Transcript mpodvinec_egee-ii - Indico

The Dengue Docking Project:
Virtual Screening on the ProtoGRID
EGEE'06 conference, Swiss Grid Track
Dr. Michael Podvinec
Biozentrum, University of Basel
&
Swiss Institute of Bioinformatics
Basel, Switzerland.
Areas infested with Aedes aegypti
Areas with Aedes aegypti and recent epidemic dengue
Data: CDC, 1999
Every year:
• 2.5 billion are at risk of infection
• 50-100 million people get infected with
Dengue
• 500'000 cases of Dengue Hemorrhagic Fever
• 25'000 deaths
No vaccination.
No specific treatment available.
Public-private partnership
• Biozentrum, University of Basel :
in silico docking
• NITD:
In vitro/in vivo follow-up
• Novartis:
Drug development at cost
• Schrödinger, Llc.:
Scientific collaboration on docking
• SwissBioGrid
Grid computing resources,
Proof of Concept for SwissBioGrid
What does it take to make a drug?
Target ID
Target
validation
Screening Optimization
HIT
LEAD
Preclinical Clinical
CANDIDATE
DRUG
~12 years
802 mio US$
(DiMasi, J.A. et al. (2003) J Health Econ, 22, 151-185).
only 1 in 10‘000 NCE survives
(Heilman, R.D. (1995) Qual Assur 4(1) 75-9.)
DRUG
Virtual screening to the rescue?
Target ID
Target
validation
Screening Optimization
HIT
LEAD
Preclinical Clinical
CANDIDATE
DRUG
 Virtual screening (computer simulations)
• Save initial investment (HTS)
• Predict likely hits in silico
• GRID-based
• Still must assay results
DRUG
Camille Pissarro, Haystack, 1873
Protein-ligand complexes
share common characteristics.
We can use these characteristics
to predict ligands for target molecules.
Structure and serotype analysis of
dengue target sites:
catalytic triad
b-OG
1: Envelope Glycoprotein
E
3: NS3 RNA
P1Arg contact
2: NS3 serine protease
b
GMP analogue
4: NS5 RNA methyl
S-Adenosylhomocysteine
SwissBioGrid Initiative
Federate resources
using GRID
technology
[BC]2
[BC]2
Linux cluster
UD PC grid
Uni ZH
provide computingAIX
platform
cluster
Basel
Zürich
enable Dengue proof-of-concept
VitalIT
Linux cluster
Lausanne
International
collaborations
CSCS
UNIX HPC
resources
CERN
EGEE
Lugano
Phase I (protoGRID)
• Evaluate requirements for productive GRID
infrastructure
– Federate pre-existing Swiss HPC ressources (non-intrusive system cycle stealing ONLY)
– Swiss HPC ressources are heterogeneous: Clusters, HPC, PC Desktop
Grids
– Geographically and administratively separate entities
– Support the specific data requirements of bioinformatics applications
• Validation of docking results on heterogeneous
architectures
II (NorduGRID)
• Productive Phase
services for
the scientific PoC
(Docking
againstbased
Dengue
targets)
• Extend
NorduGRID
on lessons
learnt from ProtoGRID (data
model, LRMS support)
• Productive services for several scientific projects (e.g. peptide mass
fingerprinting in proteomics)
SBG Phase 1: ProtoGRID
Single interface to Swiss HPC resources
QW
QW
[BC]2 PC Desktop Grid
(UD MP, Win32)
Basel
Grid Node Manager
Grid Data Manager
QW
[BC]2 HPC cluster
(SGE, x86-32)
Basel
CSCS
(PBS, Itanium 64)
Ticino
QW
Vital-IT HPC cluster
(LSF, Itanium 64/ Nocona)
Lausanne
Some hurdles in grid adoption
[as identified in the SwissBioGrid development process]
• Where do the CPUs come from?
– Most HPC resources are busy already
• Agree on dedicated compute time for grid projects?
• Buy new clusters for your grid?
– PC Desktop grids provide a huge untapped resource
• Licensing schemes
of most commercial software are not suitable for GRIDs
• Application clearing:
• Ensuring data integrity on distributed resources
• Non-intrusiveness of the application
• Security issues: Avoid accidental or malicious negative impact on running
systems
• Numerical stability in heterogeneous environments
• Data model in bioinformatics is different from HEP
• Most applications need access to large public databases
Achievements of
GRID-enabled Dengue Docking
• Technical: Phase I SwissBioGrid
infrastructure complete
• large-scale parameterization test
using Autodock 3.0.5:
500‘000 docking runs,
38‘000h CPU time
• Prioritized hit list from 127k
library screening (GLIDE) is
undergoing In vitro testing at NITD
• Some initial hits
(at 20 M)
• Currently screening the ZINC open
source compound library (~4 Mio cpd)
Acknowledgements
Biozentrum & SIB
University of Basel:
Torsten Schwede
Jürgen Kopp
Marco Scarsi
Rainer Pöhlmann
Konstantin Arnold
Vital-IT:
Victor Jongerneel
Bruno Nyffeler
Jacques Rougemont
Heinz Stockinger
Arthur Thomas
CSCS
Marie-Christine Sawley
Peter Kunszt
Sergio Maffioletti
Fraunhofer SCAI:
Martin Hoffmann
Marc Zimmermann
EGEE/CNRS:
Vincent Breton
Nicolas Jacq
Schrödinger, Inc:
Jörg Weiser
Novartis Institute for
Tropical Diseases
Alex Matter
Mark Schreiber
Subhash Vasudevan
Siew Pheng Lim
Novartis
Manuel Peitsch
René Ziegler
Eric Vangrevelinghe
Pascal Afflard