In Silico-In Vitro Screening of Protein-Protein Interactions: Towards the Next Generation of Therapeutics

Bruno Villoutreix, Karine Bastard, Olivier Sperandio, Robin Fahraeus, Jean-Luc Poyet, Fabien Calvo, Benoit Deprez, Maria Miteva
2008 Current Pharmaceutical Biotechnology  
Key words: virtual ligand screening, structure-based drug design, docking, scoring, drug discovery, protein-protein interaction. Summary Protein-protein interactions (PPIs) have a pivotal role in many biological processes suggesting that targeting macromolecular complexes will open new avenues for the design of the next generation of therapeutics. A wide range of "in silico methods" can be used to facilitate the design of protein-protein modulators. Among these methods, virtual ligand
more » ... protein-protein docking, structural predictions and druggable pocket predictions have become established techniques for hit discovery and optimization. In this review, we first summarize some key data about protein-protein interfaces and introduce some recently reported computer methods pertaining to the field. URLs for several recent free packages or servers are also provided. Then, we discuss four studies aiming at developing PPI modulators through the combination of in silico and in vitro screening experiments. Protein-protein interface: a brief overview Proteins are usually involved in interactions with an estimated average of 5-10 protein partners [41] , the binding site(s) with these partners may or may not overlap, illustrating the complexity ahead with regard to identifying, understanding and predicting protein interaction networks. In addition, different types of protein complexes have been observed, like homo-and hetero-complexes (i.e., the interaction occur between identical or non-identical chains), obligate and non-obligate complexes (a related view refers to interactions as transient or permanent) [42] [43] [44] [45] . Well-known examples can be, for a permanent complex, the interleukin 8 homodimer (PDB code 1il8), and for a non-obligate complex, the cytochrome c peroxidase associated with cytochrome c (PDB code 2pcb). Depending on the types of complexes (permanent, transient...), the nature of the interface usually differs, from somewhat hydrophobic/aromatic to a mixture of hydrophobic/aromatic and polar properties [45] . Different in silico methods have been developed to analyze the physical properties of proteins and learn more about how these properties are associated with binding. Interactions at the interface are usually measured in silico in terms of accessible surface area, shape complementarity, molecular surface and the associated mathematical objects, Voronoi diagram, Delaunay tessellation, Laguerre polyhedral decomposition and α-shape [46] [47] [48] [49] . Topographical information can also be determined using an algorithm based on the measurement of atomic density near the molecular surface [50] . Results (in term of statistics) obtained with these methods have to be taken with cautions since computations are usually performed on static structures. Nevertheless, such investigations have obviously been shedding lights on PPIs. Interfaces have been found to be either relatively flat or to present convex and concave shapes, indicating in these latter cases that shape-shape complementarity in addition to chemical complementarity can be of major importance for PPIs (just like for protein-small ligands). The importance of the "shape descriptor" essentially applies to homodimers, enzyme-inhibitor complexes and permanent heterocomplexes [51] . In some other cases, electrostatic steering plays an essential role and can drive the formation of an encounter complex and of the final functional complex [52] . In addition, analysis of packing at the interface was also performed and suggests that for homodimers, enzyme-inhibitor complexes and permanent heterocomplexes, the interfaces are usually well-packed [53] .
doi:10.2174/138920108783955218 pmid:18393867 fatcat:db63x2enijagzdo34ttc4hqshy