Abstract
Small molecules that bind at protein-protein interfaces may either block or stabilize protein-protein interactions in cells. Thus, some of these binding interfaces may turn into prospective targets for drug design. Here, we collected 175 pairs of protein-protein (PP) complexes and protein-ligand (PL) complexes with known three-dimensional structures for which (1) one protein from the PP complex shares at least 40% sequence identity with the protein from the PL complex, and (2) the interface regions of these proteins overlap at least partially with each other. We found that those residues of the interfaces that may bind the other protein as well as the small molecule are evolutionary more conserved on average, have a higher tendency of being located in pockets and expose a smaller fraction of their surface area to the solvent than the remaining protein-protein interface region. Based on these findings we derived a statistical classifier that predicts patches at binding interfaces that have a higher tendency to bind small molecules. We applied this new prediction method to more than 10 000 interfaces from the protein data bank. For several complexes related to apoptosis the predicted binding patches were in direct contact to co-crystallized small molecules.
Highlights
Protein-protein interactions play important roles in most cellular processes [1,2]
Given the three-dimensional structure of such a protein-protein interface, we aimed at developing a method for predicting where small molecule ligands would most likely bind at this interface
In a drug design project targeting a known protein interface, such a method would allow focusing the virtual or experimental screening efforts on ligands with physico-chemical properties that are complementary to the predicted binding patch at the protein interface
Summary
In the yeast S. cerevisiae, for example, interaction partners have been reported for more than 5 000 of the 6 000 yeast proteins [3]. The main approach for designing inhibitors and modulators of protein-protein interactions aims at designing peptidomimetics that compete with the natural partner protein for the same interface [4]. As some of these binding interfaces can bind small molecule ligands, modulating the activities of protein-protein complexes by competitive or allosteric small molecule protein-protein inhibitors (SMPPIs) has become an area of very active interest in current pharmaceutical research [5,6]. A prominent example is the p53-MDM2 system that is a promising putative target for cancer therapy [7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
