotScitegic Enterprise Server platform™ open operating platform, allowing seamless integration of protein modeling, pharmacophore analysis, and structure-based design, as well as third-party applications.

Product DescriptionDiscovery Studio Standalone

Discovery Studio Standalone is a complete molecular modeling platform designed for the independent modeler. This standalone environment, powered by the Pipeline Pilot open platform, includes the entire infrastructure needed to design and run modeling experiments with Discovery Studio Science. Easily visualize, model, and analyze biological and chemical data using tools for sketching 3D molecules, visualizing dynamic changes, 3D graphing and a host of other functionality. The standalone installation can be connected to a Pipeline Pilot Server for easy sharing of workfl ows and data. This confi guration also includes access to a rich set of perl-based scripting commands.

Discovery Studio Visualizer Client

Discovery Studio Visualizer Client is a powerful graphical interface to access Discovery Studio Science. DS Visualizer Clients can be inexpensively deployed and easily maintained for research teams while still offering world-class science. When deployed with a Pipeline Pilot Server, DS Visualizer Client offers unparalleled capabilities for sharing data, workfl ows, and computational resources. A rich set of perl-based scripting commands, and customized scripts, are also available for the automation and customization of common modeling operations that replicate UI actions or act on DS data models. Some examples of the large collection of scriptable actions include molecular overlay, chirality and valency checks, prediction of DSC secondary structure, access to electrostatics tools, management of constraints/restraints, and display of surfaces,

Pipeline Pilot Server

Pipeline Pilot makes the most of your information through industrial-scale data fl ow control and powerful mining capabilities. You can graphically compose data processing networks, using hundreds of different confi gurable components for operations such as data retrieval, manipulation, computational fi ltering, and display. These protocols are automatically captured as you create them and you can even publish them for enterprise-level deployment. Your colleagues have the option to invoke your protocols and run them using their own data using a simple Web interface.

DS Developer Client

This scaled-down version of the Pipeline Pilot client allows you to customize pre-existing Discovery Studio workfl ows, and also includes the necessary component collections to enable customization. Add or remove available components from existing DS protocols/components. Create a new component and add to an existing DS protocol. Increase automation of DS Protocols (e.g. automate DS protocol to run over all fi les in a specifi c folder). Easily connect to an external relational database. Integrate third-party algorithms (e.g., CORINA, proprietary codes for descriptor calculations, etc.).

The customized protocols can be run directly from the DS Developer Client, or saved into a user area and run from the DS interface for interactive modeling. A free and extensive library of customized components and protocols for Discovery Studio is available at no additional cost at the Accelrys Forumst.

Platform

Discovery StudioLife Science Modeling and Simulations

Product DescriptionDS MODELER Automatically and rapidly generate a refi ned homology model of a protein, given only the

sequence alignment to a known 3D protein structure, with this industry-standard for fast homology modeling. DS MODELER is the ideal solution for target discovery and for studying the structure and function of proteins across families. With DS MODELER, you can evaluate model quality, build protein models and mutants with ligands bound, and perform loop modeling based on a DOPE energy function; carry out structure based alignments; create sequence profi les; and perform remote homology modeling searching. DS MODELER also features SALIGN, a new method for improving the sequence alignment in low homology cases that uses sequence profi le information. Gain even further insight into protein structure and function by using DS MODELER in conjunction with Discovery Studio software for simulations and structure-based design.

Protein Modeling

Product DescriptionDiscovery Studio Free Visualizer

This free, easy-to-use visualization tool is an ideal solution for managers and researchers who need to collaborate with modelers, but do not need access to the expert-level analysis tools in Discovery Studio. Many common tasks and commands are available within the Perl-based scripting API, enabling automation and customization of common modeling tasks. View and share protein and small-molecule data in a clear and consistent way, and in a wide variety of industry-standard formats.

