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‘What’s New’ in Discovery Studio 1.7

January 2007

2

What is Discovery Studio 1.7?

• A complete modeling and simulations environment for Life Science researchers– Interactive, visual and integrated– Tools for visualization, modeling,

simulations, docking, pharmacophore analysis, and more

– Access computational servers and tools, share data, monitor jobs

– Windows and Linux clients and servers (includes Pipeline Pilot server)

DS 1.7 Interface

3

What is Discovery Studio 1.7?

50% Legacy product functionality migrated to DS

30% New Science

20% Usability and enhancements

30% New

Science

4

What’s New in Discovery Studio 1.7?Highlights!

1. Pharmacophore modeling – Core functionality migrated including new science and enhanced

functionality– Ease-of-use in Discovery Studio– Integration with

• protein modeling and simulations functionality in DS• Pipeline Pilot (PP) through Catalyst component collections

2. Simulations, Protein Modeling and Structure-based design– Integration with Pipeline Pilot (PP) through CHARMm component

collection– Majority of functionality completely migrated including new science

and enhanced functionality3. Perl Scripting introduction

New in

DS 1.7

Available through our external website athttp://www.accelrys.com/products/dstudio/whats_new_ds_17.pdf

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New Protocols Overview

• New protocols and tool panels highlighted (in red) in DS 1.7– Note many existing

protocols and tool panels from DS 1.6 have been improved

24 new protocols5 new tool panels

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Visualization

• Create multiple sided surfaces and isosurfaces for enhanced molecular visualization

• Conveniently access samples and tutorial files directly through the Files Explorer

• Browse through complex molecules and defined groups easily through the improved hierarchy view

continued

Two-sided protein surface display (top)

Hierarchy view enhancement (right)

7

Visualization

• Easily search protocols given only a keyword in the Protocols Explorer

• Easily navigate through protocol parameters which are grouped and conditionally updated

• Analyze ligand-receptor interactions through heat map generation

• Modify or build custom 3D small molecules with the fragment builder toolpanel

* DS Visualizer Pro only Protocol searching and parameter grouping (left) Fragment builder tool panel (right)

8

Customization and Scripting

• Customize the interface by adding user defined toolbars, toolpanels and shortcut keys

• Automate workflows through Perl scripting– Accessible through command-line, DS Visualizer Pro

client or Pipeline Pilot client– Access to rich Perl scripting language constructs– Scripts can be combined with other (both non-Accelrys

as well as Accelrys) scripts

Perl script examples (left)

Scripting documentation (top, right)

9

Discovery Studio and Pipeline Pilot Integration

• View all DS protocols in Pipeline Pilot (PP) including examples DS protocols

• Custom protocols can be viewed in PP and DS

Pipeline Pilot Interface

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Sequence Analysis

• Cluster sequence or structure information through interactive dendrogramanalysis

• Build phylogenetic trees with choice of distance methods, mode, and replication number

• Compare input sequence profile with a profile database (PDB_nr95) for remote (~%10 seq. identity) homology recognition – Scan Sequence Profile

protocol from MODELER

Changing dendrogram views (rect. & radial) (top)Phylogenetics Tool panel (bottom)

New science

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Nucleic Acid Modeling and Simulations

• Build and modify nucleic acids (DNA and RNA) given sequence or choosing nucleotides through the build and edit nucleic acid toolpanel

• Type and simulate nucleic acids – Solvate– Force field typing– Minimize and calculate

energy– Perform molecular

dynamics Build and type nucleic acid complexes

through tool panels (top)

Then .. perform simulations and molecular dynamic through

CHARMm-based protocols (left)

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Protein Modeling

• Access complete MODELER 9.0 functionality through command-line

• Evaluate protein models during model building, mutating and refining loops based on the MODELER DOPE (Discrete Optimized Protein Energy) energy function

• Optimize side-chains or a loop region of a protein structure using in-house developed algorithms based on CHARMm

V. Spassov,, et al. “LOOPER : A CHARMm based Algorithm for Loop prediction”V. Spassov, 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”

MODELER DOPE score for several built models (top)

Results of loop refinement protocol (bottom)

New science

New science

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Protein Analysis

• Check the quality of the protein structure and analyze regions with abnormalities using the ‘Protein Health’ toolpanel

• Evaluate model quality using the ‘Verify Protein (MODELER)’ protocol based on the MODELER DOPE (Discrete Optimized Protein Energy) energy function

Protein health tool panel for checking quality of proteins

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Simulations

• CHARMm MM/MD with explicit or several implicit solvent models– PBSA, GBSW, GBMV, GBORN, etc.

