Chemical Systems Biology of pharmaceutical off-targets
The rise of multi-drug resistant (MDR) and extensively drug resistant (XDR) bacterias around the world, including in industrialized nations, poses a great threat to human health and defines a need to develop new, effective and inexpensive anti-bacterial agents.
Phil Bourne's group at UCSD developed a chemical systems biology approach to identify off-targets of major pharmaceuticals on a proteome-wide scale. They demonstrated the value of this approach through the discovery that existing commercially available drugs, prescribed for the treatment of Parkinson's disease, have the potential to treat MDR and XDR tuberculosis. These drugs, entacapone and tolcapone, are predicted to bind to the enzyme InhA and directly inhibit substrate binding. The prediction is validated by in vitro and InhA kinetic assays using tablets of Comtan, whose active component is entacapone. Thus the active component in Comtan represents a promising lead compound for developing a new class of anti-tubercular therapeutics with excellent safety profiles.
Here a comprehensive analysis of off-target pathways build on the putative off-targets of CETP (cholesteryl ester transfer protein) inhibitors across the human structural genome identified from the off-target pipeline SMAP is represented.