Structure-Based Drug Design Conference Final Brochure.pdf

characterizing critical waters (e.g. tight-binding), assessing the affinities
of small molecule fragments, and identifying hot spots in proteinprotein
interaction targets.
4:10 Next-Generation Shape Signatures: A Powerful Tool for
Fragment-Based Drug Discovery
Randy Zauhar, Ph.D., Associate Professor, Chemistry & Biochemistry,
University of the Sciences
The original Shape Signatures method uses a ray-tracing approach to
efficiently explore the volume and surface properties of a molecule.
In our new approach, molecules are automatically partitioned into
fragments, and the Shape Signatures descriptors are now likewise
fragment-based. Query and target molecules are now compared by
matching fragment in all ways compatible with the underlying structure.
4:35 Panel Discussions:
Topic: What are the challenges and opportunities for the next
stages of development in fragment-based methods
For many targets, the identification of fragments that bind is for
the most part a solved problem. There are two main issues for the
methods. The first is deciding which fragments to take forward – there
can be hit rates of 5-10% for some targets. The second is how to guide
the early stages of chemical optimisation in the absence of crystal
structures, which is a particular problem for challenging targets such
as protein-protein interactions. The discussion will ask for opinions
on how computational methods could tackle these issues and what
developments are still needed.
5:00 Networking Cocktail Reception in the Exhibit Hall with
Poster Viewing
6:00 End of Day
FRIDAY, JUNE 10
HIGH PERFORMANCE COMPUTING AND
COLLABORATIVE DRUG DESIGN
8:10 am Chairperson’s Opening Remarks
Jonathan Essex, Ph.D., Head, Computational Systems Chemistry;
Chairman, Institute for Complex Systems Simulation (ICSS), School of
Chemistry, University of Southampton
8:15 Molecular Dynamics Drug Docking: Modeling Ligand
Interactions in the Age of High Performance Computing
Michael Kuiper, Ph.D., Computational Scientist, Victorian
Partnership for Advanced Computing
Continuing advances in computational performance now
allow researchers to routinely simulate protein molecules
in the order of hundreds of nanoseconds. At this timescale
it is possible to investigate detailed interactions of ligands
with receptors starting with the free ligand in solution. Though not
yet suitable for high-throughput drug screening, molecular dynamics
drug docking (MDDD) however does offer researchers an approach to
observe complex drug/ligand interactions not typically considered in
drug design.
8:40 The Internet is Here to Stay: Web Service Delivery of
Computational Properties
David Thompson, Ph.D., Senior Principal Systems Engineer,
Boehringer Ingelheim GmbH
A robust and extensible web services framework for the
delivery of computational properties to the medicinal
chemist’s desktop will be presented. This architecture fully
leverages our High Performance Compute environment,
exposes a wide variety of computational engines, and can be utilized
in a manner that best fits the scientists’ requirements. Use cases
including the consumption of in silico physicochemical properties and
the distribution of quantitative structure-activity relationship (QSAR)
models will be described.
FREE ENERGY APPROACH TO
STRUCTURE-BASED DRUG DESIGN
9:05 The Binding Energy Distribution Analysis Method
(BEDAM) for Structure-Based Drug Design: Theory and
Applications
Ronald M. Levy, Ph.D., Board of Governors, Professor of Chemistry &
Chemical Biology, Rutgers University
The binding energy distribution analysis method (BDEAM) for structurebased
drug design is a new approach to computing protein-ligand
binding free energies which makes use of replica exchange molecular
dynamics simulations to compute absolute binding affinities. The
balance between binding enthalpy and entropy is seen in our formalism
as a balance between unfavorable and favorable binding modes. Both
the theory and application of BEDAM will be discussed.
9:30 Fragment-Based Screening by Free Energy Simulations
Jonathan Essex, Ph.D., Head, Computational Systems
Chemistry; Chairman, Institute for Complex Systems
Simulation (ICSS), School of Chemistry, University of
Southampton
Free energy simulation is potentially a very powerful tool
for structure-based drug discovery. In this presentation,
the application of a number of these techniques to locate and score
molecular fragments and water in protein binding sites are described.
These approaches offer advantages over more conventional simulation
methods in that not only is fragment binding ranked in terms of
free energy (i.e. entropy is included), but all fragments are in direct
competition with water for the binding site.
9:55 A New Computational Method for Predicting Binding
Free Energies of Protein-Ligand Interactions
Christopher Langmead, Ph.D., Associate Professor of Computer Science,
Carnegie Mellon University
This presentation will discuss a new computational method, called
GOBLIN, for performing physics-based free energy calculations under
protein and ligand flexibility. GOBLIN compactly encodes Boltzmann
distributions over structures by exploiting conditional independencies.
Results on HIV-1 PR will be presented demonstrating that it achieves
superior quantitative accuracy than competing methods.
10:20 Small Covalent Peptidomimteic Inhibitors of Crm1
Mediated Nuclear Transport
Sharon Shechter, Head of Computational Discovery, Karyopharm
Therapeutics Inc
Nucleo-cytoplasmic transport of macromolecules is a fundamental
process of eukaryotic cells. Translocation of proteins and many RNAs
between the nucleus and the cytoplasm is carried out by shuttling
import and export receptors. CRM1 (Xpo1) is a major exporter
for proteins from the nucleus to the cytoplasm, including tumor
suppressors (TSPs) and other growth regulatory proteins (GRPs).
Here, we describe the identification of novel Crm1 inhibitors using
computational, hierarchical structure-based discovery process.
10:35 Networking Coffee Break in the Exhibit Hall with Poster
Viewing
»»
KEYNOTE PRESENTATION
11:00 Millisecond-Long Molecular Dynamics Simulations of
Proteins on a Special-Purpose Machine
David E. Shaw, Ph.D., Chief Scientist, D. E. Shaw Research
and Senior Research Fellow, Center for Computational
Biology and Bioinformatics, Columbia University
Molecular dynamics simulation provides a potentially
powerful tool for understanding the behavior of proteins
at an atomic level of detail, but its relevance to drug
design has previously been limited in part by the computational
demands of such simulations. We have constructed a specialized
supercomputer, called Anton, that has simulated the behavior
of a number of proteins for periods as long as a millisecond --
approximately 100 times the length of the longest such simulation
previously published -- revealing pharmaceutically relevant aspects
of protein dynamics that were previously inaccessible to both
computational and experimental study.
11:45 SZMAP: Mapping Solvent Sponsored by
Thermodynamics in Binding Sites
Anthony Nicholls, Ph.D., President & CEO,
OpenEye Scientific Software
Semi-continuum solvent theory captures discrete effects that can
be important in enclosed spaces such as binding cavities. Using this
model, SZMAP rapidly maps thermodynamic quantities of water
molecules near protein surfaces by employing a single explicit water
probe. The resulting quantities may be used as a correction factor for
continuum solvent calculations as well as serving to guide the design
of ligand analogues and optimizing binding affinity.
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