Reminder: CBM seminar: Friday 16 May at 11.00

[Maria Teresa Turello]

Dear All, 


you are kindly invited at CBM seminar: 



Fragment-based NMR screening: principles and applications to drug discovery 




Dr. Claudio Dalvit 

CNIO Spanish National Cancer Research Center, Madrid, Spain 

  

Moderators: Dr. Roberto Della Marina, Managing Director CBM 

                           Dr. Stefania Biffi, Optical Imaging and NMR Labs, CBM 

  

Friday, 16 May 2008 at 11.00 

Conference Room, T1 Building 

AREA Science Park - Basovizza 
  
ABSTRACT 
In recent years considerable effort has been devoted to increasing the success rate of the drug discovery process. The focus has been mainly on quantity and speed. Despite some successes, it is clear that the high-throughput paradigm has not delivered the results that were initially anticipated. In this context, another approach called Fragment-Based Drug Design (FBDD) has emerged    for the identification of quality drug leads that have high potential for development into therapeutic agents. Fragments are low molecular weight molecules that interact weakly with a biological target, but display a Binding Efficiency Index (BEI) (defined as (-logKD)/MW or (-logIC50)/MW) that is comparable to potent drug molecules. A suitable fragment represents a good chemical starting point for protein x-Ray crystallography/NMR efforts aimed at establishing the experimental structural bases for subsequent structure-based lead optimization and/or for providing guidance on the ongoing medicinal chemistry efforts. The first challenge in the FBDD process is the reliable identification of the weakly active chemical fragments. NMR, despite its low absolute sensitivity, offers some unique features that makes it an attractive methodology. The high relative sensitivity of NMR to binding events allows the identification of chemical scaffolds with very weak affinity. In addition, NMR-based quality control filters applied on the tested molecules ensure the selection of only bona fide ligands and inhibitors and the construction of a meaningful BEI table. One of the NMR methodologies, namely WaterLOGSY, utilizes the bulk water magnetization for the identification of molecules that interact with the receptor. Two other methodologies, FAXS1, a ligand competition binding assay, and 3-FABS1, a functional assay, make use of the favourable properties of 19F NMR spectroscopy. The robustness of these methodologies allows the reliable detection of molecules displaying only minute protein-ligand interactions thus capturing the broadest chemical structure diversity for potential fragments. The theoretical principles of the aforementioned techniques together with some of their applications to pharmaceutically relevant projects will be presented. 
(1) Dalvit C.    Progr. NMR Spectroscopy 51 (2007) 243-271 
  
Claudio Dalvit got his Doctoral Degree in Physics in 1981. After a five-year experience in the U.S. (Carnegie-Mellon University, Pittsburg, Pennsylvania and The Scripps Research Institute, La Jolla, California), in 1988 he moved to Switzerland, working for the University of Lausanne, La Roche and Sandoz Pharma. From 1999 to January 2008 he was Senior Scientist and Head of the NMR Screening Group in the Chemistry Department    of Pharmacia at Nerviano Medical Sciences (Milan). 
  
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