Discovery Studio 2.1: New Science and Customized Workflows for Drug Discovery Research

Webinar Abstracts

Recordings Available

Advances in Protein Modeling and Protein-Protein Interactions in Discovery Studio
Francisco Hernandez-Guzman – June 12, 2008

There has been tremendous interest in recent years in applying protein modeling methods more directly in drug discovery. Examples of this include antibody modeling and studying and disrupting protein-protein interactions. Accelrys offers a complete suite of tools for this growing area of computational research. This presentation will highlight some of these tools, including an automated antibody modeling workflow, physics-based prediction and optimization of side-chains (ChiRotor) and loops (Looper), and a complete solution for studying protein-protein interactions (RDOCK/ZDOCK).

Physics Based Protein Ionization and pK Estimation
Francisco Hernandez-Guzman – June 19, 2008

This presentation will focus on a very fast and accurate physics-based method to calculate pH dependent electrostatic effects in protein molecules, to predict the pK values of individual sites of titration, and to construct and refine all hydrogen atoms coordinates at a given pH. The use of the GBIM (Generalized Born with Implicit Membrane) CHARMm module makes it possible to model protein-membrane complexes as well. Tests on a set of 24 proteins structures from the PDB show that on average, the rmsd between predicted and experimental pK values is close to 0.5 pK units. This accuracy is achieved at an average cost of 1-2 minutes per structure. The pH-dependent assignment of hydrogen atoms also shows very good agreement with five neutron-diffraction structures: giving 94% accuracy across 849 residues, including 100% of tautomeric states of histidines and 82% of Asn and Gln amide groups. Applications of the method include:

Optimizing the protonation state of proteins for downstream calculations, such as accurate docking or more stable Molecular Dynamics simulations
Estimating maximum stability by studying the pH dependent folding energy of proteins
Calculating the electrostatic component of protein-ligand binding energies or protein-protein binding energy
Using unusual tritation curves to find active site residues

Towards Increased Accuracy in Computational Drug Discovery with QM/MM
Dipesh Risal – June 26, 2008

This presentation will describe a method that combines a quantum mechanical (QM) program and a molecular mechanics (MM) force field, to give a so-called QM/MM treatment of a given protein-ligand complex. Specifically, the ligand and optional protein residue atoms in the binding site are treated with the density functional program DMol 3 (QM), while the rest of the protein is subjected to the CHARMm force field (MM). Both single point energy calculations, as well as geometry optimizations can be performed. The workflows have been deployed to address specific questions that are relevant to computational drug discovery. Specifically:

Do QM-derived charges for ligands (within a point-charge representation of the protein) improve the accuracy of MM minimization, when compared to minimization using standard force field charges?
Starting from a reasonable protein-ligand complex structure, does QM/MM geometry optimization improve the quality of the ligand structure, when compared to force field-based minimization?
In a real-world scenario where experimentally observed bound conformations of ligands are not available, can QM/MM methods combined with docking be used to obtain reasonable ligand poses?

Result will be presented that address each of these questions.

Pharmacophore Guided Fragment-Based Drug Design
Tien Luu – July 10, 2008

Pharmacophores describing interactions between biological targets and ligands are an established screening tool at early stages of drug discovery. The use of fragment-based approaches in drug discovery has gained widespread popularity in recent years. We have recently introduced an in silico method that utilizes pharmacophores for a combinatorial fragment-based approach applicable to the design of novel compounds, and for lead optimization. Starting with a pharmacophore (no requirement for protein structure) small molecular fragments can be rapidly assembled into new molecules. Advantages of starting from fragments include an increased diversity in chemical space, but also the flexibility to incorporate drug-like properties at early stages of the design.

Advances in Pharmacophore Modeling and Parallel Screening
Ragi Raghavan – July 17, 2008

This presentation will highlight the substantial new features and enhancements that have been added to the Discovery Studio 2.1 release in the area of Catalyst-based pharmacophore modeling. Highlights include the availability of the Inte:Ligand database for activity profiling, customizable pharmacophore features, and significant usability enhancements for pharmacophore modeling in general.

Workflow Customization with DS Developer Client
Luke Fisher – July 24, 2008

“Automated Workflow” or “Customized Workflow” are frequently used buzz words, but what do they really mean to the research scientist? How can they address common hurdles researchers face everyday? With the new release of Discovery Studio (DS) 2.1, Accelrys is pleased to announce a new addition to its modeling and simulations environment to address these questions.

The DS Developer Client can be used to perform the following levels of customization of Pipeline Pilot-based DS Protocols:

Customize (i.e. promote or de-promote) parameters of existing DS protocols/components
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.)

We will provide some useful and simple examples of how users can take advantage of this easy customizability of DS science.

Tips and Tricks in using Discovery Studio
Al Maynard – July 31, 2008

Discovery Studio (DS) now contains a rich set of tools and methods designed to address most, if not all, of the needs of a computational scientist in the Life Sciences. The Perl-based scripting environment opens up the possibilities of customizing the graphical environment of DS even further. In this session, we will highlight simple Tips and Tricks that will enhance the usability of DS and thus ensure that the tools/features you need on a daily basis are right at your fingertips.