Protein Allostery in Rational Drug Design

This chapter focuses on protein kinases that transfer the phosphate group of ATP to the hydroxyl group of a substrate protein. Five hundred eighteen human protein kinases are classified into serine/threonine kinases and tyrosine kinases and individually or synergistically transduce physiologic stimuli into cell to promote cell proliferation or apoptosis, etc. Protein kinases are identified as drug targets because dysfunction of kinases leads to severe diseases such as cancers and autoimmune diseases. A large number of the crystal structures of the protein kinase inhibitor complex are available in Protein Data Bank and facilitated the drug discovery targeting protein kinases. The protein kinase inhibitors are classified into categories, Type-I, Type-II, Type-III, Type-IV, and Type-V, and as a separate class, covalent-type inhibitors. In any type, a protein kinase inhibitor bound to the allosteric region is advantageous in terms of selectivity compared to the traditional ATP-competitive one. In the following sections, the successful and promising examples of the partially or fully allosteric protein kinase inhibitors are illustrated in the following pages.