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The receptors tyrosine kinase (RTKs) for the colony stimulating factor-1 (CSF-1R) and the stem cell factor (SCFR or KIT) are important mediators of signal transduction related to the proliferation, survival and differentiation of macrophages and cells from the hematopoietic lineage, respectively.

The normal function of these receptors can be compromised by gain- of-function mutations that lead to the constitutive activation of the receptors, associated with cancer diseases and inflammatory disorders. A secondary effect of the mutations is the alteration of the receptor's sensitivity to tyrosine kinase inhibitors, such as imatinib, compromising the use of these molecules in the clinical treatment.

The mutation V560G in the juxtamembrane (JMR) domain of KIT increases the receptor's sensitivity to imatinib, while the mutations S628N and D816V, in KIT, and D802V in CSF-1R, trigger resistance. The last two being located at the activation loop (A-loop) of the receptors. The JMR and the A- loop constitute two regulatory fragments that undergo a dramatic conformational change during the receptors' activation, due to the loss of essential interactions with the rest of the protein.

Our goals in this thesis consisted in (i) study the structural and dynamics effects on the intracellular domain of CSF-1R induced by D802V mutation and compare the results with those obtained for KIT in the native wild-type (WT) and mutated forms; (ii) study the affinity of imatinib to the WT and mutant forms of the TK domain of KIT (V560G, S628N and D816V) and CSF-1R (D802V), correlating the theoretical predictions with the available experimental.

By means of molecular dynamics (MD) simulations, we have showed that the D802V mutation in CSF-1R does not produce the same dynamic and structural effects caused by the D816V mutation in KIT. The D802V mutation has a local impact on the A-loop structure and disrupts the allosteric communication between this fragment and the JMR. However, the disruption is not sufficient to induce the JMR's departure from the TK domain, due to the strong coupling between the JMR's distal region and the TK domain, stabilized by highly prevalent H-bonds. The subtle effect of the mutation in CSF-1R was associated with the difference in the primary sequence between both receptors in the native form, particularly in the JMR region, and this could explain why this mutation is not frequently found in cancer.

In the following step, we have characterized by docking, MD simulations and energy calculations, the binding affinity of imatinib to the different targets. The free energy associated with the binding of imatinib was consistent with the experimental data. The energy decomposition in the different terms contributing to the binding energy evidenced that the electrostatic interactions are the main force that drives the sensitivity or the resistance of the targets to imatinib.

The mutations D802V and D816V showed to be the most deleterious in the energy contribution to the binding of imatinib, due to the charge redistribution of positive charges in the vicinity of the binding site. Our data also indicated that the JMR domain has a minor role in the resistance mechanism.