Sviluppo "hit-to-lead" di inibitori delle proteine Rac: da molecola bioattiva a candidato farmaco

Starting from the available information on hit compounds identified in a previous study, a similarity search will be performed in order to select all compounds presenting a certain similarity degree (computed on the basis of Tanimoto indexes) with the parent compounds. Selected compounds will be evaluated through computational docking techniques and the most promising compounds for each subset will be acquired for biochemical evaluation. We plan to obtain 10-25 analogues for each hit, for a total of 50-125 compounds A biochemical primary screening will be performed on compounds selected in WP1. Compounds will be evaluated for their ability to inhibit Rac1 protein by measuring the amount of Rac1-GTP through a G-LISA assayStarting from pharmacological results obtained in WP2, Classical and Quantitative Structure Activity Relationship (SAR and QSAR, respectively) models will be derived and used to support the design and to predict the activity of new compounds. In the meanwhile, virtual focused libraries will be generated by using computational combinatorial techniques. Those libraries will be subjected through computational analysis by applying previously derived QSAR models and by performing molecular docking. Those compounds resulting the most promising will be selected for synthesis. Starting from the information obtained from precedent Wps, the synthesis of a new generation of Rac1 inhibitors will be planned and realized. The obtained compounds will be thoroughly characterized through instrumental analysis. We plan to synthesize 5-10 compounds for each class of inhibitors. Synthesized compound will be subjected to biological assays in order to obtain a complete pharmaco-toxicological profile. Pharmacological analysis of novel compounds will be conduced by the Department of Pharmacological Sciences, University of Milan, where the potential antiatherosclerotic activity will be evaluated, and by The Haematology and Oncology Division, Children’s Hospital Boston, where the antitumoral potential of new compounds will be evaluated, with a particular interest toward leukemia.