Modulating Protein-Protein Interactions: From Structural Determinants of Binding to Druggability Prediction to Application

Abstract

During the last decades, a large amount of evidence has been gathered on the importance of protein-protein interactions in tuning and regulating most important biological processes. Since many of these pathways are deeply involved in diseases, extensive research efforts have been undertaken towards the modulation of protein-protein interactions. At the early stage of this challenge most of the attention was drawn to the drawbacks of such a therapeutic approach. Encouragingly, however, several recent studies provided a proof of concept that protein-protein interactions are actually valuable targets and that they do have a promising therapeutic potential. This review is divided into three sections. In the first section we summarize the general features of protein-protein interfaces, focusing on the characteristics that make them different from classical protein-ligand binding sites, as well as on problematic aspects that hamper the application of classical drug discovery approaches. In the second section, we present how some of the characteristics of protein-protein interactions can be exploited fruitfully in drug design, hence focusing on the druggability of protein-protein interfaces. Methods successfully applied to protein-protein interactions will be introduced, giving special attention to the computational ones. In the third section, three case studies are presented. First, we describe protein-protein interaction modulators targeting HDM2 and the computational methods applied to identify them. Next, we present the retrospective application of the discussed approaches on the well-examined target IL-2. We conclude with a prospective application to the NHR2 protein, a target just recently validated experimentally with the aid of computational methods.

Role of Protein–Protein Interactions in Cytochrome P450-Mediated Drug Metabolism and Toxicity

“…Additionally, from a pharmacological point of view, modulating protein–protein interactions may provide an avenue for therapeutic intervention. 168 It is likely that additional CYP protein–protein interactions remain to be discovered. Conceivably, CYPs might also interact with phase II, or drug conjugating, enzymes such as glucuronidases, sulfotransferases, or gluthione- S -transferases to modulate their activity as well.…”

Fragment-based drug discovery and protein–protein interactions

“…Abbott Laboratories carried out a fragment screening campaign using the structure-activity relationship (SAR) by NMR approach 56 to identify potent inhibitors that bind to the hydrophobic groove of Bcl-x L and disrupt this PPI (Table 2). 57 Initially, a screen of 10,000 fragments using 15 N-HSQC NMR identified fluoro-biaryl acid ( of the highly potent (Bcl-x L FP assay K i ,5 nM) inhibitor ABT-263 (navitoclax) ( Table 2, compound 3), which has entered Phase II clinical trials in patients with small-cell lung cancer and B-cell malignancies. 5 Navitoclax is larger and more liphophilic than non-PPI inhibitors, violating three "rule-of-5" criteria (MWT =975 Da; cLogP =12; number of hydrogen bond acceptors =12).…”

“…15 This is most likely attributable to the ability of the more predominant residues to form a variety of comparatively strong interactions with protein-binding partners. Databases are available of experimentally identified hot spots, such as ASEdb, 16 and also of computationally flagged regions likely to act as hot spots, such as HotRegion 11 (http://prism.ccbb.ku.edu.tr/hotregion) and FTMap 17 (http://ftmap.bu.edu).…”

Analysis and Ranking of Protein-Protein Docking Models Using Inter-Residue Contacts and Inter-Molecular Contact Maps

“…Interest in both inhibitors of protein-protein interactions [1][2][3][4][5][6] and protein drugs themselves [7][8][9][10] is indeed constantly increasing. For these and other applications, structural information, ideally with the availability of the experimental structure of the complex of interest, is invaluable.…”