• Create complex simulation workflows in Pipeline Pilot with CHARMm Component Collection– Access to all CHARMm functionality

through a custom component

New parameters in simulation protocols

New science

Example of workflow in Pipeline Pilot using CHARMm Component

Collection

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MM-GBSA and MM-PBSA Scoring

10. Kuhn B. and Kollman P.A., JMC, 2000, 43, 3786-3791.11. Brown S.P., and Muchmore S.W., J. Chem. Inf. Modeling, 2006, 46, 999-1005.

R = 0.96

R = 0.85

R = 0.84

R = 0.91

R = 0.92

−70

−60

−50

−40

−30

−20

−10

0

10

-25 -20 -15 -10 -5 0

Experimental ΔGbind, kCal/mol

Calculated Δ

Gbind , kC

al/mol

Kuhn andKollman (10)MD-PBSA

Brown andMuchmore (11)MD-PBSA

DiscoveryStudio MM-GBSA, ImplicitSolvent

DiscoveryStudio MM-GBSA, ExplicitSolvent

DiscoveryStudio MM-PBSA, ImplicitSolvent

More at http://www.accelrys.com/info/charmm_sbd/

• Biotin and analogs manually docked to Avidin (1AVD)

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Analysis of Trajectories

Hydrogen bondmonitors

Interaction Energy (“INTER”)Between random subsets of atoms

Pairwise Cα RMS deviationsbetween frames along

trajectories

17

Receptor-Ligand Interaction

• Ligand Preparation – Automated, accessible,

extensible and customizable

• De novo Evolution (AutoLudi) – Quick mode– Full Evolution– Combinatorial mode

Ligand Preparation protocol (top)

Building ligand using the de novo Evolution protocol (right)

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Analysis of Docked Poses

• H-bond analysis– Molecule, chain, residue, atom

levels• Close contact analysis

– Polar and non-polar contacts• RMSD analysis on poses vs. user-

specified pose

ARG222 ALA224 TYR225 SER226

Doc

ked

Pose

sHeat map:# of H bonds per residue

for each pose

19

ADMET

• Filter undesirable compounds by calculating absorption, distribution, metabolism, and excretion (ADME) properties derived from chemical structures

• Compute and validate assessments of the toxic and environmental effects of chemicals solely from their molecular structure through toxicity prediction (TOPKAT®)

Create confidence ellipses plots by calculating AlogP98 and PSA_2D for BBB and absorption analysis

TOPKAT protocol example results

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Pharmacophore Modeling

• Refine and analyze pharmacophoremodels through automated clustering, analysis, merging, and charting

• Rapidly process millions of molecules with the superfastconformer generation algorithm (CAESAR) using the efficient divide and conquer approach

• Explore focused yet diverse chemical space with pharmacophore based de novofragment linker

• Elucidate pharmacophore models from known or putative protein active site (structure-based pharmacophore method)

Ligand-based pharmacophore

Receptor-based pharmacophore

PharmacophoreTool panel

New Science

New Science

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Pharmacophore Modeling

• Screen libraries with automated permutations of pharmacophore models

• Rapidly analyze per feature contributions for selectivity and promiscuity with heat-map charting

• Filter-out undesirable ligand orientations in the protein active site with pharmacophore based scoring

• Seamlessly integrate fast 3D pharmacophore search ability with accuracy of force field scoring

Results of a Screen Library protocol and heat map analysis

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Pharmacophore Modeling

• Enable 3D chemistries through Pipeline Pilot with Catalyst Components

Training Ligands

Conformer Generation

Model Building

3D Database Searching

Select Hits

FAST

BEST

CAESAR

Shape

HipHop/Hypogen

Excluded Volume

DB Building

DB Searching

Pharmacophore Scoring