Systematic analysis of helical protein interfaces reveals targets for synthetic inhibitors.
Synthetic inhibitors of protein-protein interactions are being discovered despite the inherent challenge in targeting large contact surfaces with small molecules. An analysis of available examples identifies common features of complexes that make them tractable for small molecules. We deduced that relative disposition and energetic contributions of "hot spot" residues provide a predictive scale for the potential of protein-protein interactions to be inhibited by small molecules. On the basis of this model, we analyzed the full set of helical protein interfaces in the Protein Data Bank to identify those that are potentially suitable candidates for synthetic ligands.
Jochim
Andrea L
AL
Department of Chemistry, New York University, New York, New York 10003, USA.
Arora
Paramjit S
PS
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
D011506:Proteins; D054852:Small Molecule Libraries