Biomedical Engineering Reference
In-Depth Information
ridges, about 1500 isolated cliffs were identified across all data sets. The activity
ridge structure is a model for the formation of coordinated activity cliffs. Given
the considerable number of ridges that were detected, compound subsets forming
coordinated activity cliffs are expected to be widely distributed. Such compound
arrays represent a rich source of SAR information, more so than isolated cliffs.
16.6.3 Preferred R-Groups and Scaffolds
In another survey, about 200 chemical substitutions were identified to form activity
cliffs with high frequency across different compound classes and biological targets
[49]. This analysis was based on systematic extraction and comparison of MMPs from
active compounds. Hence, a fairly large number of defined R-group replacements
preferentially formed activity cliffs in different structural environments. Surprisingly,
similar trends were detected for molecular scaffolds in an independent study. On the
basis of currently available data, a total of about 100 Bemis and Murcko scaffolds
of different size and composition were identified that displayed a statistically sig-
nificant tendency to participate in activity cliffs across different target families [50].
The high propensity of selected molecular scaffolds of varying complexity to form
activity cliffs is less intuitive than the involvement of specific chemical substitutions
because core structures are usually involved in critical ligand-target interactions less
frequently than R-groups. However, considerable numbers of chemical substitutions
and molecular frameworks have been identified that should merit special considera-
tion in the exploration of activity cliffs and in compound design.
16.7 ACTIVITY CLIFFS AND SAR INFORMATION
Because activity cliffs are regarded as the most prominent features of activity land-
scapes, they are usually the initial focal point of SAR analysis. However, this also
raises theoretical and practical questions. For example, are there relationships between
activity cliffs and other SAR components? Also, how should one best interpret activity
cliff information in chemical terms in order to deduce SAR determinants?
16.7.1 SAR Discontinuity vs. Continuity
Continuous and discontinuous local SARs are often found to coexist in compound data
sets, giving rise to global SAR heterogeneity. However, this does not necessarily mean
that individual compound series are exclusively continuous or discontinuous in their
SARbehavior. For example, careful analysis of SARI score combinations has revealed
that SAR continuitymight also be observed in the vicinity of activity cliffs, a SARphe-
notype referred to as
heterogeneous-constrained
[9]. This means that modifications
of active compounds might often be tolerated as long as one or more groups involved
in critical ligand-receptor interactions are present. A textbook example of this
SAR phenotype would be sulfonamide-containing inhibitors of carbonic anhydrases.
