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Figure 1.1 Fragment development strategies. Top: fragment linking, where fragments found to
bind in adjacent regions of the binding site are linked to create a larger, more potent compound.
Middle: fragment fusion, where fragments in overlapping space are amalgamated to form a
larger more potent compound. Bottom: fragment growth, where rational design is used to grow
the core fragment into adjacent regions of the binding site.
is good, and if not, then it is suboptimal, giving the medicinal chemist a qualitative guide
to designing the next round of molecules. Kuntz et al . [ 32 ] extended the analysis, looking
at the maximum affinity of ligands. Strong binding ligands were taken as references for
understanding potential free energy gains as the number of heavy atoms in a molecule is
increased. They came to the conclusion that increasing the number of non-hydrogen atoms
up to 15 heavy atoms can increase the affinity by
1.5 kcal mol 1 per atom; beyond that, the
free energy was found not to increase linearly with increasing molecular size. Interestingly,
van der Waals interactions and hydrophobic effects are now able to explain affinities for
most ligands and only in particular cases do atoms such as metal ions dominate binding. The
work of Kuntz et al . was instrumental in the use of ligand efficiencies to assess the binding
affinity of compounds. With access to superior datasets, subsequent studies suggested that
ligand efficiency is dependent on molecular size and does not exhibit the linear relationship
below 16 atoms as proposed by Kuntz et al . Reynolds et al . [ 33 ] noted that smaller molecules
can demonstrate considerably higher ligand efficiencies than observed for larger drug-like
molecules. This has important implications when comparing hits from a wide range of
molecular sizes; indeed Reynolds et al . propose a size-normalized efficiency scale termed
'fit quality' as a metric for assessing the goodness of fit between ligand and receptor. Essen-
tially, a maximum ligand efficiency is calculated, based on existing data, for each heavy
atom count and the ligand efficiency for a particular molecule is scaled according to the
optimum curve. Murray and Verdonk [ 29 ] also stated that smaller molecules necessitate more
optimal binding interactions in order for the intrinsic free energy to surmount the entropic
free energy penalty.
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