In silico Drug Design: some concepts & tools - Protein-Protein interaction
Bioinformatics: Protein-protein and protein-membrane interactions
Your target can be DNA, RNA, or a protein... it can also be a mechanism, for instance, you may want to modulate protein-protein interactions or a transient protein-membrane interaction, to do these, again many approaches have been developed starting around 1990, you may need docking tool, tools to find hotspots etc...
In many cases, one needs to predict interface residues. Several approaches can be used, those investigating specific features of protein sequences and/or structures, they look at amino acid composition, physico-chemical properties and can use machine learning strategies. For example, some tools use evolutionary information to try to predict interface residues that tend to be more conserved that other residues on the rest of the protein surface. Amino acid features and evolutionary information can then be combined to analyze amino acid sequences and perform some predictions. Of course, predictions based only on sequences are often (but not always) limited and it is important when possible to add 3D information. Thus it is possible to map sequence evolution onto the molecular surface. Analysis of the surface in term of hydrophobicity, desolvation energy can also be used. These approaches are said to belong to the mapping approaches, for instance ODA (physics based)... but some others are based on descriptors and machine learning...Because these types of prediction are difficult, meta-predictors have been developed and tend to give better results over individual methods (e.g., meta-PPISP).
Template-based methods can also be used. Because interfaces tend to be conserved in homologous complexes, such data can help to make predictions.
For additional information, you can for example check our recent review introducing several aspects of PPI and in silico approaches:
Drug-Like Protein-Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology (review). Villoutreix BO, Kuenemann MA, Poyet J-L, Bruzzoni-Giovanelli H, Labbe C, Lagorce D, Sperandio O, Miteva MA. Molecular Informatics 2014; 6-7: 414-437. (open)
Different types of interactions could in theory be modulated. We were among the first to propose the modulation of transient interactions between a protein and the cell membrane with a small molecule and to observe that next to membrane binding regions, proteins often tend to have a cavity large enough to bind a small ligand. The work was for instance reported with application on blood coagulation cofactors by Segers et al., PNAS 2007, or Nicolaes et al., Blood 2014. This molecular mechanism is still essentially unexplored in 2015 for therapeutic intervention.
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