ActiveX Control The Discovery Studio Visualizer ActiveX Control is a fully integrated, 3D molecular renderer for the Windows environment, and provides a powerful method of sharing scientifi c results with colleagues via presentations, web pages, etc. The Control can be inserted into any application that can host a COM component, such as Internet Explorer, PowerPoint, or VC clients. The OpenGL capabilities of ActiveX Control allow you to render sophisticated molecular images. In addition to the Viewer’s native format, the ActiveX Control can read many industry standard molecular fi le formats.

Product DescriptionDS Sequence Analysis

Take the fi rst steps toward identifying a protein’s biological function by comparing its sequence to the sequences of other known proteins. Sequence Analysis allows you to use the popular BLAST and PSI-BLAST algorithms to identify homologs for your protein sequences by searching databases that are either installed locally or available over the internet at NCBI. Results are presented in an interactive report format that facilitates further analysis and manipulation with other Discovery Studio software. In addition, access tools for performing phylogenetic analysis and Evolutionary Trace analysis that involves creation of a protein family dendrogram using the hierarchical clustering method and mapping of the information onto your 3D structure. New functionality in the area of Antibody Modeling uses a pre-compiled CDR loop database to automate the process of CDR identifi cation and annotation. A sequence alignment fi le of the best aligned hits enables automated loop grafting of the CDR regions.

Sequence Analysis

Platform (continued)

Product DescriptionDS Biopolymer Simplify model building and electrostatics analysis with Biopolymer. Biopolymer provides

access to easy-to-use tools for building and modifying nucleic acids (DNA, RNA), proteins and peptides as well as protocols for calculating electrostatic potentials and solvation energies of both large and small molecules using Poisson-Boltzmann electrostatics (formerly available in DelPhi). With Biopolymer, you can also estimate 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. In the area of X-ray crystallography, build protein models (with X-BUILD technology) and fi t ligands (with X-LIGAND technology) into X-ray electron density maps.

Biopolymer Building and Analysis

Product DescriptionDS Protein Refi ne Optimize a loop region of a protein structure using an in-house developed algorithm based

on CHARMm. Generate multiple energy optimized variants of the loop region and browse through loop structures and chart results. In addition, optimize the side-chain of a protein structure using an in-house developed algorithm based on a systematic searching method and CHARMm energy minimization. Both optimization algorithms have no dependency on initial structure (ab initio approach).

DS Protein Families

Gain a better understanding of the mechanism of protein function at the molecular level by analyzing the sequence conservation patterns within a family of protein sequences, as well as the position of those conserved residues on the 3D structure. Get started with your analysis quickly by taking advantage of DS Protein Families’ easy-to-use protocols that step you through aligning a family of proteins based on sequence or structure, as well its tools for performing phylogenetic analysis and Evolutionary Trace analysis that involves creation of a protein family dendrogram using the hierarchical clustering method and mapping of the information onto your 3D structure.

DS Protein Health Access the validity of a protein structure (or part of the structure) derived from modeling studies or experimental data. Protein Health uses a method called Profi les-3D Verify to evaluate the protein structure by comparing its structural environments with the preferred environments of amino acids. Misfolded protein segments within a protein structure can be identifi ed by this method, indicating where additional consideration should be given to structural packing. In addition, check the quality of the protein structure and analyze regions with abnormalities using the ‘Protein Health’ tool panel.

DS Protein Docking

Predict protein-protein structure interactions of novel targets rapidly and accurately with DS Protein Docking. Perform rapid rigid body docking with the well-published ZDOCK algorithm, which employs an FFT-based method using a pair-wise shape complementarity function for identifying docked conformations and scores hits based on atomic contact energies. Increase the accuracy of docked poses using the ZRANK scoring function. Use the RDOCK algorithm to refi ne ZDOCK hits based on a CHARMm energy minimization, and score the poses by CHARMm energy and desolvation energy. Narrow the search and identify poses of interest with advanced clustering methods.

