Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations.
As the ultimate function of proteins depends to a great extent on their binding partners, protein-protein interactions (PPIs) represent a treasure trove of possible new therapeutic targets. Unfortunately, interfaces involved in PPIs are not well-suited for effective small molecule binding. Nevertheless, successful examples of small-molecule PPI inhibitors (PPIIs) are beginning to accumulate, and the sheer number of PPIs that form the human interactome implies that, despite the relative unsuitability of PPIs to serve as "druggable" targets, small-molecule PPIIs can still provide novel pharmacological tools and new innovative drugs in at least some areas. Here, after some illustrative examples, accumulating information on the binding efficiency, molecular size, and chemical space requirements will be briefly reviewed. Therapeutic success can only be achieved if these considerations are incorporated into the search process and if careful medicinal chemistry approaches are used to address the absorption, distribution, metabolism, and excretion requirements of larger molecules that are often needed for this target class due to the lower efficiency of binding.
Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. pbuchwald@med.miami.edu
Peter
P
Buchwald
D015195:Drug Design; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D054852:Small Molecule Libraries
D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries