To consider also complexes and cascades, drug targets which are linked via other drug targets to the functional sub network are included. It is difficult to predict which mode of perturbation has a higher impact. Directly inhibiting a RAD001 Everolimus pivotal sub network member can completely disrupt a function. Nonetheless, biological signaling networks often have multiple alternative routes and protein isoforms to rescue the cell. Drug targets acting at the periphery can modify significantly the function through interaction or modulation of a modification, e.g, phosphorylation. By thismechanism, the inactivation of different branches and isoforms is possible. Furthermore, functional boundaries are often loosely defined and incompletely annotated.
We thus treat both perturbation modes equally and therefore the perturbed functional sub network combines the uniform functional KU-55933 subnetworks with all interactions to the peripheral drug targets. This combination could result in joining otherwise disjoint uniform functional sub networks via a drug target as linker. The direct targets are already members of the uniform functional sub networks. Scoring the impact of bafetinib We define a score snet which predicts how strong functional subnetworks are perturbed by bafetinib. For this purpose different features of the perturbed functional sub network are combined. The first feature describes how frequent the annotation is present in the sub network. Peripheral drug targets don,t share the functional annotation, hence they dilute the functional annotation of the sub networks.
To ensure that the function is not underrepresented in the network, a first factor of the score is the ratio of the number nannot,net of nodes which have a specific annotation to the total size nnet of the perturbed functional sub network. The second feature puts the drug impact in relation to the subnetwork size. Generic biological functions result in very big subnetworks, in which the drug targets play overall no important role anymore. Furthermore, the drug should preferentially perturb a function at several different points. Hence, the proportion of the number ndrug,net of drug target nodes to the number nnet of all nodes in the perturbed functional sub network resembles a good measure. Lastly, the binding affinity at of bafetinib to its targets or the potency of inhibition is important for effective perturbation.
In theory, the affinities can be measured in biochemical assays which are not always available. However, we propose hereafter an ad hoc affinity measure derived from chemical proteomics data directly. The impact is summarized in the sum of drug affinities to its targets in the perturbed functional sub network Tdrug,net divided by the overall affinity of all possible drug targets Tdurg. Combining these factors results in a score for each disrupted functional network: snet nannot,net nnet | ndrug,net nnet | P t. Hence, the peptide count pt of each protein is a rough estimate of the amount of pulled down protein. If soluble bafetinib is supplemented, the soluble drug blocks the binding pocket of its target yielding a reduced amount of pulled down proteins that are specific drug binders and thus, their peptide counts pt,comp decrease. This observation is expresse