Discovery StudioLife Science Modeling and Simulations

Product DescriptionDS CHARMm Lite Obtain more accurate scoring and prioritization of ligands based on predicted receptor

affi nities using DS CHARMm Lite, a customized version of CHARMm with minimization capabilities. DS CHARMm Lite performs in situ ligand minimization using the well-validated CHARMm and CFF forcefi elds and several minimization algorithms. Selected atoms from the receptor can be included in the minimization protocol. DS CHARMm is scalable for high throughput analysis of large numbers of ligands; all jobs can be run in parallel and in background mode.

DS CHARMm Leverage this industry-standard program to study the energetics and fl exibility of molecules—from small ligands to multi-component physiological complexes. DS CHARMm is regularly updated to include the latest functionality developed by the scientifi c community. DS CHARMm is now completely integrated into Accelrys drug discovery applications within Discovery Studio. Sample receptor fl exibility prior to docking using CHARMm-based side-chain and loop-sampling and refi nement methods. Use the power of CHARMm to perform accurate small molecule docking by using CDOCKER. Use prior-knowledge to guide docking by adding pharmacophore restraints (requires additional products). Calculate accurate interaction energies between docked poses of ligand(s) and the receptor in high-throughput mode, and obtain a residue-level analysis of interaction energies. Re-optimize poses derived from third-party docking methods by minimizing poses and (optionally) adjacent receptor atoms/residues. Refi ne the accuracy of docked poses further with physics-based scoring functions available with DS CHARMm (MM-PBSA, MM-GBSA, LIE), the former of which now have an option to calculate the entropic energy of molecular systems (options: normal modes, quasi-harmonic modes or translational/rotational components). Improve the accuracy of protein-ligand or protein-protein docking, binding energy and protein stability calculations with a CHARMm-based fast and accurate protein pK estimation method.

Deploy well-validated force fi elds (CHARMm, charmm27, charmm22, charmm19) and solvation models such as Poisson-Boltzmann (PB), Generalized Born, Generalized Born with molecular volume (GBMV) or simple switching (GBSW). Access the CHARMm scripting language (command line) for a greater degree of customization and fl exibility. Use the stand-alone typing tool in batch mode to type a library of compounds using the CHARMm forcefi eld (automatic parameter estimation option available). Simulate nucleic acids with an appropriate forcefi eld, PME for electrostatics, and the ability to add counter ions during solvation. Create complex simulation workfl ows by accessing CHARMm from the Pipeline Pilot client for an unprecedented level of customization. Integrate your workfl ows with other upstream or downstream computational applications such as homology modeling, docking or pharmacophore analysis: deploy the workfl ows in either Pipeline Pilot or Discovery Studio.

CFF Advanced Class II Forcefi eld

Optimize DNA, RNA, carbohydrates, lipids, proteins, peptides, and small-molecule models with high confi dence on accuracy of results. The forcefi eld parameters in CFF (Consistent Forcefi eld) were developed by computing the properties of 1,768 different molecules spanning 19,432 molecular structures, resulting in a robust and diverse collection of parameters applicable to most biomolecules and small molecules.

Merck Molecular Force Field (MMFF)

Study the energetics and interaction between macromolecules and ligands with the industry-validated forcefi eld MMFF94s that has been broadly parameterized for organic and bio-organic systems and for the intermolecular interactions crucial to enzyme binding.

Simulation

Product DescriptionDS Flexible Docking

Perform rational fl exible docking with this new method that combines the strength of CHARMm for accurate receptor sampling with effi cient, features-based docking. DS Flexible Docking is a realistic approach to fl exible docking in which the docking of small molecules is infl uenced by existing low-energy conformations of side chains in the active site. DS Flexible Docking can be parallelized in multi-core machines or compute clusters for virtual high-throughput screening.

DS LigandFit Gain direct insight into the complementary features of ligands and their potential as lead candidates. DS LigandFit lets you easily dock ligands into the binding site of receptors using shape-based searching and Monte Carlo sampling of ligands. Parameters are customizable, and your settings can be saved and shared with other users. DS LigandFit can be parallelized in multi-core machines or compute clusters for virtual high-throughput screening.

