Chemistry Reference
In-Depth Information
Drug- & Lead-likeness
Collect drug- & lead-like screening compounds from
renowned vendors and assess drug-likeness
Elimination of toxic & protein reactive compounds
Apply published filters for toxic & reactive moieties
MW filter
150-310Da; average 256Da
Clog
P
filter
0.5-3.5; average 2.2
H-bond donors, H-bond acceptors, rotatable bonds filter
Immediate Validation of Bioactivity
Tailor MW and Clog
P
for cellular follow-up assays
Fast SAR follow-up
Ensure availability of analogues & chemical accessibility
Avoid unnecessary chemical restraints
Tailor fragment assays amenable to diverse chemistries
Size and Diversity
Screen as many fragments as economical for a given target
Library extensions/modifications
Store & operate library as dynamically as feasible, adding
novel fragments as they become available
Figure 3.2
Process for the assembly and use of Evotec's NMR fragment library.
the NMR fragment library has to contain optimal chemical matter for the most druggable
sub-pocket(s) that allow(s) for fragment elaboration at one or a few positions not involved
in target interactions. Fragment moieties that mediate highly efficient target interactions are
ideally maintained throughout F2L optimization because 'scaffold hopping' of such moi-
eties is challenging. In our opinion, optimal chemical matter for NMR fragment screening
should meet the following criteria, which we have applied by using simplified, but very
accessible parameters.
3.3.1 Drug- and Lead-likeness
Fragments should be composed of drug-like chemical matter because substantial parts of a
fragment hit will end up in the final lead candidate for
in vivo
assays. Therefore, we selected
our NMR screening library from commercially available compound repositories that have
a proven track record in lead discovery (e.g. by many years of use in HTS) and also as
they include structures and substructures that occur in known marketed drugs, as well as in
clinical and preclinical candidates. This ensures that the fragment library is built on several
decades of experience in drug discovery.
