The Laboratory Robotics Interest Group
Mid Atlantic Chapter
November 2004 Meeting
Computational Methods
Date: Wednesday, November 3,
2004
Place: Somerset Marriott Hotel, 110 Davidson Ave., Somerset, NJ 08873
Phone: 732-560-0500, Fax: 732-560-3669
Itinerary: Social Period - 4:00pm to 6:00pm
Meeting & Presentations - 6:00pm to
8:30pm
Registration: REQUESTED, not required. Registering will
allow us to more accurately gauge seating requirements and refreshment
needs. Register
on the web at
https://www.lab-robotics.org/member/meetings.asp?rid=1. There will be
drawings from the web registrants for LRIG
laser pointers, photon keyring lights and any other donated prizes.
Door Prizes:
Laser Pointers (LRIG)
Photon Keyring Lights (LRIG)
Door prizes for the drawings gratefully accepted - a great way to get your
name out!
Agenda:
Computational chemistry and molecular modeling have emerged as obligatory tools
in the drug discovery armentarium under the broad aegis of CHEMINFORMATICS,
loosely defined as follows: "mixing of information resources to transform data
into information, and information into knowledge, for the intended purpose of
making better decisions faster in the arena of drug lead identification and
optimization (http://www.warr.com/wzarc00.html).
As such, the field has benefited from an extraordinary explosion in popularity
and awareness. To wit, citation of the term (via Google) has increased from
700 times in July 2000 vs 35,000 times in July 2004 (http://www.molinspiration.com/chemoinformatics.html).
LRIG is pleased to offer this session, which will strive to present the
'flavors' of Computational Chemistry, and its associated infrastructure for data
management, to our members.
Click here
for an overview of Computational Methods.
Food and refreshments will be available FREE OF CHARGE during the
Social Period.
There is always a Job posting board at the social. Please encourage your recruiters to
give you material to post and distribute. Openings may also be posted at
https://www.lab-robotics.org/forum/default.asp?CAT_ID=2.
There is no fee to attend the meeting.
Presentation: PREDICT modeling and in
silico screening for GPCR: From amino acid sequence to the clinic
Sharon Shacham1, Yael Marantz2,
Silvia Noiman2, Oren, M Becker2,
and Michael, G Kauffman1
(1) Predix Pharmaceuticals, 10K Gill St, Woburn, MA 01801, (2) Predix
Pharmaceuticals Ltd, 3 Hayetsira St, Ramat Gan, 52521, Israel
GPCRs constitute a major family of drug targets, involved in many physiological
responses. However, the use of structure-based drug discovery methods for GPCRs
has been limited by the fact that only one x-ray structure of a non-drugable
GPCR (i.e. bovine rhodopsin) is known. The homology between rhodopsin and other
GPCRs is very low and existing structural information is not sufficient for
accurate structure prediction and drug discovery or optimization using standard
homology modeling. Predix Pharmaceuticals has developed a suite of algorithms
that permit the structure-based discovery and optimization of drug candidates
binding to GPCRs and Ion Channels. Predix' discovery platform includes a novel
technology for modeling the 3D structure of any GPCR based solely on its
amino-acid sequence (PREDICT); The model is then used initially for in-silico
screening against any library. The 50-200 virtual hits with best scores are sent
for affinity studies in vitro. In several programs the initial hits were
converted into early drug candidates using Predix ICELR-3D platform, which
includes novel algorithms for the prediction of oral bioavailability, GPCR
selectivity, and potential for QTc prolongation through HERG ion channel
binding. The accuracy of the PREDICT models, was extensively validated,
including: (a) agreement with rhodopsin X-ray structure; (b) reproduction of
site-directed mutagenesis data: (c) PREDICT models yield novel hits with
nanomolar activity in binding assays in 6 different programs (d) PRX-0023, a
novel, non-azapirone lead clinical candidate 5-HT1A agonist with preclinical
activity in anxiety and attention deficit hyperactivity disorder successfully
completed Phase I clinical trails.
Presentation: Strategies for analyzing
discovery data
Glenn J. Myatt, Paul Blower, Kevin Cross, Chihae Yang
Leadscope, 1393 Dublin Road, Columbus, Ohio 43215
The presentation will review different approaches for analyzing data sets of
chemical structures and biological activity data. Techniques for becoming
familiar with the data set will be described including methods for assessing
structural diversity. Methods for integrating, assessing and filtering the data
set prior to analysis will be described. Depending on the nature of the data set
(size, data distribution, and structural diversity) different methods for
analyzing the data should be adopted. The presentation will review these
alternative chemical structure-based data analysis approaches. Trends in the
data may be further qualified by searching other databases, such as collections
of toxicity data to determine any known safety liabilities with the chemical
series identified. Case studies will be used to illustrate this process.
