Reminder: CBM seminar: Friday 16 May at 11.00

[Daniela Valentini, ICTP - Trieste, phone +39 40 2240551....]

>
> 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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>