DS LibDock Perform effi cient docking by using polar and apolar features (hotspots) on the receptor binding site to guide docking. Use the industry-standard Catalyst engine to generate small molecule conformations (DS Catalyst Conformation, optional but strongly recommended) to increase accuracy of docking. DS LibDock can be parallelized in multi-core machines or compute clusters for virtual high-throughput screening.

LigandFit/CAP Accelerate your search for drug candidates with quick access to commercially available structures that have been prepared from the Chemicals Available for Purchase (CAP) and CAPScreening databases. LigandFit/CAP allows you to avoid the frustration of having 2D compound data from commercial libraries, but needing 3D data for your ligand docking experiments.

DS LigandScore Evaluate ligand-protein interactions with well-validated and trained scoring functions and their individual descriptors. Insight gained with DS LigandScore will help you identify potential problems in a binding mode hypothesis, discriminate between correct and incorrect poses from docking, and prioritize posed ligands for downstream efforts such as screening or synthesis. Parameters are customizable and your settings can be saved and shared with other users. DS LigandScore can be parallelized in multi-core machines or compute clusters for virtual high-throughput screening.

Simulation (continued)

Product DescriptionDS Analysis Gain new insights into molecular processes by using DS Analysis to animate, graph, and

tabulate results of CHARMm molecular dynamics, small molecule docking, or protein modeling. Analyze MD trajectories in an intuitive, easy-to-use manner by computing the Radius of gyration (RGYR), radial distribution function, clustering of trajectories with ability to select clusters through a dendogram plot, Principle Component Analysis (PCA), and Phi-Psi Time series. Compute RMSD, hydrogen bonds and close contacts for thousands of docked ligand poses in a single job. Calculate RMSD of residues/atoms during the course of a trajectory; display the result in a dendrogram or heat map.

Check the quality of the protein structure and analyze regions with abnormalities using the ‘Protein Health’ toolpanel. Evaluate model quality based on the MODELER DOPE (Discrete Optimized Protein Energy) energy function.

Receptor-Ligand Interactions

Receptor-Ligand Interactions (continued)

Discovery StudioLife Science Modeling and Simulations

Product DescriptionDS Ludi Rapidly identify drug-like scaffolds with DS Ludi, a de novo drug discovery application that

uses interaction sites in the receptor binding pocket to search fragment libraries and identify and rank molecules.

DS Ludi’s robust set of design tools allows you to simulate screening before performing experimental assays, to explore libraries of commercially-available ligand scaffolds, and to modify existing ligands by scoring candidate derivatives in the receptor binding site. DS Ludi contains a library of drug-like fragments, but also gives the ability to add custom fragments.

DS De Novo Evolution

Generate complete, drug-like molecules with DS De Novo Evolution by linking and growing fragments onto a scaffold. Choose from three modes that are optimized for either speed or accuracy: In Quick mode, a single best scoring inhibitor is suggested after each generation ranked by any one of the DS Ludi (pre-requisite) or DS LigandScore (optional) scores. In Full Evolution mode, survivors are selected from generations of inhibitors. In Combinatorial mode, all combinations of derivatives of the scaffold are enumerated.

Ludi/CAP Accelerate your search for drug candidates with quick access to commercially available structures that can be acquired immediately for further development. Ludi/CAP provides access to Chemicals Available for Purchase (CAP), a structural database of commercially available compounds, and CAPScreening, a database of compounds available from suppliers of screening libraries. Focus results by fi ltering out redundant hits and restricting searches. Known compounds retrieved from Ludi/CAP can be used as bases for generating ideas for the synthesis of novel compounds.

Additional Features in Receptor-Ligand Interaction

Save time by preparing ligands in high-throughput mode for docking applications: • enumerate ionization states for a given pH range, generate tautomers and isomers, apply Lipinski fi lters, and generate 3D coordinates, all in a single experiment within seconds.

