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Register
Today!
Arrive early to attend Protein
Kinase Targets (June 4 - 6)
Friday, June 8
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Breakfast Technology Workshop
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Sponsored
by
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Structural Studies of Membrane Proteins: A Survey of Successful Techniques
and the Design of Rational High-Throughput Strategies
Christopher M. Koth, PhD, Research Scientist II, Membrane Protein
Structural Biology, Vertex Pharmaceuticals Inc.
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Approximately one third of the proteins encoded in prokaryotic and eukaryotic
genomes reside in the membrane. Moreover, the majority of drugs on the market
target membrane proteins. However, membrane proteins comprise only a minute
fraction of the entries in protein structural databases. This disparity is
largely due to inherent difficulties in their expression and purification. To
begin addressing the challenges of membrane protein production for drug
discovery and structural genomics efforts, it is necessary to develop simple
strategies that permit the standardization of procedures and the exploration
of large numbers of proteins and/or constructs. I will present an in-depth
survey of successful methods that have yielded membrane protein crystals
suitable for structure determination. A number of recurrent trends in the
expression, solubilization, purification and crystallization techniques will
be summarized. We have developed robust strategies, based largely on these
observations, that rapidly identify highly expressed membrane protein targets
and simplify their production for structural studies.
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8:30 Chairperson's Opening Remarks
8:40 Using Glide XP to Rank Order the Binding Affinities of Protein-Ligand
Complexes
Richard A. Friesner, Ph.D., Professor, Chemistry, Columbia University
This talk will describe ongoing efforts to improve the Glide extra precision
(XP) scoring function and sampling approach to the point where it can yield
useful results in rank ordering diverse compounds. The key elements of the
methodological improvements are augmentation and reparametrization of the
current scoring function, coupled with the incorporation of receptor flexibility
to enable the correct structure to be generated even if the ligand does not
"fit" in the receptor conformation used in the screening. The scoring
function can be tested by using structures generated via native self-docking,
and this will be the emphasis of the present talk. Preliminary results for the
second phase of the project,
modeling induced fit effects, will be presented for a small number of targets.
9:10 Protein and Ligand Structure-Based Design for GPCRs
Sid Topiol, Ph.D., Associate Director, Computational Chemistry, Lundbeck
Research, USA, Inc.
Protocols to do drug design for soluble proteins is becoming straight
forward, albeit non-trivial. For GPCR targets, structure based approaches are a
new frontier and likely to be limited to homology models for some years.
Nevertheless, experience gained from soluble protein design can be capitalized
on for GPCRs. We demonstrate that such approaches are able to provide valuable
results, particularly when coupled to a broad platform of ligand based
approaches. Studies illustrating lead finding, optimization and novel template
identification will be presented.
9:40 Coffee Break, Exhibit & Poster Viewing
10:15 Structural Interactions of CCR5 with HIV-1 Entry Inhibitors
Debananda Das, Ph.D., Senior Research Fellow, HIV & AIDS Malignancy
Branch, National Cancer Institute, National Institutes of Health
Effective treatment of HIV continues to be a daunting challenge due to the
emergence of drug resistant mutations in the target viral enzymes. CCR5 is a
novel cellular target for the intervention of HIV replication. However, an X-ray
or NMR structure of CCR5, a GPCR, does not exist. By combining the results of
site directed mutagenesis experiments, homology modeling, and docking that
accounted for the flexibility of the receptor side chains, we characterized the
structural and molecular interactions of CCR5 with multiple CCR5 inhibitors
active against R5 HIV-1 including a potent in vitro and in vivo CCR5 inhibitor
aplaviroc. The quality of the structural model was evaluated by carrying out new
saturation binding experiments by mutating CCR5 residues predicted to be
important by the model. The structural model enabled us to precisely define the
binding site of CCR5 inhibitors within CCR5 and elucidated the key binding site
interactions responsible for the anti-viral activity in the inhibitors. We will
discuss preliminary virtual screening results and structure- based drug design
strategies that target specific residues of CCR5 to minimize toxic side effects.
10:45 3D Clustering – A Tool for Processing High-Throughput Docking
Results
John P. Priestle, Ph.D., Discovery Technologies, Novartis Institute for
BioMedical Research
Because the number of hits coming out of a high-throughput docking analysis
usually far exceeds the number of compounds that can actually be biologically
tested, various filtering procedures are used to reduce these hits to attain a
much smaller set of compounds that best represents the whole set. One of the
most valuable procedures is the clustering of molecules, usually based on 2D
chemical descriptors, which allows the selection of a few representative
compounds from groups of related molecules based on the assumption that similar
molecules bind to the target molecule in a similar manner. While generally a
reasonable assumption, there are cases of closely-related molecules binding to
proteins in surprisingly different ways. We propose a method for clustering
docking poses based on their 3D coordinates as well as on their chemical
structure.
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11:15 Technology Watch
Integrated Environment for Docking Small Molecules into Flexible Receptors
Dipesh Risal, Ph.D., Product Manager, Lifesciences, Accelrys, Inc.
We have developed new solutions in the integrated environment of Discovery Studio for docking where both ligand and receptor flexibility are taken into account. These solutions can further be combined withpharmacophore-based methods to create customized workflows using the tight integration with Pipeline Pilot that exists in Discovery Studio.
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Sponsored by
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11:30 Bringing it all Together: the Role of Structure, Virtual Screening, Fragments and Modeling in Generating Lead
Compounds
Roderick E. Hubbard, Professor, Senior Fellow, Department of Structural Sciences, Vernalis
Ltd.
