Estudi de les característiques diferencials de la proteïna ZAP-70 pel disseny de nous inhibidors selectius


Bosch Plana, Anna 


ZAP-70 (Zeta-chain-associated protein kinase 70) is a tyrosine kinase protein that is expressed in T and Natural Killer (NK) lymphocytes and it is essential for close signaling of the TCR (T cell antigen receptor). In previous projects, the therapeutic potential of blocking TCR signaling by inhibiting ZAP-70 has been demonstrated in peripheral T-cell lymphoma. However, the selective inhibition of this target is still a challenge. As a tyrosine kinase protein belonging to the Syk/ZAP-70 family, it has very similar characteristics to other proteins. This fact can cause that the molecules which inhibit ZAP-70, also bind to other proteins inhibiting their functionality and consequently producing problems in the metabolism.
In the present work, it is studied how to include selectivity for ZAP-70 in the design of inhibitors by means of computational methods. Therefore, it has been determined which characteristics of the active centers of the tyrosine kinase domain of ZAP-70 are different from 6 alternative targets (off-targets): SYK, JAK3, ITK, BTK, FLT3, BRAF. The information obtained has allowed obtaining a pharmacophoric model for the virtual screening of large molecular databases.



Estrada Tejedor, Roger


IQS SM - Master’s Degree in Pharmaceutical Chemistry