Towards drugs targeting multiple proteins in a systems biology approach.
Protein-protein interactions are increasingly becoming drug targets. This is understandable, since they are crucial at all levels of cellular expression and growth. In practice, targeting specific disease-related interactions has proven difficult, with success varying with specific complexes. Here, we take a Systems Biology approach to targeting protein-protein interactions. Below, we first briefly review drug discovery targeted at protein-protein interactions; we classify protein-protein complexes with respect to their types of interactions and their roles in cellular function and as being targets in drug design; we describe the properties of the interfaces as related to drug design, focusing on hot spots and surface cavities; and finally, in particular, we cast the interactions into the cellular network system, highlighting the challenge of partially targeting multiple interactions in the networks as compared to hitting a specific protein-protein interaction target. The challenge we now face is how to pick the targets and how to improve the efficiency of designed partially-specific multi-target drugs that would block parallel pathways in the network.
Keskin
O
O
Koc University, Center for Computational Biology and Bioinformatics and College of Engineering, Rumelifeneri Yolu, 34450 Sariyer Istanbul, Turkey.
Gursoy
A
A
Ma
B
B
Nussinov
R
R
D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D019151:Peptide Library; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D049490:Systems Biology / Q000379:methods*
D019151:Peptide Library; D011506:Proteins