Targeting Allosteric Pockets in Protein Kinases Using Molecular Modeling and Simulations

The deregulation of protein kinases is often related with the development of several malignancies such as cancer. Therefore, inhibition of protein kinases is an established and often effective pharmacological strategy. However, point mutations in kinases are frequently the cause of drug resistance. To overcome this issue, many efforts are directed towards the design of allosteric drugs, with the goal to inhibit the mutated forms of kinases. In this regard, the comprehension of the molecular basis of the allosteric control of protein kinases is essential for the design of novel allosteric drugs. In this thesis, we studied the molecular basis that allosterically regulates the function of Abelson (Abl) kinase, a relevant pharmaceutical target for the treatment of several malignancies, as chronic myelogenous leukemia. This study proposes a novel mechanism according to which conserved structural motifs dynamically cooperate to regulate allosterically the function of Abl. The information retrieved from this study can be employed for the rational design of new Abl allosteric inhibitors. In addition, we also developed a new algorithm for the detection of protein pockets in MD simulations. This algorithm has been conceived to identify and analyze all the pockets of a given protein without any user a priori information of their localization. It also enables the detection of pockets' network, characterizing possible allosteric signaling pathways that connect the functional with the allosteric sites. Overall, this tool allows the study of the dynamic properties of pockets and might be employed in the early stages of the drug discovery process to design both orthosteric and allosteric binders.