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4 - NMR in fragment-based drug discovery

from PART I - STRUCTURAL BIOLOGY

Published online by Cambridge University Press:  06 July 2010

By
Christopher A. Lepre ,
Peter J. Connolly  and
Jonathan M. Moore
Edited by
Kenneth M. Merz, Jr ,
Dagmar Ringe  and
Charles H. Reynolds
Kenneth M. Merz, Jr
Affiliation:
University of Florida
Dagmar Ringe
Affiliation:
Brandeis University, Massachusetts
Charles H. Reynolds
Affiliation:
Johnson & Johnson Pharmaceutical Research & Development
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Summary

AN INTRODUCTION TO FRAGMENT-BASED LEAD DISCOVERY

For decades, molecular starting points for drug discovery have been found by screening large numbers of natural and synthetic compounds for biological activity in phenotypic and biochemical assays. Then, beginning in the mid to late 1990s, several pharmaceutical groups developed new approaches [such as structure/activity relationship by nuclear magnetic resonance (SAR by NMR), the SHAPES strategy, and needle screening] in which simple, low-molecular-weight compounds were screened for binding to the target of interest, and these relatively weak binding molecules were then used to systematically construct larger, more potent, drug leads. Such small screening molecules are now commonly called fragments and the related processes collectively called fragment-based lead discovery (FBLD).

NMR was the first experimental method used to screen fragments, and although a variety of other techniques (including x-ray crystallography, surface plasmon resonance, high concentration bioassays, and mass spectroscopy) have also been applied, NMR is still the most widely used. This chapter reviews the use of NMR for FBLD, beginning with an explanation of the principles behind fragment screening. NMR screening methods are then described, followed by a series of examples that illustrate the process through which fragment screening hits are converted into leads.

Type
Chapter
Information
Drug Design
Structure- and Ligand-Based Approaches
 , pp. 41 - 58
Publisher: Cambridge University Press
Print publication year: 2010

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