The majority of functionally important biological processes are regulated by allosteric
communication within individual proteins and across protein complexes. The proteins controlling
these communication networks respond to changes in the cellular environment by switching between
different conformational states. Targeting the interface residues mediating these processes through the
rational identification of molecules modulating or mimicking their effects holds great therapeutic potential.
Protein-protein interactions (PPIs) have shown to have a high degree of plasticity since they
occur through small regions, called hot spots, which are included in binding surfaces or in binding
clefts of the proteins and are characterized by a high degree of complementarity. This prompted several researchers to
compare the protein structure to human grammar proposing terms like “protein language”. The decoding of this language
represent a new paradigm not only to clarify the dynamics of many biological processes but also to improve the opportunities
in drug discovery. In this review, we try to give an overview on intra-molecular and inter-molecular protein communication
mechanisms describing the protein interaction domains (PIDs) and short linear motifs (SLiMs), which delineate
the authentic syntactic and semantic units in a protein. Moreover, we illustrate some novel approaches performed on
natural compounds and on synthetic derivatives aimed at developing new classes of potential drugs able to interfere with
intra-molecular and inter-molecular protein communication.
Keywords: Drug discovery, Hot spots, Inter-protein communication, Intra-protein communication, Natural products, Protein
interaction domains, Short linear motifs.
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