Biomedical Engineering Reference
In-Depth Information
CHAPTER 11
Recent Advances in Biomolecular
NMR for Drug Discovery
CARINE FARENC AND GREGG SIEGAL*
Protein Chemistry Group, Leiden Institute of Chemistry, Leiden University,
Gorlaeus Laboratories, 2300 RA Leiden, The Netherlands
*E-mail: g.siegal@chem.leidenuniv.nl
11.1 Introduction
The use of NMR in industrial drug discovery has come and gone in waves over
the years. In the 1990s, significant investments in high-field instruments and
personnel were made on the basis of NMR as a tool to rival X-ray
crystallography in the elucidation of 3D structures of protein-small molecule
complexes. Unfortunately the field did not deliver within the timescales and
throughput required to support commercial efforts and many NMR
departments were reorganised. Subsequently the group at Abbott
Laboratories led by Stephen Fesik introduced the concept of using NMR to
screen through collections of so-called drug fragments for binding to a protein
target. Although the underpinnings of Fragment Based Drug Discovery
(FBDD) can be traced back to academia,
1
the clear demonstration of the
usefulness of NMR for commercial ends led to substantial new interest. In the
intervening 15 years NMR has become a mainstay of the fragment screening,
validation and elaboration process.
The primary reason that NMR is so useful for characterising fragments is
the exquisite sensitivity of the technique to intermolecular interactions. This
sensitivity is manifested in two different phenomena: the chemical shift and
relaxation. The chemical shift with its intimate relationship to the immediate
