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access icon free Topological alternate centrality measure capturing drug targets in the network of MAPK pathways

© The Institution of Engineering and Technology
Received 04/10/2017, Accepted 30/04/2018, Revised 04/04/2018, Published 30/04/2018

A new centrality of the nodes in the network is proposed called alternate centrality, which can isolate effective drug targets in the complex signalling network. Alternate centrality metric defined over the network substructure (four nodes – motifs). The nodes involving in alternative activation in the motifs gain in metric values. Targeting high alternative centrality nodes hypothesised to be destructive free to the network due to their alternative activation mechanism. Overlapping and crosstalk among the gene products in the conserved network of MAPK pathways selected for the study. In silico knock-out of high alternate centrality nodes causing rewiring in the network is investigated using MCF-7 breast cancer cell line-based data. Degree of top alternate centrality nodes lies between the degree of bridging and pagerank nodes. Node deletion of high alternate centrality on the centralities such as eccentricity, closeness, betweenness, stress, centroid and radiality causes low perturbation. The authors identified the following alternate centrality nodes ERK1, ERK2, MEKK2, MKK5, MKK4, MLK3, MLK2, MLK1, MEKK4, MEKK1, TAK1, P38alpha, ZAK, DLK, LZK, MLTKa/b and P38beta as efficient drug targets for breast cancer. Alternate centrality identifies effective drug targets and is free from intertwined biological processes and lethality.

Inspec keywords: genetics; molecular biophysics; biochemistry; drugs; cellular biophysics; cancer; biomedical materials

Other keywords: MEKK4 nodes; MCF-7 breast cancer cell line-based data; DLK nodes; drug targets; MEKK2 nodes; ZAK nodes; node deletion; MAPK pathways; P38beta nodes; cellular mechanisms; pagerank nodes; MLK1 nodes; complex signalling network; MLTKa/b nodes; ERK2 nodes; TAK1 nodes; MKK4 nodes; MLK2 nodes; MEKK1 nodes; ERK1 nodes; MLK3 nodes; LZK nodes; MKK5 nodes; P38alpha nodes

Subjects: Biomolecular structure, configuration, conformation, and active sites; Physical chemistry of biomolecular solutions and condensed states; Cellular biophysics; Biomedical materials; Patient care and treatment

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