Structure of protein interaction networks and their implications on drug design.
Protein-protein interaction networks (PINs) are rich sources of information that enable the network properties of biological systems to be understood. A study of the topological and statistical properties of budding yeast and human PINs revealed that they are scale-rich and configured as highly optimized tolerance (HOT) networks that are similar to the router-level topology of the Internet. This is different from claims that such networks are scale-free and configured through simple preferential-attachment processes. Further analysis revealed that there are extensive interconnections among middle-degree nodes that form the backbone of the networks. Degree distributions of essential genes, synthetic lethal genes, synthetic sick genes, and human drug-target genes indicate that there are advantageous drug targets among nodes with middle- to low-degree nodes. Such network properties provide the rationale for combinatorial drugs that target less prominent nodes to increase synergetic efficacy and create fewer side effects.
Hase
Takeshi
T
Department of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.
Tanaka
Hiroshi
H
Suzuki
Yasuhiro
Y
Nakagawa
So
S
Kitano
Hiroaki
H
D016000:Cluster Analysis; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D023281:Genomics / Q000379:methods*; D006801:Humans; D054730:Protein Interaction Domains and Motifs / Q000502:physiology*; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015003:Yeasts
D005656:Fungal Proteins; D011506:Proteins