Rapidly analyze multiple crystal forms and/or conformations by identifying receptor-• ligand interactions of superimposed protein-ligand complexes and mapping interactions to the receptor sequence window to create a sequence-specifi c “Heat Map” to identify sequence-activity and structure-activity relationships.

Integrate third-party applications into your structure-based design workfl ows. Access the • GOLD* docking protocol from within Discovery Studio.

* GOLD is a genetic algorithm-based docking program from the Cambridge Crystallographic Data Centre. A separate license for GOLD is required. For further details about this product, visit www.ccdc.cam.ac.uk

Product DescriptionDS QUANTUMm Increase accuracy of protein-ligand modeling during lead optimization by using accurate

Quantum Mechanics/Molecular Mechanics (QM/MM) methods that combine the Density-Functional Theory program DS DMOL3 Molecular (QM) and CHARMm (MM). Perform single point energy calculations or geometry optimization using a wide variety of exchange-correlation functionals and basis sets. Obtain accurate ligand partial charges for docking or simulation applications. Model specialized interactions such as cation- Pi and metal-ligand-receptor interactions with a high level of accuracy. Access all of these QM/MM methods with easy job setup and a customized set of pre-confi gured parameters.

QM/MM

Product DescriptionDS Catalyst Build and DS Catalyst Search

Easily create a 3D compound database for querying pharmacophore models and identifying potential lead compounds. With DS Catalyst Build, convert compounds into a 3D database that stores a diverse sampling of all the energetically accessible conformations under physiological conditions for any given structure. With unrivaled performance, DS Catalyst Search will carry out rapid database searches using a pre-defi ned or customized query that accounts for your pharmacophore model, specifi ed 3D shape, and/or necessary substructure binding features. Because the 3D Catalyst database stores detailed conformational information, your searches will consider multiple molecular orientations for each compound.

DS Catalyst Hypothesis

Automatically create qualitative or quantitative pharmacophore models that identify the essential chemical and structural features required for target binding. You can automatically generate hypotheses from a known set of compounds with a diverse range of chemical and structural features, and biological activities. Improve the selectivity of your model by setting up exclusion volumes to account for steric constraints with inactive molecules or with a specifi c biological active site. DS Catalyst Hypothesis also offers a one-of-a-kind tool that can automatically identify the minimum required excluded volume features necessary to account for steric constraints. Alternatively, you can develop a pharmacophore hypothesis from the alignment of specifi ed molecules against drug candidates or known active compounds without considering the requisite biological activity.

DS Catalyst Shape Expand or refi ne your search query by developing a 3D representation of a molecule from a specifi ed conformation to fi nd compounds that satisfy the 3D spatial constraints imposed by a receptor active site. Use this representation to perform a 3D database search to identify molecules that possess a similar shape with or without considering specifi c chemical entities. Because overall shape is considered, the search hits will exhibit a far greater topological diversity than standard 2D searches, resulting in set of compounds that much more accurately emulate the shape of the biological target.

DS Catalyst Score Quickly evaluate and prioritize compounds from your experiments and database queries. Fit the hit results from a database search onto your hypothesis to determine which ones best refl ect the requirements of your pharmacophore. DS Catalyst Score will calculate the predicted fi t or activity value for each compound. Based on the size of your returned search hit list, have the fl exibility to broaden or narrow your search results by specifying the minimum and maximum feature requirements of your pharmacophore model. You can also align specifi c molecules and compare their structural and chemical features to determine the degree of similarity between them.

DS Catalyst Conformation

Rapidly calculate conformational models for small molecules that provide diverse representations of all the molecule’s energetically accessible conformations. Access the new CAESAR algorithm for rapidly generating biologically relevant ligand conformations. Choose from among three conformation generators to select the algorithm that is best suited to each drug discovery project. Within each algorithm, customize parameters to further optimize the conformational sampling for your specifi c application. From these generated conformers, create pharmacophore hypotheses for querying compound libraries of both rigid and fl exible molecules.