Presentation: A High-Performance
Workflow Automation System for Drug Discovery
Dr. Srini Chari; General Manager, Solutions
TurboWorx, Inc.
Many scientific problems are solved by analyzing large quantities of data using
multiple compute-intensive applications linked together in complex ways. In
pharmaceutical research and development, identifying lead compounds requires
first computing various properties for large numbers of individual compounds,
filtering the compounds based on specific property-based criteria, and
performing further modeling and simulation calculations.
Today networked computing environments can be excellent platforms for
processing these computational workflows because they make available large
numbers of highly capable individual machines. However, the job of creating,
managing, and deploying distributed workflows is daunting to most users. Very
few of them are able to write robust programs or scripts that deal with issues
such as authenticating users, selecting proper machines to run given
applications, moving data between applications, and handling application errors
and hardware failures.
In this talk we will address solutions effectively address all these issues and
more. Users benefit from reduced development effort and execution time, leading
to increased personnel productivity and higher analysis throughput. The
TurboWorx Enterprise system allows computational workflows to be built
visually, using boxes to represent application and data access tasks, and using
directed lines to specify task dependencies and data paths. At runtime, the
system dynamically decomposes each workflow job into its constituent tasks and
arranges for task execution on appropriate compute nodes. The system also
coordinates all the task executions in order to honor task dependencies and to
ensure efficient data transfer along specified data paths.
This system also provides an open, extensible environment that includes visual
tools that make it easy to add to the system any application that can be run
from a command line. Furthermore, it offers rich support for fault tolerance,
custom user authentication, data parallelism, and flow controls. To those
scientists who need to analyze large amounts of data using complex computational
pipelines, TurboWorx Enterprise will be an invaluable solution.
Presentation: PredictionBase for
Screeners
Scott Lee
IDBS
The pharmaceutical industry is under mounting commercial pressure to increase
NMEs, while containing costs. Automated screening has led to greater efficiency,
but has not delivered large numbers of NMEs as originally hoped. It has,
however, generated vast amounts of information. The key to solving this problem
lies in unlocking the knowledge in databases, such as ActivityBase to learn from
past experimentation and direct activities to find hits faster and just as
importantly fail early.
IDBS has developed PredictionBase, a software suite that can help HTS
biologists make intelligent decisions to identify successful candidates while
minimizing unnecessary testing. PredictionBase puts practical in silico
prediction in the hands of screeners, rather than confining it to a few expert
users.
In this presentation, we demonstrate how PredictionBase is used to:
?Generate validated prediction models
?Direct screening campaigns in order to enrich hit rates
?Provide early alerts of ADME/T problems and develop knowledge models to guide
effective assay selection
?Filter virtual or corporate compounds libraries for more focused screening
campaigns
DON'T FORGET TO REGISTER TO INSURE THAT THERE IS ENOUGH FOOD AND SEATS.
https://www.lab-robotics.org/member/meetings.asp?rid=1
Directions:
http://www.marriott.com/dpp/PropertyPage.asp?MarshaCode=SOSNJ
Leverage Your Time!
LRIG is pleased to announce the arrangement of a 15% tuition discount for
LRIG members for Owicki Consulting's short courses on Methods in Drug Discovery,
to be held 3-5 November 2004 in this same venue. If you are not a member,
consider joining LRIG so that you can take advantage of the discount. Simply
click on
https://www.lab-robotics.org/member/member.asp.
Fluorescence Assays
All day November 3 and morning of November 4, 2004
Enzyme & Binding Assays
Afternoon of November 4 and all day November 5, 2004
Topics for the Fluorescence course:
Fluorescence fundamentals
Labels and labeling chemistries
Instrumentation
Interferences and limitations
Survey of principal fluorescence methods
Biochemical and cellular applications
Topics for the Enzyme & Binding course:
Enzyme kinetics
Enzyme inhibition: Competitive, noncompetitive, uncompetitive, irreversible, and
promiscuous
Multiple-substrate enzymes
Binding equilibria and kinetics
Deviations from classical textbook behavior
Optimizing enzyme and binding assays for primary vs. secondary screening
Understanding mechanisms and extracting information from your data
Discussion of commercial data-analysis and simulation software
Case studies, including receptor binding, kinases, and proteases
For details, see www.owicki.com.
Pre-registration is required for these short courses - download the form at:
http://www.owicki.com/Nov 2004 Short Course Registration Form.pdf
Visit The Laboratory Robotics
Interest Group homepage at https://www.lab-robotics.org
