2 research outputs found
A Strategy Based on ProteināProtein Interface Motifs May Help in Identifying Drug Off-Targets
Networks are increasingly used to study the impact of
drugs at
the systems level. From the algorithmic standpoint, a drug can āattackā
nodes or edges of a proteināprotein interaction network. In
this work, we propose a new network strategy, āThe Interface
Attackā, based on proteināprotein interfaces. Similar
interface architectures can occur between unrelated proteins. Consequently,
in principle, a drug that binds to one has a certain probability of
binding to others. The interface attack strategy simultaneously removes
from the network all interactions that consist of similar interface
motifs. This strategy is inspired by network pharmacology and allows
inferring potential off-targets. We introduce a network model that
we call āProtein Interface and Interaction Network (P2IN)ā,
which is the integration of proteināprotein interface structures
and protein interaction networks. This interface-based network organization
clarifies which protein pairs have structurally similar interfaces
and which proteins may compete to bind the same surface region. We
built the P2IN with the p53 signaling network and performed network
robustness analysis. We show that (1) āhittingā frequent
interfaces (a set of edges distributed around the network) might be
as destructive as eleminating high degree proteins (hub nodes), (2)
frequent interfaces are not always topologically critical elements
in the network, and (3) interface attack may reveal functional changes
in the system better than the attack of single proteins. In the off-target
detection case study, we found that drugs blocking the interface between
CDK6 and CDKN2D may also affect the interaction between CDK4 and CDKN2D
A Knowledge-based Integrative Modeling Approach for <em>In-Silico</em> Identification of Mechanistic Targets in Neurodegeneration with Focus on Alzheimerās Disease
Dementia is the progressive decline in cognitive function due to damage or disease in the body beyond what might be expected from normal aging. Based on neuropathological and clinical criteria, dementia includes a spectrum of diseases, namely Alzheimer's dementia, Parkinson's dementia, Lewy Body disease, Alzheimer's dementia with Parkinson's, Pick's disease, Semantic dementia, and large and small vessel disease. It is thought that these disorders result from a combination of genetic and environmental risk factors. Despite accumulating knowledge that has been gained about pathophysiological and clinical characteristics of the disease, no coherent and integrative picture of molecular mechanisms underlying neurodegeneration in Alzheimerās disease is available. Existing drugs only offer symptomatic relief to the patients and lack any efficient disease-modifying effects. The present research proposes a knowledge-based rationale towards integrative modeling of disease mechanism for identifying potential candidate targets and biomarkers in Alzheimerās disease. Integrative disease modeling is an emerging knowledge-based paradigm in translational research that exploits the power of computational methods to collect, store, integrate, model and interpret accumulated disease information across different biological scales from molecules to phenotypes. It prepares the ground for transitioning from ādescriptiveā to āmechanisticā representation of disease processes. The proposed approach was used to introduce an integrative framework, which integrates, on one hand, extracted knowledge from the literature using semantically supported text-mining technologies and, on the other hand, primary experimental data such as gene/protein expression or imaging readouts. The aim of such a hybrid integrative modeling approach was not only to provide a consolidated systems view on the disease mechanism as a whole but also to increase specificity and sensitivity of the mechanistic model by providing disease-specific context. This approach was successfully used for correlating clinical manifestations of the disease to their corresponding molecular events and led to the identification and modeling of three important mechanistic components underlying Alzheimerās dementia, namely the CNS, the immune system and the endocrine components. These models were validated using a novel in-silico validation method, namely biomarker-guided pathway analysis and a pathway-based target identification approach was introduced, which resulted in the identification of the MAPK signaling pathway as a potential candidate target at the crossroad of the triad components underlying disease mechanism in Alzheimerās dementia