Hot-spot analysis for drug discovery targeting protein-protein interactions

Abstract

Protein-protein interactions are important for biological processes and pathological situations, and are attractive targets for drug discovery. However, rational drug design targeting protein-protein interactions is still highly challenging. Hot-spot residues are seen as the best option to target such interactions, but their identification requires detailed structural and energetic characterization, which is only available for a tiny fraction of protein interactions. Areas covered: In this review, the authors cover a variety of computational methods that have been reported for the energetic analysis of protein-protein interfaces in search of hot-spots, and the structural modeling of protein-protein complexes by docking. This can help to rationalize the discovery of small-molecule inhibitors of protein-protein interfaces of therapeutic interest. Computational analysis and docking can help to locate the interface, molecular dynamics can be used to find suitable cavities, and hot-spot predictions can focus the search for inhibitors of protein-protein interactions. Expert opinion: A major difficulty for applying rational drug design methods to protein-protein interactions is that in the majority of cases the complex structure is not available. Fortunately, computational docking can complement experimental data. An interesting aspect to explore in the future is the integration of these strategies for targeting PPIs with large-scale mutational analysis.

Docking-based identification of small-molecule binding sites at protein-protein interfaces

“…Protein-protein interactions (PPIs) are involved in the majority of diseases, and thus are essential to understand, prevent and correct pathological situations. Indeed, experimental studies show that many pathological mutations can affect protein-protein interactions, either by disrupting the entire interaction network of the mutated protein, or by specifically affecting some interactions [1] , [2] , [3] . In this context, PPIs emerge as attractive targets for drug discovery, and the field is shifting the focus of target identification and characterization from individual proteins to interaction networks [4] .…”

“…However, the path from a hit to a therapeutic drug is challenging. Indeed, few small-molecule PPI inhibitors have already been approved by FDA or are in clinical trials [2] , [15] .…”

Monte Carlo simulations using PELE to identify a protein–protein inhibitor binding site and pose

“…3 Qualitative computational methods have emerged as useful to identify possible binding site and interaction "hot-spots". 10,11 Site nding methods such as FTMap 12 and SiteMap 13 can provide guidance for regions where small molecules may interact, but their power to discriminate true from false sites breaks down for less druggable sites. 14 Given the dynamic nature of protein-protein interactions, 15 it is perhaps not surprising that methodologies based on molecular simulation are proving useful.…”

Extraction of molecular features for the drug discovery targeting protein‐protein interaction of Helicobacter pylori CagA and tumor suppressor protein ASSP2

“…Many protein‐protein interactions (PPIs) regulate the disease state; therefore targeting the PPIs is crucial for drug discovery . Usually, the PPI‐interacting surfaces are large, flat, and lack the deep and well‐defined binding cavities.…”

“…9,17,19,20 Many protein-protein interactions (PPIs) regulate the disease state; therefore targeting the PPIs is crucial for drug discovery. 12,14,[21][22][23][24] Usually, the PPI-interacting surfaces are large, flat, and lack the deep and well-defined binding cavities. However, mutational analyses of PPI interfaces revealed that the binding affinity is not evenly distributed across the binding interfaces, but instead contributed by the small patch of amino acid residues know as hot spot.…”