Pharmacophore Modeling and Analysis

QSAR and Library Design

Product DescriptionDS QSAR and DS QSAR+

DS QSAR provides easy access to the hundreds of molecular descriptors, proven in biological systems to correlate with activity. Easily apply modeling techniques such as Bayesian models, multiple linear regression, Partial Least Squares (PLS), Genetic Functional Analysis (GFA), and more. Extend the basic functionality of the package by adding an advanced neural network component and VAMP descriptors, a semi-empirical quantum mechanical method for rapidly calculating accurate electronic properties for thousands of candidate compounds.

DS DMol3

DescriptorsThe density-functional theory (DFT) program DMol3 can use used for calculating electronic properties of compounds at a very high level of accuracy.

DS Library Design DS Library Design provides a full suite of similarity and diversity clustering methods specifi cally tailored for chemical library design. Use Pareto Optimization methods to optimize multiple properties within a chemical library design. All protocols within this package are designed to select the most effective chemical libraries, and members within those libraries, for specifi c research projects.

Product DescriptionDS Catalyst Structure Based Pharmacophore (SBP)

Provide value in a whole new way by introducing fast and easy activity profi ling to understand potential side-effects at the very beginning of the drug design process with Ligand Profi ler in DS SBP. Add the curated pharmacophore database, HypoDB, from Inte:Ligand for access to thousands of pharmacophore models to use in activity profi ling. Also create pharmacophore models from protein structures to rapidly produce hit lists that are uniquely tailored to fi t your specifi ed receptor. Interactive maps of the target active site can be edited and clustered using proprietary knowledge of the receptor to retain only essential information from virtual screening. Easily integrate protein structural features with ligand features to create a more complete model of the features critical for binding. This ability to integrate protein data with ligand data can be especially powerful when protein structures are not completely defi ned, like many kinases.

DS De Novo Ligand Builder

DS De Novo Ligand Builder is a unique fragment based design tool because it uses pharmacophores to guide the placement of fragments. This results in hits that not only complement the protein active site, but that also complement each other to create realistic new drug leads. This powerful tool can rapidly produce lists of completely novel compounds that all contain the features thought to be critical for binding to a specifi c drug target.

HypoDB HypoDB is a database of high-quality pharmacophore models from Inte:Ligand containing 1846 individual pharmacophore models from 187 targets. The database can be used to explore the selectivity and specifi city of candidate compounds across a wide variety of therapeutically relevant targets. This method of profi ling can also help identify potential mechanism of action, potential adverse targets or new targets for candidate drug compounds.

Discovery StudioLife Science Modeling and Simulations

Pharmacophore Modeling and Analysis (continued)

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Discovery StudioLife Science Modeling and Simulations

ADMET and Predictive ToxicologyProduct DescriptionDS ADMET Descriptors

Get an early assessment of your compounds by calculating the predicted absorption, distribution, metabolism, excretion and toxicity (ADMET) properties for collections of molecules such as synthesis candidates, vendor libraries, and screening collections. Use the calculated results to eliminate compounds with unfavorable ADMET characteristics and evaluate proposed structural refi nements, designed to improve ADMET properties, prior to synthesis. Optimizing these properties during early drug discovery efforts is critical for reducing problems in later development phase. Included are models for human intestinal absorption, aqueous solubility, blood brain barrier penetration, plasma protein binding, cytochrome P450 2D6 inhibition, and hepatotoxicity. Filter a set of small molecules and select only those molecules that meet the rules specifi ed by the set of selected SMARTS® rules.

DS TOPKAT Evaluate your compounds’ performance in experimental assays and animal models. Compute and validate assessments of the toxic and environmental effects of chemicals solely from their molecular structure. TOPKAT employs robust and cross-validated Quantitative Structure Toxicity Relationship (QSTR) models for assessing various measures of toxicity and utilizing the patented Optimal Predictive Space validation method to assist in interpreting the results.