What’s New in Discovery Studio 2.1

Discovery Studio® provides the most advanced modeling and simulation software solutions for life science researchers available today. From project conception to lead optimization, Discovery Studio includes a diverse collection of sophisticated software applications in a single, easy-to-use Linux- or Windows-based environment. Because Discovery Studio is built upon Scitegic Enterprise Server™ platform, Accelrys’ scientifi c operating platform, any software that you need can be integrated into the research environment, whether it’s from Accelrys, in-house developers, or other vendors to provide a truly customized solution.

Major New Functionality: • Help identify potential mechanism of action of Protocol Customization compounds • Leverage unprecedented graphical customization • Screen early for potential adverse targets or of protocols using DS Developer Client (a scaled fi nding new targets

down version of Pipeline Pilot Professional Client • Determine compound selectivity to projected 21 that is available as a part of the Discovery Studio . target families release) • Create ensemble therapeutic pharmacophore • Customize DS protocols/components screens

• Create a new component and add to an existing DS • Screen against ADMET Pharmacophore models protocol

• Increase automation of DS Protocols (e.g. automate Visualization DS protocol to run over all fi les in a specifi c folder) • Quickly create a Group from the current selection • Easily connect to an external relational database in the Hierarchy View using a shortcut key (context menu) • Integrate third-party algorithms or proprietary codes • Edit and save forcefi eld parameters interactively from the DS Visualizer Client

Major New Functionality: QM/MM • Navigate easily through the Tools Explorer using a • Increase accuracy of protein-ligand interaction scroll bar. Access buttons instead of dropdown lists modeling during lead optimization using a in the tool panel title bars combination of Density-Functional Theory • Calculate solvent accessibility while taking (QM) and CHARMm (MM) presence/absence of ligand into account • Perform single point energy calculations or • Explore multiple binding sites in the docking geometry optimization using a wide variety protocols due to the ability to support structures of exchange-correlation functionals and basis with more than one site sphere sets • Access hydrogen bond angle data in the Data Table • Obtain accurate partial charges for ligands for View of the 3D Window docking or simulation applications • Specify the angle criteria for Hydrogen Bond • Model specialized interactions such as cation- monitors Pi, Pi-Pi and metal-ligand-receptor interactions • Seamlessly export data from a plot to a comma Major New Functionality: HypoDB separated value fi le • Access thousands of pharmacophore models • Add error bars to a 2D plot from our partner database, Inte:Ligand, for • Import all charges from MOL V3000 fi les activity profi ling • Merge pharmacophores with a single click • Add/remove query/bond/atom labels from the Library Design and Analysis display in a single click • Filter out ligands with missing properties • Add excluded volumes by distance from a known in the Find Similar Molecules by Numeric binding site Properties protocol

• Highlight minimum and maximum values in the • Specify a Custom Score protocol and a Custom Heat Map to improve visualization Score Property when using both the Optimize • Track the alternate conformations removed from a Subset Library with Pareto Method and protein structure via the Protein Clean report Optimize Combinatorial Library with Pareto Method protocols, using an example protocol • Retain customized coloring schemes for sequence (accessible via DS Developer Client or Pipeline alignments in BSML fi les. Pilot Professional Client)

DiscoveryScript Perl Application Pharmacophore Analysis Programming Interface (API) • Quickly convert SMARTS rules to Discovery Studio • Access a large collection of customized scripts for pharmacophores using a protocol specifi c scientifi c tasks through the Scripts menu in DS 2.1, as well as from the Accelrys Community • Customize conformation generation by defi ning website(Accelrys.org) rigid fragments in the CAESAR protocol

• Create scripts using more than 70 common high- • Customize conformation generation by level operations in the user interface using a new constraining bonds and atoms in the CAESAR category called Commands that replicate UI actions mode of the Diverse Conformation Generation or act on DS data models protocol

