New strategies for drug development towards Protein-Protein Interactions: Targeting MAPK

DEFELIPE, LUCAS ALFREDO; LOPEZ, ELIAS DANIEL; LANZAROTTI, ESTEBAN; TURJANSKI, ADRIAN GUSTAVO

Bariloche

Simposio; The Second South American Spring Symposium in Signal Transduction and Molecular Medicine; 2012

Signal transduction pathways that involve kinase cascades are often dysregulated in disease and therefore drugs development towards the kinase active site are among the most developed fields in basic and applied pharmacology. However, it is widely known that the kinase catalytic domain is highly conserved and thus, selectivity is difficult to achieve2-3. On the other hand protein-protein interactions are specific of each kinase and are also related to specific functions. Therefore, to find drugs towards binding sites is the most promising strategy in drug discovery. Drug discovery through docking simulations has proven successful strategy but has its limitations.4 Selections of good lead compounds from big databases of compounds and to correctly dock the selected molecules is extremely difficult when dealing with protein surfaces and shallow cavities. In order to overcome these limitations we have surveyed protein kinase interactions and propose to add additional information related to aromatic residues located at protein surfaces to overcome these difficulties and achieve specificity. We combined available structural information with an inhouse aromatic-aromatic interaction method5 to apply pharmacophoric restraints to show that this methodology can accurately reproduce protein-drug structures and differences in binding affinities for molecules directed towards protein surfaces. The structural characteristics of MAPKs have been studied in great detail with several crystal structures of members of the ERK, p38 and JNK groups solved. MAPKs achieve specificity through docking sites that are far away from the active site. The DEJL and the FXF Doking sites have aromatic residues in the pockets identified by our drugabilitty program. We used our docking protocol to screen compounds towards MAPK Kinases docking sites. Development of selective inhibitors for the three main MAPK families (ERK2, p38 and JNK) was done by a high throughput docking simulation with 100.000 compounds of our curated database. We identified lead compounds for further experimental test and development. We have shown that our methodology can be successfully used to design drugs specifically directed towards protein surfaces.