In recent years the development of small organic molecules modulating protein-protein interactions (P-PIs) has drawn major attention in both academic and industrial research. Despite the appreciable progress being made, targeting such extensive interaction areas with comparatively small, drug-like agents has proven to be an ambitious objective. This review highlights the reasons rendering this task highly challenging and provides an overview on the latest developments in rational design approaches for P-PI modulators. The significance, scope and limitations of computational methods in this particular field of research are analyzed. Recent successfully identified and designed P-PI modulators are discussed. Thereby, particular focus is taken on small organic molecules disrupting protein-protein interfaces of protein kinases.
Keywords: Protein-protein interactions, protein-protein interaction modulators, virtual screening, rational drug design, protein kinases, molecular modeling, drug-like agents, vascular endothelial growth factor (VEGF), affinity, alanine scanning mutagenesis, Molecular Mechanics Poisson-Boltzmann/surface area (MM-PBSA)approach, LIE (linear interaction energy) models, FEP, thermodynamic integration (TI), electrostatic effects
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