P4T Approach

The computational approaches we use to guide the synthesis of tailored chemical probes are:

• Virtual screening (VS, structure- and ligand-based) makes use of computational models to filter either existing databases, internal collections or virtual libraries to identify molecules with potential activity against the target of interest;
• Homology modeling for constructing a three-dimensional model of a protein from its amino acid sequence to be used in structure-based VS;
• Molecular dynamics (MD) simulations to optimize the docking studies and account for protein flexibility, to include solvent effects and account for induced fit, to calculate binding free energies and to provide an accurate ranking of the potential ligands;
• Hit optimization is an iterative process where biological data provide the input to refine theoretical models that in turn can be used to predict new chemical entities with improved activity and selectivity to be submitted to the synthesis and biological assays.

Highly functionalized chemical probes are generated via combinatorial approaches. We develop atom- and cost-efficient multicomponent strategies that, coupled with microwave-assisted techniques, allow to quickly generate new chemical probes for drug discovery purposes.
Different synthetic techniques are regularly used to produce chemical diversity around targeted, privileged and natural scaffolds: solid-phase synthesis, parallel synthesis, microwave-assisted synthesis, click-chemistry, and multicomponent reactions.
These combinatorial methodologies are also used as an input to design large virtual libraries of synthetically-accessible compounds for virtual screening and hit-optimization campaign.