This project aims to study, mainly using a computational approach, the interaction between MKK7 kinase domain and DTP3 peptide and to define a binding pocket onto MKK7. In particular the project is devoted to the elucidation of the the following points:
- the binding site of tripeptide DTP3, a potential new drug for Multiple Myeloma, within the MKK7 kinase domain;
- the atomic disposition of tripeptide in the DTP3 binding pocket and the atomic interactions of the MKK7 / DTP3 complex
Local installed algorithms and remote systems will be used, as servers and metaservers for the prediction of potential binding sites of small molecules on proteins.
Once the putative binding pocket has been defined with appropriate plausibility we will proceed to investigate the disposition of DTP3 in putative pocket/s using molecular docking approach, trying to predict the atomic details of this interaction. We will work in close collaboration with experimental groups to support and confirm the results we will obtain and even in order to allow an optimization of the docking protocol used. This interchange of predictions/results will allow to give remarkable plausibility to the final DTP3 / MKK7 interaction model and to the predicted interactions between the peptide and the protein, in order to profitably continue in the subsequent studies of DTP3 optimization as a potential new drug for the multiple myeloma
Although the details of the molecular interactions regulating the DTP3 binding as well as the hindrance of the Gadd45b/MKK7 protein complex are obscure, they represents a key step towards the full understanding of the Gadd45b/MKK7 activity. With these premises, an atomistic modelling of the processes involved in the inhibition of the Gadd45b-MKK7 complexes constitutes an essential step in the comprehension of the molecular interactions which might lead to design of new and more potent drugs. Despite the absolute need of subsequent experimental validation, in-silico approach might furnish, as a first step, a possible effective picture of the molecular details involved in the regulation of the biochemical process. In the presented case, where the possibility to provide experimental data is inhibited by very complex conditions, in-silico approaches can be effectively used in order to build a model of interaction between DTP3 peptide and MKK7.
This model, in combination with the structural and dynamical predictions obtained by in silico analysis, will be exploited to design mutant forms of MKK7 and DTP3 variants, which will be used for a variety of functional analyses.
Because of the peptide structure, DTP3 also features poor cell uptake and tissue penetration. Such properties can lessen the DTP3 activity , reducing its overall therapeutic potential. We thus also aim to transform DTP3 into small molecules that mimic the original structure but have the potential to afford similar effects on MM.