LRIG MidWest

Ohio Regional Meeting

 

March 20, 2003

 

Kings Island Conference Center

Cincinnati, OH

http://www.kingsislandresort.com

 

Welcome to the Ohio regional meeting of the Laboratory Robotics Interest Group.  Guest speakers for the evening are Dr. Boris Y. Zaslavsky. and Dr. Matthew A. Sills. Brief biographies and presentation abstracts are attached.

 

4:00 - 5:00 PM                         Cocktails                     Vendor Sponsor Displays

 

5:00 - 6:00 PM                         Dinner Buffet               Vendor Sponsor Displays

 

                                                Introductions

 

6:00 - 6:50 PM                         Structural Signature Technology for Characterization of Biopharmaceuticals

 

6:50 ?7:00 PM                        Questions

 

7:00 ?7:50 PM                        Will the Real Lead Compounds Please Stand Up?:  Dilemmas Resulting From Screening Compounds Using Different Technologies for the Same Assay

 

7:50 ?8:00 PM                        Questions

 

 

Meeting Sponsors

 


 

 


 

 

 

 

 

Presenter Biographies

Dr. Boris Zaslavsky is the Vice-President of Research and Development  for Analiza Inc., a privately-held corporation dedicated to discovering, developing, and commercializing new technologies for the life science industries.  Dr. Zaslavsky is the author of over 100 professional papers and the holder of several patents.  He received the M.S. degree (1967) in physical chemistry form the Moscow M.V. Lomonsov State University, Russia, the Ph.D. degree (1974) in the chemistry of natural products and analytical chemistry from the M.M. Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, and the D.Sc. degree (1986) in bioanalytical chemistry from the A.N. nesmeyanov Institute of Elementoorganic Compounds, Russian Academy of Sciences, Moscow.

 

 

 

 

Matthew Sills, Ph.D. is currently the Director of Pharmacology at Pharmacopeia.  Prior to joining Pharmacopeia, Dr. Sills was the Executive Director for the U.S. program of the global Drug Discovery Center (DDC) at the Novartis Institute for Biomedical Research in Summit, New Jersey.  Dr. sills received his B.S. in Pharmacy from Rutgers University and his Ph.D. in Pharmacology from the University of Pennsylvania.  Following postdoctoral training at the NIH, he accepted a position at Ciba-Geigy Pharmaceuticals in 1986, as a receptor pharmacologist in the Neuroscience department.  In 1989, Dr. Sills was promoted to Manager of the Biochemical Profiling group, which was, in part, responsible for expanding the company high throughput screening efforts.  Since that time, and through the formation of Novartis, Dr. Sills was responsible for directing the US lead discovery program.  The program, as part of a global lead discovery effort, includes responsiblility for assay development and optimization, high throughput screening, automation and information technologies.  In addition, Dr. Sills was one of the original members of the SBS Board of Directors, and served as both Council chairman and President of the Society.  Dr. Sills was the recipient of the Pioneer Award in Novartis in 1999, in recognition of his contributions to Lead Discovery, and the President Award from the Society for Biomolecular Screening in 1997, for distinguished service to the Society.  His current research focuses on addressing the question of why different screening results are obtained when using different assay technologies.

 

 

 

Structural Signature Technology for Characterization of Biopharmaceuticals

 

Boris Zaslavsky,  Analiza, Inc., Cleveland, OH, USA

 

Abstract

 

Biological function, activity, and behavior of proteins are all governed by their 3-D structure in vitro as well as in vivo. The scarcity of applications using structural description of biopolymers may be attributed to the inherent complexity in determining their tertiary structure. In practice, however, one is rarely interested in the actual structure itself, i.e., in the detailed atomic configuration of the macromolecule. Rather, it is usually sufficient for a structural signature of a given protein to be evaluated and compared with those for the protein under certain known conditions. A new analytical technology is described for characterizing the 3-D structures of biomolecules and examples of a variety of its applications.

The technology provides a numerical fingerprint of the proteins 3-D structure directly in solution. The signature is developed for each application separately under protein-specific conditions. The technique is extremely sensitive to changes in the protein structure from chemical modifications, such as single-point mutations, altered glycosylation pattern, phosphorylation, etc., from environmental factors, such as changes in pH or ionic composition of the aqueous media, from aggregation, or from ligand binding. The technology has been recently automated, using customized robotic liquid handlers, plate readers and unique software, and is available for screening in 96 well plate format. In this presentation we outline several applications in biopharmaceutical industry and drug discovery.

The experimental portion of the technology is based on novel analytical applications of the technique of aqueous two-phase partitioning as a means to derive an overall structural descriptor. This information is subsequently used in conjunction with proprietary mathematical algorithms to provide a numerical and/or visual signature of the specific conformation being interrogated. The exact interpretation of the signature is protein specific and is viewed in a framework that is particular to the information being sought. For example, separation of binding events between a series of ligands and a receptor into agonists or antagonists could be evaluated using a signature that describes the receptor conformation specific for the two classes of ligands. Other applications of the technology are numerous. In this presentation we concentrate on the following applications:

?span style="font:7.0pt "Times New Roman"">         Quality control testing of recombinant biopharmaceuticals.

?span style="font:7.0pt "Times New Roman"">         Analysis of effects of various excipients on recombinant proteins in formulation development.

?span style="font:7.0pt "Times New Roman"">         Comparative analysis of protein products from different manufacturers

?span style="font:7.0pt "Times New Roman"">         Quantitative Structure-Activity Relationship (QSAR) for several series of peptides and proteins.

?span style="font:7.0pt "Times New Roman"">         Analysis of conformational changes in a protein induced by binding of compounds with different biological activity.

 

 

Will the Real Lead Compounds Please Stand Up?:  Dilemmas Resulting From Screening Compounds Using Different Technologies for the Same Assay

 

Dr. Matthew A. Sills

 


Abstract


Today, there are many assay technologies that can be utilized
to develop and run a high throughput screen.  A common assumption in selecting
an assay technology is that the same active compounds will be identified
regardless of which assay technology is utilized.  In a previous study, we
demonstrated differences in identified compounds for a tyrosine kinase assay
when the same set of compounds were evaluated in three different versions of the
kinase assay.  In this presentation, results from a study will be discussed
where 40,000 compounds were evaluated in three versions of a nuclear receptor
assay, using the AlphaScreen, Time-Resolved Fluorescence (TRF), and
Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) technologies. In
addition, the active compounds from all three of the assays were evaluated in a
cell-based functional assay to determine the extent to which each of the
biochemical assays is able to identify functional antagonists.


 

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