Designing a Fragment Process to Fit Your Needs - Fragment-Based Drug Discovery - page 29

very active molecules. However, this is the least likely of the approaches to work without
significant expenditure of resources (typically in modifying the target). In cases where this
is most routinely shown to work, the researchers start with one fragment guaranteed to bind
(a warhead specific to the target or a covalently modified target-ligand complex) and the
screen is initiated to find a second fragment that binds in proximity to the first fragment.
This is reviewed in Chapter 10.
Still, there is no strong theoretical reason to expect that anabolic, catabolic or even
linking strategies will generally apply and it is easy to imagine how non-additive effects
could combine in a molecule whose binding and affinity emerge only once a critical number
of functional groups are present. With all of these caveats to consider, FBDDis an essential
method by which to start a new drug design project.

2.4.4 Keys to FBDD Success

The concepts that underpin the chemical fragments approach can be traced back to the pion-
eering work of Jencks [ 113 ] and Farmer andAriens, [ 114 ] who showed that drug-like molecules
can be regarded as the combination of two or more individual binding epitopes (fragments).
The success of FBDD ultimately resides in the hands of the medicinal chemist. This is not
to underestimate the importance of designing a robust process as outlined here. In the end,
no matter what the quantity and quality of data around a given target are, if chemists do
not make molecules the project dies. Therefore, for all the steps of this process, it is best
to have the end-users (chemists) involved in the design. The interaction between chem-
ist, biologist and structure biologist should allow for rapid, iterative collaboration. Project
teams should include all of these aspects from the beginning such that alignment can be
obtained constructively. FBDD is not a stand-alone endeavor.

2.5 Abbreviations

ADME/TOX adsorption, disposition, metabolism and toxicity

Da dalton

DMSO dimethyl sulfoxide

EffCo efficiency coefficient

FBDD fragment-based drug discovery

FPA fluorescence polarization anisotropy

H2L hit-to-lead

HTS high-throughput screening

ITC isothermal titration calorimetry

LE ligand efficiency

LLDD lead-like drug discovery

MS mass spectrometry

MW molecular weight

NMR nuclear magnetic resonance

SAR structure-activity relationship

SBDD structure-based drug discovery

SPR surface plasmon resonance