Sigillo di Ateneo

Research

 

Discovery of allosteric inhibitors of protein kinases as anticancer drugs

 

We are currently searching for small-molecules able to bind to kinase pockets distinct from the ATP binding site and stabilize inactive conformations of these enzymes in which the conserved Alpha-C helix is displaced. Such allosteric inhibitors should be less prone to selectivity issues and could show extended drug target residence times with respect to traditional ATP competitive inhibitors. The project is in collaboration with Dr Massimo Broggini (Istituto di Ricerche Farmacologiche Mario Negri, Milano) and Prof. Daniele Passarella (Università di Milano), and is generously sponsored by the Nando Peretti Foundation.



 

 

Targeting the Hsp90 interactome using in silico polypharmacology approaches

 

This project is focused on setting up and exploiting computational protocols for targeting the Hsp90 interactome with polypharmacology approaches. We aim at identifying the most promising target combinations and at exploiting them for multi-target drug design. To this end, we are investigating Hsp90 client proteins belonging to different protein families. Integrated ligand- and structure-based virtual screening methods are applied to design multi-target ligands. The project is in collaboration with Prof. Jürgen Bajorath (University of Bonn) and Dr. Leonard Neckers (NIH, USA).



 

 

BEAR (Binding Estimation After Refinement)

 

The MMDDLab has developed BEAR (Binding Estimation After Refinement), an automated post-docking procedure that integrates structural refinement of docking poses with molecular dynamics and re-ranking of ligands with more accurate scoring functions such as MM-PBSA and MM-GBSA. We are continuously validating and improving BEAR, and exploiting it in virtual screening campaigns.



 

 

Design of irreversible inhibitors of protein kinases

 

In the last decade we have been interested in the development of inhibitors targeting specific members of the protein kinase family, which provides a wealth of targets for anti-cancer drug discovery. This project was focused on the design, synthesis and biological evaluation of irreversible protein kinase inhibitors targeting a cysteine residue conserved in a subset of 46 kinases. The project was sponsored by AIRC (Associazione Italiana per la Ricerca sul Cancro).