Protein–protein interactions between membrane-localized receptors and intracellular signaling molecules control neuronal function and theoretically provide a rich source of vastly overlooked targets for drug discovery in neuropsychopharmacology. But, unlike the well-defined binding pocket of transporters and receptors, the flat, expansive, and adaptive topology of the protein–protein interface presents a sizeable challenge to the goal of identifying small molecules that result in a gain or loss of function of the protein complex. This is offset by the growing body of evidence to suggest that a few amino acids at the interface (‘hot spot’) contribute to the majority of the binding energy in protein–protein interactions suggesting that modulators with a high degree of specificity could be developed. Furthermore, recent advances in screening technologies and accessibility to an ever-increasing diversity of small molecules suggest that protein–protein interactions are a viable option for drug discovery (Simeonov et al, 2008; Wells and McClendon, 2007).
Much of the groundwork to suggest that targeting ‘hot-spots’ could result in either loss or gain of cellular function is found in the cancer field (Simeonov et al, 2008; Wells and McClendon, 2007). For example, the interaction between the C-terminal domain of the breast cancer gene 1 (early onset; BRCA1) protein and BRCA1-associated carboxyl terminal helicase (BACH1) protein is essential for DNA damage-induced checkpoint control. A competitive, high-throughput assay has allowed the identification of small molecule BRCA1-BACH1 inhibitors, which are currently being validated in cell-based assays and ultimately in preclinical studies to improve the efficacy of breast and ovarian cancer therapeutics (Simeonov et al, 2008).
Protein–protein interactions also hold promise as a target for medications development in neurology and psychiatry. Bertaso et al (2008) found that uncoupling of the metabotropic glutamate receptor 7a (mGluR7a) from protein interacting with kinase 1 (PICK1) is sufficient to induce absence seizures in rodents. A small molecule enhancer of this protein–protein interaction would be predicted to provide therapeutic potential for epilepsy. Therapeutic potential also may exist in the disruption of protein–protein interactions with the serotonin 5-HT2C receptor (5-HT2CR), an important protein in normal and abnormal psychiatric states (Bubar and Cunningham 2008). The 5-HT2CR interacting protein multiple PDZ (MPDZ) domain protein encodes the first bona fide quantitative trait gene underlying physical dependence to abused drugs (Shirley et al, 2004). A small molecule inhibitor of the 5-HT2CR-MPDZ interaction could alter downstream signaling associated with this receptor. Small peptide inhibitors of the 5-HT2CR-MPDZ interaction have been developed (Sharma et al, 2007) but have yet to be tested for their ability to alter addiction- (or psychiatric-)relevant phenotypes. Thus, 5-HT2CR protein–protein interactions represent a fruitful ground for the rational development of small molecular inhibitors to treat psychiatric illnesses.
A third example is the intracellular scaffolding protein Homer. Homer proteins form a network, which brings together key signaling molecules at the postsynaptic density (eg, mGluR5 and NMDA receptors) to regulate intracellular calcium cascades. Homer-2 expression critically regulates the responses to cocaine and alcohol (Szumlinski et al, 2008) probably through disruption of protein–protein interactions in which it participates. The design of small molecule inhibitors of Homer protein–protein interactions also holds promise for novel pharmacotherapies in psychiatry.
We are just beginning to appreciate the relationship between protein–protein interactions and neuronal function. Targeting protein–protein interactions has great therapeutic potential as noted in the above examples. Making these interactions ‘druggable’ is a critical challenge in the development of new treatments for psychiatric and neurological disorders. Thus, mining protein–protein interactions is opening the way for a paradigm shift in drug discovery efforts to identify new therapeutics for neurological and psychiatric disorders.
DISCLOSURE/CONFLICT OF INTEREST
The authors declare that except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional services, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Reilly, M., Cunningham, K. & Natarajan, A. Protein–protein interactions as therapeutic targets in neuropsychopharmacology. Neuropsychopharmacol 34, 247–248 (2009). https://doi.org/10.1038/npp.2008.167
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