Chemistry Reference
In-Depth Information
there is not a one size fits all process; each target has different needs and presents different
challenges. This chapter will discuss how to go about creating a workable framework for
initiating FBDD efforts and discuss the options available at each step. It will be up to
practitioners to develop processes specific to their individual needs.
For the purpose of this chapter, we have divided the FBDD process into three phases:
Phase I is the assessment phase, Phase II is the screen/re-screen
1
phase and Phase III is
the post-screen phase (Figure 2.1). Phase I involves three assessments: target, assay and
compound. Phase II is initiated with hypothesis generation, followed closely by screen-
ing and iterative confirmation, rescreening and hypothesis evaluation. Phase III starts the
moment the first compound comes out of Phase II and continues in parallel with Phase
II efforts. Phase III efforts are the same as lead-like post-screen efforts, even though for
fragment-based drug discovery they proceed with different rules and paradigms for eval-
uating success (discussed in this chapter and elsewhere in this topic). The criteria for exit
from Phase III are exactly the same for a compound that is initially found by more typical
library-based discovery: a high-potency compound that shows
in vivo
activity. The key to
FBDD is its highly iterative nature that occurs rapidly due to the low inherent complex-
ity of the molecules. All of the individual parts must be seamlessly integrated; 'siloed'
components do not work well together. The chief reasons for utilizing FBDD are greater
diversity
2
with fewer compounds, higher hit rates leading to more possible avenues to
explore and completely rational and
d
eliberate medicinal chemistry efforts, ideally suited
for 'undruggable' and novel targets.
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7 12
]
Figure 2.1
Schematic representation of the FBDD process. Individual steps are discussed in
the chapter.
1
For the purpose of this Chapter, screening will generally refer to biochemical and biophysical assays with the generic term
assay or screen. When the differences are significant, the two will be differentiated.
2
Diversity in this context refers to the coverage of available chemical space.
