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Scientific Advances in Discovery Studio 2.0 : Webinar Series

Webinar Abstracts

 

Overview of Discovery Studio 2.0 - Dr. Paul Flook - Accelrys R&D

Discovery Studio 2.0 marks a major milestone in Life Sciences product development at Accelrys. This release delivers a unified environment for performing a comprehensive range of modeling and simulation tasks. View this webinar to learn more about features in Discovery Studio 2.0 that will help you:

  • Access a complete set of Life Sciences analysis tools within the Discovery Studio Visualizer
  • Employ new scientific functionality for analyzing macromolecular, small molecule and sequence data
  • Build, customize and deploy scientific workflows using Pipeline Pilot
  • Automate critical workflows in Discovery Studio and Pipeline Pilot using Perl scripting

 

New Simulation Methods for Drug Discovery: Fast Accurate pK Prediction and More - Dr. Dipesh Risal - Accelrys Product Marketing

In this webinar, we will discuss the pK prediction and other new science in Discovery Studio 2.0 in the simulation area. Depending on the structural environment in a protein, pK shifts away from standard pK values of acidic and basic residues are frequently observed, especially for residues on the catalytic site of enzymes. We have developed a method using the generalized Born model to predict the pK of titratable residues in a given protein system. Initial validation results show that the method is more accurate than existing methods and is much faster then the existing methods using Poison-Boltzman approach. The calculation can be performed in the presence of ligands and the underlying Pipeline Pilot component can be integrated as part of the ligand docking or protein docking experiment to provide the electrostatic energy as part of the docking score. The method also protonates the residues at a user specified pH according to the predicted pK values. Protonation states of residues with tautomeric states and ASN/GLN side-chain flips are optimized based on CHARMm energy.

  • Improve results of protein-ligand and protein-protein docking
  • Increase accuracy of protein-ligand scoring
  • Increase stability of molecular dynamics trajectories
  • Study stability of proteins and mutants

 

A Rational Approach to Receptor-Flexible Docking: Method and Validation Results - Dr. C. M. (Venkat) Venkatachalam - Accelrys Fellow, life sciences

Experimental evidence shows that protein structures adopt varying conformations when different ligands are bound to it. Virtual high-throughput screening generally employs a single receptor structure with a wide variety of ligands. However, protein flexibility may play a vital role in the mechanism of ligand docking. We have developed an automated method for docking ligands where ligand flexibility and protein side chain flexibility are both taken into account. The ongoing validation of the methodology is aimed at answering questions about the correct identification of flexible residues and the accuracy of both side chain placement and ligand docking. Results of ligand docking with several protein systems have been obtained and investigated. The method can be easily extended to consider loop conformation changes as well.

  • A rational approach to flexible docking
  • Stellar cross-docking validation results
  • Ideal for vHTS applications

 

Going where no Pharmacophore has Gone Before: Fragment-based design and activity profiling - Dr. David Lorber - Accelrys Product Marketing

Pharmacophore modeling is a powerful method to rapidly identify new potential drugs. Pharmacophore modeling in Discovery Studio is based on Catalyst®, the industry gold-standard for over a dozen years. In Discovery Studio 2.0 we have added a 21-century interface to the core Catalyst® technology and introduced new science to extend the capabilities of pharmacophore modeling. New Science includes:

  • DS De Novo Ligand Builder uses the proven capabilities of pharmacophore modeling to guide the placement of ligand fragments for realistic fragment-based drug design
  • Ligand Profiler in DS Structure-Based Pharmacophore is a tool that instantly profiles a lead compound or series of compounds against a panel of existing pharmacophores.
    • Identify potential toxicities or side-effects early in the discovery process
    • Identify additional targets against which lead compounds might also be effective
  • The Inte:Ligand HypoDB pharmacophore database provides over 2,000 curated pharmacophores for profiling new compounds.
  • Dozens of additional enhancements, full integration of all pharmacophore tools into the discovery studio suite, plus componentized functionality for integration into customized Pipeline Pilot-based workflows

 

Practical QSAR and Library Design: Advanced Tools for Research Teams
Dr. David Lorber - Accelrys Product Marketing

Understanding Quantitative Structure-Activity Relationships (QSAR) is core to many drug discovery efforts. Discovery Studio QSAR provides a full suite of tools for creating accurate QSAR models proven effective in designing new drugs. DS Library Design applies these capabilities together with new Pareto Optimization methods for simultaneous optimization of multiple variables to create chemical libraries. These tools integrated into the easy to use Discovery Studio interface present a complete solution for designing new compounds.

  • Rapidly calculate hundreds of descriptors with proven correlation to activity
  • Easily apply validated model building techniques to confidently understand SAR
  • Optionally extend the power of the standard QSAR package with ultra-fast semi-empirically based quantum mechanical descriptors and advanced modeling tools
  • Apply Pareto Optimization to create libraries simultaneously optimized for multiple parameters
  • Provide non-expert users with sophisticated analysis tools via web deployment

 

Antibody Modeling: New Tools for Improved Success - Dr. Francisco Hernandez-Guzman - Accelrys Solutions Scientist

Template based homology modeling involves finding homologous sequences with known experimental structure, and constructing a model using an array of molecular methods. Typically the challenge is to create a good sequence alignment, and in general the regions of interest such as an active site in the case of enzymes, show a high degree of local homology. However, in the case of antibodies, we have a reverse situation where the regions of interest known as the Complimentary Determining Regions (CDR) often present very low local homology. This does not come as a surprise given the incredible diversity of binding that the immunoglobulin family presents. In Discovery Studio we introduce a new algorithm within DS Sequence Analysis specifically designed to simplify the process of creating antibody homology models and improve the accuracy of the models. The algorithm will:

  • Given an initial homology model of the antibody of interest, the algorithm will automatically find all six CDR loop regions of the antibody, and provide the key signatures for each CDR loop if such a signature exists.
  • Provide a sequence alignment and template information in preparation for homology modeling
  • Optionally, automatically construct new homology models that will incorporate new CDR loops based on the highest homologous CDR template using MODELER.

 

Elegant Protein-Protein Docking in Discovery Studio - Dr. Francisco Hernandez-Guzman - Accelrys Solutions Scientist

As novel targets involving multiple protein interactions are uncovered in the area of systems biology and drug design, awareness has grown for methods that can assist in the prediction of such interactions. In contrast with small molecule docking where the binding site is often known, or can be found with relative ease, in silico protein-protein docking presents a much more difficult task given that knowledge of areas of interaction may be limited, and proposed orientations can be in the thousands if not millions. To address this challenge Discover Studio introduces the DS Protein Docking tool kit which offers:

  • Use of ZDOCK* for rigid body docking.
  • New visualization and clustering methods to narrow the search and to help identify poses of interest that can be used for further refinement.
  • Access to the CHARMm based RDOCK* refinement program for optimization and enhanced scoring of docked poses.

*ZDOCK and RDOCK have been highly successful top performers at the world renowned CAPRI (Critical Assessment of Predicted Interactions http://capri.ebi.ac.uk/ ) meetings. Therefore, addition of new visualization and clustering methods makes protein-protein docking in Discovery Studio the solution of choice.