Biomedical Engineering Reference
In-Depth Information
FIGURE 16.3
Dual-target activity and selectivity cliffs. For a pair of inhibitors active against
three cathepsin thiol proteases (K, L, and S) potency values are binned (as reported on the left)
to illustrate the formation of special types of cliffs. Based on their relative potencies against
the three cathepsins, the two inhibitors form single-target cliffs, a directed dual-target cliff,
and a selectivity cliff. Further details are discussed in the text.
Although activity landscapes and activity cliffs are typically derived from small-
molecule data, activity cliffs might also be rationalized at the target structure level.
SAR discontinuity detected in compound data sets results at least in part from the
modulation of critical ligand-receptor interactions through chemical substitutions. It
has been shown that the formation of activity cliffs can often be reconciled on the basis
of interactions seen in x-ray structures of ligand-target complexes [46]. However,
this is clearly not always the case because short-range interactions in x-ray structures
reflect only a part of the binding process, in the course of which entropic effects and
solvation/desolvation energies might also make large contributions. Nevertheless, it
has also been attempted to define activity cliffs computationally solely on the basis of
ligand-target interactions. This approach has been termed
identification of structure-
based activity cliffs (ISAC)
[47]. Here, interaction energies between ligand and protein
atoms are calculated using force field-based scoring functions to derive an interac-
tion fingerprint for a given active compound. Then, SALI scores are derived using
the interaction fingerprint instead of conventional fingerprints for the calculation of
Tanimoto similarity of different ligands. If activity cliffs are formed by compounds
with similar interaction fingerprints, individual contacts that differ between the cliff
partners can be identified, and protein atoms (residues) involved in these discrimi-
natory interactions are regarded as hotspots for activity cliff formation. Compared
to other approaches defining activity cliffs, the distinguishing feature of the ISAC
