Drug-like inhibitors of protein-protein interactions: a structural examination of effective protein mimicry.
Protein-protein interactions represent targets for drug discovery that are highly relevant in a biological sense, but have proven difficult in a practical sense. Nevertheless, there have been recent successes in discovering drug-like small molecule inhibitors of protein-protein systems. To build on this progress, it is worth analyzing successful cases to understand at a molecular level the strategies by which these compounds effectively interfere with protein-protein pairing. A commonly observed situation is one wherein the small molecule acts as a direct mimic of one of the protein partners. This review focuses exclusively on cases where this strategy is employed, and examines the structural characteristics of the binding sites and the conformational attributes of the small molecule ligands. Common traits shared among these successful examples are identified, and formulated into potentially useful guidance for drug discovery efforts within this target class.
Roche Research Center, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. david.fry@roche.com
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D001665:Binding Sites; D032701:Biomimetics; D015195:Drug Design; D007376:Interleukin-2; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000737:chemistry
D007376:Interleukin-2; D008024:Ligands; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051636:X-Linked Inhibitor of Apoptosis Protein; D051736:Proto-Oncogene Proteins c-mdm2