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Fragment screening with biophysical methods presents unique challenges
due to the need to combine high fragment concentrations with ultra-
sensitive detection technologies. For this reason, it's best practice to use
a second, orthogonal method in addition to the primary approach to
confirm on-target activity and help rule out interference from the high
concentrations of fragment used
17
. Additionally, because of the strengths
and limitations of each technique, there is no single method guaranteed to
detect binding of a particular fragment
10
. Use of an orthogonal biophysical
method is therefore the best way to avoid identifying false positives
that waste valuable time and resources or missing billion-dollar lead
compounds due to false negatives.
The top biophysical methods for fragment-based screening are described
next, including how they work as well as their strengths and weaknesses.
Top biophysical methods
for fragment-based
screening
3
