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Design and NMR-Based Screening of LEF, a Library of Chemical Fragments with Different Local Environment of Fluorine.

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Bibliographic Details
Title: Design and NMR-Based Screening of LEF, a Library of Chemical Fragments with Different Local Environment of Fluorine.
Authors: Vulpetti, Anna1 anna.vulpetti@novartis.com, Hommel, Ulrich1, Landrum, Gregory1, Lewis, Richard1, Dalvit, Claudio1,2 claudio.dalvit@iit.it
Source: Journal of the American Chemical Society. 9/16/2009, Vol. 131 Issue 36, p12949-12959. 11p. 1 Chart, 12 Graphs.
Subjects: Fluorine, Nuclear magnetic resonance, Carrier proteins, Chemical research, Halogens
Abstract: A novel strategy for the design of a fluorinated fragment library that takes into account the local environment of fluorine is described. The procedure, based on a fluorine fingerprints descriptor, and the criteria used in the design, selection, and construction of the library are presented. The library, named LEF (Local Environment of Fluorine), combined with 19F NMR ligand-based screening experiments represents an efficient and sensitive approach for the initial fragment identification within a fragment-based drug discovery project and for probing the presence of fluorophilic protein environments. Proper setup of the method, according to described theoretical simulations, allows the detection of very weak-affinity ligands and the detection of multiple ligands present within the same tested mixture, thus capturing all the potential fragments interacting with the receptor. These NMR hits are then used in the FAXS experiments for the fragment optimization process and for the follow-up screening aimed at identifying other chemical scaffolds relevant for the binding to the receptor. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
Abstract:A novel strategy for the design of a fluorinated fragment library that takes into account the local environment of fluorine is described. The procedure, based on a fluorine fingerprints descriptor, and the criteria used in the design, selection, and construction of the library are presented. The library, named LEF (Local Environment of Fluorine), combined with 19F NMR ligand-based screening experiments represents an efficient and sensitive approach for the initial fragment identification within a fragment-based drug discovery project and for probing the presence of fluorophilic protein environments. Proper setup of the method, according to described theoretical simulations, allows the detection of very weak-affinity ligands and the detection of multiple ligands present within the same tested mixture, thus capturing all the potential fragments interacting with the receptor. These NMR hits are then used in the FAXS experiments for the fragment optimization process and for the follow-up screening aimed at identifying other chemical scaffolds relevant for the binding to the receptor. [ABSTRACT FROM AUTHOR]
ISSN:00027863
DOI:10.1021/ja905207t