Allo-network drugs: harnessing allostery in cellular networks

Abstract

Allosteric drugs are increasingly used because they produce fewer side effects. Allosteric signal propagation does not stop at the 'end' of a protein, but may be dynamically transmitted across the cell. Here, we propose that the concept of allosteric drugs can be broadened to allo-network drugs, whose effects can propagate either within a protein, or across several proteins, to enhance or inhibit specific interactions along a pathway. We posit that current allosteric drugs are a special case of allo-network drugs, and suggest that allo-network drugs can achieve specific, limited changes at the systems level, and in this way can achieve fewer side effects and lower toxicity. Finally, we propose steps and methods to identify allonetwork drug targets and sites outlining a new paradigm in systems-based drug design.

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

“…The propagation of conformational changes is usually anisotropic and traverses across a pathway, thereby facilitating signal transduction over large distances (hundreds or thousands of angstroms). Thus, binding to a protein may elicit a limited, specific, and distant functional change in the network [15,33,115,148].…”

“…(1), [15]). In this concept, instead of targeting a malfunctioning protein directly, a different protein in the cellular network neighborhood is targeted by the allo-network drug.…”

“…Moreover, drug-target network studies revealed that in more than half of the established 922 drug-disease pairs, drugs do not target the actual disease-associated proteins, but bind to their 3 rd or 4 th neighbors. However, the distance between drug targets and disease-associated proteins was regarded as a sign of palliative drug action [3,13], and the expansion of the concept of allosteric drug action to the interactome level has been formulated only recently [15].…”

“…On the contrary, in other diseases such as diabetes or neurodegenerative diseases, efficient drug targets are not directly involved in major cellular pathways but indirectly influence them in a highly efficient manner [1]. Thus, the indirect but highly directed action of allo-network drugs can achieve specific, limited changes at the systems level, with fewer side-effects and lower toxicity than those of conventional drugs [15]. In agreement with this assumption, drugs with targets less than 3 steps (or more than 4 steps) from a disease-associated protein were suggested to have more sideeffects and to fail more often [176].…”

“…Further, we describe the benefits and the limitations of network-based methods to analyze allosteric action. Then we introduce the concept of allo-network drugs [15], i.e. drugs acting indirectly, via the inter-protein propagation of changes in cellular networks.…”