Our approach is to generate as much structural information as possible in the hit identification phase, using our proprietary virtual screening system, rDock and our NMR-based fragment-based discovery process, called SeeDs. We use crystallography to determine the structures of SeeDs fragments and rDock hits bound to the target as well as the structure of any known literature compounds. This structural information is then used to design novel hit compounds, often combining together key interaction features from a number of fragments and compounds. These hits are then optimized using the structural information to guide the medicinal chemistry. This approach has been successful in a number of projects, producing lead series of compounds against kinases such as PDK1 and CHK1 and ATPases such as Hsp90. A number of these compounds have advanced into pre-clinical and full development. This presentation will review how structural methods were used to optimize medicinal chemistry properties into lead series and the lessons learnt (and methods developed) to deal with solvent and protein flexibility.
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12:15 - 1:30 Lunch on your own
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1:30 Chairperson's Remarks
1:40 Structure-Based Discovery of Aliskiren (Tekturna ®)
N. Claude Cohen, Ph.D., President & Chief Executive Officer, Synergix
Ltd.
At Ciba-Geigy (now Novartis), the clinical development of the CGP38560 renin
inhibitor was halted due to insufficient pharmacokinetics. This indicated
that the peptidomimetic approach to the development of antihypertensive
agents was improper. Real non-peptide drug candidates were then expected to
provide the necessary framework for obtaining the desired properties. For
this purpose a homology model of the enzyme was used to characterize the
binding mode of CGP38560 in complex with the renin model and served as a
basis for the four chemistry laboratories that were assigned to this
project. The renin team worked in a full structure-based perspective with
this model, and four chemically-unrelated non-peptide series were
discovered acting as renin inhibitors at the 1-3 nanomolar level. One of
these leads was selected for further development and led to Aliskiren, which
has been just approved by the FDA (in March 2007). X-ray structures of the
complexes with these inhibitors were solved. These confirmed the validity of
the concept and also revealed some unexpected features of the enzyme. This
opened a new era at Ciba-Geigy/Novartis where the modeler is named as the
inventor in the patent applications - along with the chemists. I will
present the successful structure-based strategy that enabled the discovery
of several non-peptide inhibitors and the recent launch of a new drug that
will be commercialized in the United States under the name Tekturna® (for
the treatment of high blood pressure as monotherapy or in combination with
other high blood pressure medications).
2:10 Structure-Based Discovery of DPP4 Inhibitors for Diabetes Therapy
(Two in One Case Studies)
Kent Stewart, Ph.D., Research Fellow, Structural Biology, Abbott
Dipeptidyl peptidase IV (DPP4) is a therapeutic target of active interest for
treatment of diabetes. This talk will present the scientific stories of two drug
discovery programs - one peptide-based and the other non-peptide based - which
lead to candidate compounds ABT-279 and ABT-341, respectively. After a detailed
discussion of both programs, common and contrasting scientific themes will be
identified. Structure-based technologies, both protein x-ray and modeling,
played key roles in both programs.
2:40 Technology Watch (Sponsorship Available)
2:55 Refreshment Break, Exhibit & Poster Viewing
3:30 B Discovery and Optimization of Novel Drug Like Molecules via The
ConTour™ Design Technology
David Claremon, Ph.D., Vice President of Chemistry, Vitae Pharmaceuticals
A novel de novo technology will be described that allowed the design of
structurally distinct classes of PPAR-alpha agonists, and also the design of
innovative renin inhibitors. The underlying methodology uses, ConTour™, a
growth and scoring algorithm that is based on predicting binding free energies
of protein-ligand complexes. The iterative use of the technology rapidly allowed
us to design, score, and rank thousands of ideas leading to a select set of
attractive targets for synthesis. The select set of compoundssynthesized
exhibited high potency in in vitro assays. The success of this approach relies
on the medicinal chemists’ abilities to capitalize on their creativity using
the scoring function results as a virtual in vitro assay, such that the time
spent in the laboratory maximizes production of molecules having appropriate
biological activity within the confines of properties predicting bioavailability.
Furthermore, the philosophical hurdle of accepting modeling predictions as a
surrogate for actual biological results relies on the quality of the scoring
function’s performance, which is validated as results materialize from the
biological screening assays. A critical component of the paradigm for drug
discovery at Vitae is to obtain in vitro results to drive the objectives of a
project team, in addition to harvesting these results to improve the accuracy of
the in silico prediction tools.
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4:00
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Closing Panel Discussion
LESSONS TO TAKE HOME
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Highlights will include:
- What do we mean by (traditional) structure-based drug design today?
- Build and/or Buy: What do we want from software vendors?
- Validation Studies: What can be done to improve the quality of our
software?
- What have we learned?
- What are we still losing sleep over?
- What do we need to seriously consider going forward?
Moderator:
Mark Murcko, Ph.D., Vice President & Chief Technology Officer, Scientific
Advisory Board, Vertex Pharmaceuticals Inc.
Panelists:
Celerino Abad-Zapatero, Ph.D., Associate Research Fellow, Protein
Crystallography Laboratory, Abbott Laboratories
Jose S. Duca, Ph.D., Senior Scientist, Computer Assisted Drug Design,
Schering-Plough Research Institute
Richard A. Friesner, Ph.D., Professor of Chemistry, Columbia University
Jeremy L. Jenkins, Ph.D., Research Investigator, Lead Discovery Center,
Novartis Institutes for BioMedical Research Inc.
Ulrich Rester, Ph.D., Senior Research Scientist, Medicinal
Chemistry, Bayer HealthCare AG
Tomi K. Sawyer, Ph.D., Senior Director, Chemical Sciences,
Pfizer Research Technology Center
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4:50 Chairperson's Closing Remarks
5:00 Close of Conference
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