Chemistry Reference
In-Depth Information
donors and acceptors, were represented as
+
s and -s with a positive interaction occurring
+
between a
on the receptor anda-ontheligand or vice versa. An exhaustive calcula-
tion was then performed, computing the probability of finding an exact match between a
receptor of given complexity and a ligand with increasing complexity and, as expected,
the probability diminishes rapidly as the number of possible permutations increases. It is
also the fact that as one increases the complexity of a molecule the probability of negative
interactions increases, leading to suboptimal binding. This has a direct bearing on the size
of a screening library, with studies suggesting that even a million compounds in an HTS
collection barely scratches the surface of the number of possible molecules in drug-like
chemical space
[
35
]
. Counter to the argument of reducing complexity to a bare minimum
in order to maximise the probability of identifying hits, there is a lower limit imposed on
the complexity due to the sensitivity of the screening protocol. Hence there is a balance
between the probability of there being an exact match between receptor and ligand and the
ability to detect that match in a screen. For a particular screening protocol, this leads to an
optimum level of ligand complexity, which in turn dictates the size of the screening library
necessary to maintain a sufficient hit rate.
Fragment-based drug discovery goes some of theway to compensating for our incomplete
understanding of biological interactions and provides a complementary if not alternative
route to finding chemical matter for discovery programmes:
•
The smaller, less complex nature of fragments increases the probability of finding amatch
to a receptor; moreover, instances have shown that removing complexity by screening
fragments can succeed where HTS has failed [6].
•
Fragment libraries can be smaller than HTS libraries as hit rates are generally higher than
in traditional HTS due to better sampling and the increased probability of identifying a
match to the receptor. This has many advantages associated with the construction, storage
and screening of fragment libraries versus HTS libraries.
•
Fragment-based screening can also identify more optimal matches (higher ligand
efficiency) to the receptor without the need first to deconstruct a hit compound.
•
Fragment hits then provide greater scope for development when following a standard
medicinal chemistry development strategy (Figure 1.2).
•
Screening fragments requires more sensitive detection methods, but at the same time
these methods provide invaluable information in the development from hits to drug
candidates.
1.4 Practical Implications of Using Fragments in Drug Discovery
The primary application of fragments is in the identification of chemical matter to take
forward into drug development. As the intention is to identify molecules that are typically
in the micromolar to millimolar potency range, a method of detection is required that is
more sensitive than a biochemical screen at 10-30 M. Assays can be adapted to screen
molecules at higher concentrations but, as discussed above and in following chapters on
fragment library design, more stringent requirements are placed on the molecules. It is also
paramount to obtain confirmation of the mechanism of action as screening at higher con-
centrations leads to higher false positive rates. Most if not all fragment screening strategies