• Improve customization by defi ning the folder used • Analyze results of the Cluster Pharmacophore when running protocols via DiscoveryScript protocol by accessing Inter-feature distances and RMS values used to calculate the distance matrix • Directly enter input parameters for scripts from the UI in the Arguments tab of the Script Window • Visualize pharmacophores aligned to the ligands after running the Ligand Profi ler protocol • Run DS protocol through a script using the RunPath path specifi cation • Append to databases created with earlier versions of Catalyst using catDB. • Color proteins using the proteinColorByMolecule data type, that has been added to Mdm:: • Access Customized Features that have the ProteinColorScheme following enhancements

• Quickly list all property names for an object using ◦ Improved feature visualization for quick a function analysis of chemistry associated with the feature • Run the following commands/tools via scripting: molecular overlay, predict DSC secondary structure, ◦ Elements in the Hierarchy view renamed for Electrostatics tools, manage constraints/restraints, the standard pharmacophore features to aid current window extents understanding ◦ Create queries of the type (Pharmacophore A ADMET OR Pharmacophore B) with one click • Filter a set of small molecules and select only ◦ Automation when creating customized those molecules that meet the rules specifi ed by queries to improve usability (e.g. aromatic the set of selected SMARTS® rules. bonds are automatically perceived and set) Electrostatics added ◦ • Access the reference titration curves for each Ability to use Customized Feature in Feature titratable residue in a protein while running Mapping protocol added the Calculate Protein Ionization and Residue pK protocol ◦ Improved error handling (check features • Increase accuracy of docking using the Dock before adding to the dictionary and disallow Ligands (LibDock) protocol due to improved additions of bad queries) hotspot matching. Track the hotspots used for docking in the LibDock protocol • Browse for Database Files, and get a report of 3 the failed compounds, in the Build D Database Simulations protocol • The performance of all CHARMm based • Get a report of failed compounds in the Build 3D protocols has been improved by using the Database protocol FAST nonbond routine using lookup tables for • Analyze non-fi tted ligands in the Screen Library solvent-solvent, solvent-solute and solute- protocol solute interactions

• Catalyst Server enhancements: • All protocols have been enhanced to use the newly optimized Generalized Born parameters ◦ Create and modify large (>2 GB) database fi les by default ◦ Append to and merge databases in the legacy • The Calculate Interaction Energies protocol format has been enhanced to report residue level ◦ Access effi cient shape indexing which is now interaction energies done on disk rather than in memory and uses • Track the charging algorithm for each very little memory. molecule in the Data Table View of the 3D Protein Modeling Window for several protocols • Employ the accurate ZRANK scoring option for • Choose from van der Waals or user specifi ed the ZDOCK Protein docking protocol radii for GBMV, GBSW, and PBSA implicit solvent models • Use secondary structure information for improved alignments in the Align and • Access the GBMV option in the minimization Superimpose protocol and molecular dynamics protocols

• Import Insight II – ZDOCK data into DS 2.1 • Use the molecular surface defi nition for the using a utility protocol dielectric boundary in the GBSW protocol

• Access the updated ZDOCK server (version 2.3) • Specify the salt concentration for the GBSW (2.1 also available for backward compatibility) implicit solvent model

QSAR • Quickly identify the forcefi eld used in all protocols in the output Report.html fi le • Delete user models generated by Discovery • Access the enhancements available in Studio using a protocol CHARMm version updated to CHARMm34b1 • Access molecular properties in the Calculate ◦ Column fft for better parallel performance in Molecular Properties protocol in pre-organized PME form in 1D, 2D, and 3D categories 3 ◦ Image facility added to the Constant pH • Run DMol geometry optimization as an molecular dynamics (CPMD) module to use on option in the Calculate Molecular Properties periodic boundary systems protocol ◦ Parallelization of the SCP-ISM solvent model Receptor-Ligand Interactions using standard MPI routines • Run the Flexible Docking protocol effi ciently due to signifi cant performance (disk space and memory) and usability improvements, as well as elimination of redundant poses